Supplementary appendix

This appendix formed part of the original submission and has been peer reviewed.
We post it as supplied by the authors.

Supplement to: Werring DJ, Dehbi H-M, Ahmed N, et al. Optimal timing of
anticoagulation after acute ischaemic stroke with atrial fibrillation (OPTIMAS): a
multicentre, blinded-endpoint, phase 4, randomised controlled trial. Lancet 2024;
published online Oct 24. https://doi.org/10.1016/S0140-6736(24)02197-4.
Optimal timing of anticoagulation after acute ischaemic stroke with atrial fibrillation (OPTIMAS): a
multicentre, blinded-endpoint, phase 4, randomised controlled trial

Online appendix
Table of contents

Committees Page 3

Collaborators at sites that recruited at least one participant Page 4

Table e1: Direct oral anticoagulant type initiated, dose, and classification of participants who Page 8

were inappropriately overdosed or underdosed according to UK guideline dosing

recommendations

Table e2: Baseline characteristics of participants excluded from the analysis and those included Page 9

in the modified intention to treat population

Table e3: First occurrence of all primary and secondary outcome events during follow-up in the Page 10

severe stroke (NIHSS >21) subgroup

Figure e1: Time-to-event plot risk of all-cause mortality according to allocated treatment Page 11

Figure e2: Time-to-event plot for the primary outcome and all-cause mortality according to Page 12

allocated treatment

Figure e3: Time-to-event plot for systemic embolism and recurrent ischaemic stroke according Page 13

to allocated treatment

Figure e4: Time-to-event plot for symptomatic intracranial haemorrhage according to Page 14

allocated treatment

Figure e5: Time-to-event plot for recurrent ischaemic stroke according to allocated treatment Page 15

Figure e6: Time-to-event plot for systemic embolism according to allocated treatment Page 16

Trial protocol version 5.0 Page 17

Statistical analysis plan version 1.0 Page 97

Committees
Trial Steering Committee
Prof G Ford (Chair), Consultant Physician, Oxford University Hospitals NHS Foundation Trust; Prof C Price,
Professor in Stroke and Applied Health Research, Population Health Sciences Institute, Newcastle University; Dr
R Yu, Head of Public and Patient Involvement (PPI) and Communications, University College London (UCL);
Prof A Farrin, Professor of Clinical Trials and Evaluation of Complex Interventions, University of Leeds; Prof H
Cohen, Consultant Haematologist, University College Hospitals NHS Foundation Trust, and Professor of
Haematology, UCL; Prof S Engelter, Professor of Neurology, University Department of Geriatric Medicine Felix
Platter, Basel, Switzerland; Prof M James, Consultant Stroke Physician, Royal Devon & Exeter Hospital, Exeter
and Honorary Clinical Professor, University of Exeter Medical School; Prof G Lip, Professor of Cardiovascular
Medicine, University of Liverpool; Prof B Norrving, Professor of Neurology, University of Lund, Sweden; Prof
N Sprigg, Professor of Stroke Medicine, University of Nottingham; Prof D Werring, Professor of Clinical
Neurology and Chief Investigator, UCL Queen Square Institute of Neurology; Prof N Freemantle, Professor and
Director, UCL Comprehensive Clinical Trials Unit (CCTU); H-M Dehbi, Unblinded Trial Statistician, UCL
CCTU; N Ahmed, Trial Statistician, UCL CCTU; E Bordea, Health Economist, UCL CCTU; R Hunter, Senior
Health Economist, UCL; A Ndoutoumou, Clinical Project Manager, UCL CCTU; S Massingham, Stroke
Research Clinical Trial Coordinator, Queen Square Institute of Neurology; A Gill, Clinical Trials Manager, UCL
CCTU; H Sims. Clinical Trials Manager, UCL CCTU; A Jayanthi, Clinical Trials Manager, UCL CCTU; T
Vanniyasingam, Data Manager, UCL CCTU; Shannon Amoils, Funder Representative, British Heart Foundation.
Independent External Adjudication Committee
Dr A Webb, Clinical Reader in Stroke Medicine, Department of Brain Sciences, Faculty of Medicine, Imperial
College London; Dr C Smith, Professor of Stroke Medicine, Manchester University; Dr E Warburton, Consultant
Stroke Physician, Cambridge University Hospitals NHS Foundation Trust.
Independent Data Monitoring Committee
Dr J Bamford (Chair), Consultant in Neurology and Cerebrovascular Physician, Leeds Teaching Hospitals NHS
Trust; Prof J Camm, Professor of Clinical Cardiology, St George’s Medical School; Prof T Clayton, Professor of
Applied Medical Statistics, London School of Hygiene and Tropical Medicine; Prof K Klijn, Professor of
Neurology, Radboud University, Nijmegen, The Netherlands; Dr A Cohen, Vascular Physician and
Epidemiologist, King’s College London and Guy’s and St Thomas’ NHS Foundation Trust.
Internal Event Validation Committee
Prof D Werring (Chief Investigator, Chair), Professor of Clinical Neurology, UCL Queen Square Institute of
Neurology and University College Hospital; Dr P Nash, Clinical Research Fellow, UCL Queen Square Institute
of Neurology and University College Hospital; S Massingham, Stroke Research Clinical Trial Coordinator, UCL
Queen Square Institute of Neurology.
Trial Management Group
Prof D Werring (Chief Investigator, Chair), Professor of Clinical Neurology, UCL Queen Square Institute of
Neurology; Prof H Cohen, Consultant Haematologist, University College Hospitals NHS Foundation Trust, and
Professor of Haematology, UCL; Prof M James, Consultant Stroke Physician, Royal Devon & Exeter Hospital,
Exeter and Honorary Clinical Professor, University of Exeter Medical School; Prof G Lip, University of
Liverpool; Prof N Sprigg, Professor of Stroke Medicine, University of Nottingham; Dr P Nash, Clinical Research
Fellow, UCL Queen Square Institute of Neurology; Prof N Freemantle, Professor and Director, UCL CCTU; N
Ahmed, Trial Statistician, UCL CCTU; E Bordea, Health Economist, UCL CCTU; R Hunter, Senior Health
Economist, UCL; A Ndoutoumou, Clinical Project Manager, UCL CCTU; S Massingham, Stroke Research
Clinical Trial Coordinator, IoN, UCL; A Gill, Clinical Trials Manager, UCL CCTU; H Sims. Clinical Trials
Manager, UCL CCTU; A Jayanthi, Clinical Trials Manager, UCL CCTU; T Vanniyasingam, Data Manager, UCL
CCTU.

3
Collaborators at sites that recruited at least one participant, listed in descending order of the number of

participants recruited (quantified in brackets) with Principal Investigators denoted by PI

University Hospital of Wales, Cardiff (175) (Dr B Jelley (PI), Dr T Hughes, M Evans, D G Esteban, L Knibbs, L
Broad, R Price, L H Griebel, S Hewson)

Royal Bournemouth Hospital, Bournemouth (166) (Dr K Thavanesan (PI), L Mallon, A Smith, M White)

St Georges Hospital, London (158) (Dr L Zhang (PI), Dr B Clarke, Dr Y Abousleiman, L Binnie, C H Sim, M
Castanheira)

University College London Hospitals NHS Foundation Trust, London (147) (Dr F Humphries (PI), S Obarey, S
Feerick, Y C Lee, A Lewis, R Muhammad, N Francia, N Atang, A Banaras, M Marinescu)

Royal Stoke University Hospital, Stoke (131) (Dr P Ferdinand (PI), R Varquez, I Ponce, S Saxena)

Addenbrooke's Hospital, Cambridge (111), (Dr E O'Brien (PI), Dr J D Reyes, J Mitchell-Douglas, J Francis)

Charing Cross Hospital, London (93) (Dr S Banerjee (PI), V Dave, S Mashate, T Patel)

Luton & Dunstable University Hospital, Luton (88) (Dr L Sekaran (PI), Dr W Murad, Dr A Asaipillai, Dr S
Sakthivel, T L Margaret, J Angus, L Reid, C Fornolles, S Sundayi, L Poolon, F Justin, S Hunte)

Watford General Hospital, Watford (84) (Dr M Bhandari (PI), S Sundayi, J Kho)

Victoria Hospital, Fife (79) (Dr V Cvoro (PI), Dr R Parakramawansha, M Couser, H Hughes)

Royal Hallamshire Hospital, Sheffield (75) (Dr A Naqvi (PI), Dr K Harkness, E Richards, J Howe, C Kamara, J
Gardner)

John Radcliffe Hospital, Oxford (75) (Dr H Bains (PI), R Teal, J Joseph, J Benjamin)

James Cook University Hospital, Middlesborough (73) (Dr S Al-Hussayni (PI), Dr G Thomas, F Robinson, L
Dixon)

Morriston Hospital, Swansea (71) (Dr M Krishnan (PI), Dr P Slade, Dr T Anjum, S Storton)

Royal Cornwall Hospital, Truro (68) (Dr K Adie (PI), K Northcott, K Morgan, E Williams)

Leighton Hospital, Crewe (67) (Dr H Chandrashekar (PI), H Maguire, C Gabriel, D Maren, H David, S Clarke)

Royal Berkshire, Reading (66) (Dr K Nagaratnam (PI), Dr V Nelatur, N Mannava, L Blasco)

Northwick Park Hospital, Harrow (62) (Dr J Devine (PI), Dr R Bathula, P Gopi, N Mehta S Sreedevi Raj)

King's College Hospital NHS Foundation Trust, London (60) (Dr J Teo (PI), Dr L Sztriha, Dr Y Mah, Dr S
Ankolekar, B Sari, M tibajai, A Morgan, M Recaman, S Bayhonan, C Belo)

Royal Devon & Exeter Hospital, Exeter (60) (Prof M James (PI), S Finch, S Keenan, A Bowring)

Nottingham University Hospitals NHS Trust, Nottingham (57) (Dr A Shetty (PI), Dr S Chan, L Gray)

Royal London Hospital, London (53) (Dr T Harrison (PI), Dr O Spooner, E Kinsella-Perks, E Erumere, B Sanders)

Queen Elizabeth University Hospital, Birmingham (48) (Dr D Sims (PI), Dr M Willmot, Dr E Littleton, E Spruce,
L Moody, C Sheriden, S Luxmore-Brown, A Neal, S Beddows)

Wycombe Hospital, High Wycombe (45) (Dr M A Tuna (PI), Dr A Misra, R Penn, S Mariampillai)

North Tees Hospital, Stockton-on-Tees (45) (Dr I Anwar (PI), Dr A Annamalai, Dr S Whitehouse, L Shepherd, E
Siddle)

4
Countess of Chester Hospital, Chester (44) (Dr K Chatterjee (PI), S Leason, A Davies)

Southampton General Hospital, Southampton (42) (Dr R Marigold (PI), S Frank, A Baird, T Hannam-Penfold, L
Inacio, S Smith)

Leicester Royal Infirmary, Leicester (41) (Dr D Eveson (PI), Dr K Musarrat, S Khan, T Harris)

Ipswich Hospital, Ipswich (41) (Dr M R Chowdhury (PI), Dr S Alam, Dr E Jamieson, Dr E Anyankpele, Dr F Al
Shalchi, V Rivers, S Bell, R Francis, D Beeby, J Finch)

Aberdeen Royal Infirmary, Aberdeen (41) (Prof M J Macleod (PI), Dr G Guzman-Gutierrez, Dr K Carter, J Irvine)

Royal United Hospital, Bath (40) (Dr L Gbadamoshi (PI), T Costa, S Heirons, H Stoney, L Shaw, J Choulerton, D
Catibog)

Sunderland Royal Hospital, Sunderland (39) (Dr N Sattar (PI), Dr M Myint, A Smith, K Serac)

Royal Preston Hospital, Preston (38) (Dr H Emsley (PI), Dr S Sultan, B Gregary, A Brown)

Maidstone Hospital, Maidstone (38) (Dr A Mahmood (PI), Dr N Chattha, Dr W Old, C Pegg, M Davey, M Page, B
Sandhu, E Phiri)

Yeovil District Hospital, Yeovil (37) (Dr K Rashed (PI), Dr E Wilson, Dr E Hindley, S Board, S Antony, A Tanate)

Royal Victoria Infirmary, Newcastle (37) (Dr M Davis (PI), Dr A Dixit, V Slater, M Fawcett)

Royal Derby Hospital, Derby (36) (Dr T England (PI), Dr J Scott, Dr J Beavan, A Hedstrom)

Musgrove Park Hospital, Taunton (36) (Dr D Karunatilake (PI), K Gillmain, N Singh, T Hallows)

University Hospital Monklands, Airdrie (36) (Dr M Barber (PI), Dr L Yates, Dr C Micallef, D Esson)

Ninewells Hospital and Medical School, Dundee (34) (Dr Wai Meng Yu (PI), Dr B Jaa Ming New, Dr A Matos, C
Burt, L Cabrelli, G Wilkie)

Broomfield Hospital, Chelmsford (33) (Dr M Meegada (PI), Dr R Kirthivasan, C Fox, V Mead, A Lyle)

Colchester General Hospital, Colchester (32) (Dr R Saksena (PI), A Bakshi, A O'Kelly)

Kings Mill Hospital, Sutton-in-Ashfield (31) (Dr J Rehan (PI), Dr O Ebueka, Dr M Cooper, I Wynter, S Smith)

Prince Philip Hospital, Llanelli (31) (Dr S Kumar (PI), L O'Brien, Cerrys Parker, Emma Parker)

Bradford Royal Infirmary, Bradford (31) (Dr N Khan (PI), Dr C Patterson, Dr S Maguire, O Quinn, R Bellfield)

Milton Keynes University Hospital, Milton Keynes (29) (Dr Y Behnam (PI), Dr J Costa, C Padilla-Harris, L
Moram)

Bronglais General Hospital, Aberystwyth (29) (Dr S A Raza (PI), H Tench, T Sims, H McGuinness, R Loosley, R
Wolf-Roberts)

Southmead Hospital, Bristol (29) (Dr S Buddha (PI), Dr I Salt, K Lewis)

Whiston Hospital, Prescot (28) (Dr S Mavinamne (PI), C Ditchfield, S Dealing)

Derriford Hospital, Plymouth (27) (Dr A Shah (PI), Dr G Crossingham, M Mwadeyi)

University Hospital of Coventry, Coventry (27) (Dr A Kenton (PI), F Omoregie)

Kent and Canterbury Hospital, Canterbury (27) (Dr D Hargroves (PI), Dr S Abubakar, A Warwick, G Hector)

Leeds General Infirmary, Leeds (26) (Dr S Maguire (PI), Dr Hassan, E Veraque, M Farman, L Makawa)

Forth Valley Royal Hospital, Larbert (26) (Dr A Byrne (PI), Dr J Kirkham, Dr G Blayney, Prof J Selwyn)

5
Epsom General Hospital, Epsom (26) (Dr P Kakar (PI), Dr M Al Khaddour, R Dhami, E Baker)

Hull Royal Infirmary, Hull (25) (Dr B Esisi (PI), E Clarkson, D Fellowes)

Southend Hospital, Southend (24) (Dr J Kresmir (PI), Dr P Guyler, Dr D Ngo, Dr I Wijenayake, S Tysoe, J
Galliford, P Harman)

Northumbria (Hexham, North Tyneside, Wansbeck), Cramlington (24) (Dr M Garside (PI), Dr M Badanahatti,
A Smith, V Riddell)

Gloucestershire Royal Hospital, Gloucester (24) (Dr G Gramizadeh (PI), Dr D Dutta, Dr M Bajoriene, Dr H
Erdogan, D Ward)

Royal Infirmary of Edinburgh, Edinburgh (20) (Dr F Doubal (PI), Dr N Samarasekera, S Risbridger, A
MacRaild)

West Suffolk Hospital, Bury-St-Edmunds (19) (Dr A Azim (PI), L Wood, R Tempest)

Queen Elizabeth Hospital, King’s Lynn (19) (Dr R Shekhar (PI), Dr U Rai, T Fuller, A Joshy, E Nadar)

Calderdale and Huddersfield NHS Foundation Trust, Halifax (19) (Dr M Kini (PI), Dr S Ahmad, M Robinson, L
King)

Northampton General Hospital, Northampton (19) (Dr V Srinivasan (PI), Dr M Karwacka-Cichomska, V Moore,
K Smith, B Kariyadil)

Lincoln County Hospital, Lincoln (17) (Dr K Kong (PI), Dr K Jergovic, K Hubbard, S Arif)

Peterborough City Hospital, Peterborough (17) (Dr M Hasan (PI), N Temple, D Arcoria, Z Horne)

James Paget University Hospital, Great Yarmouth (16) (Dr T Soe (PI), Dr H Wyllie, C Hacon, H Sutherland)

Arrowe Park Hospital, Birkenhead (15) (Dr B Menezes (PI), V Johnson)

Royal Hampshire County Hospital, Winchester (14) (Dr N Smyth (PI), Dr Z Mehdi, Dr E Tone, A Bradley, E
Levell)

Great Western Hospital, Swindon (14) (Dr A Ekkert (PI), Dr S Mazzucco, L McCafferty. L Vonoven, S Dewan)

Glangwili General Hospital, Carmarthen (13) (Dr P Sridhar (PI), J Thomas, S Coetzee, B Icke, J Williams)

Fairfield General Hospital, Bury (13) (Dr N Saravanan (PI), P Bradley, R M Gibson, J Antony)

Darent Valley Hospital, Dartford (13) (Dr I Ashraf (PI), J Mabutti, C Kamundi, P Patiola, N Oakley)

Dorset County Hospital, Dorchester (12) (Dr H Proeschel (PI), Dr D Keely, W Longley, A Cave, C Ambrico)

Salisbury District Hospital, Salisbury (11) (Dr T Black (PI), Dr E Porretta, A Anthony)

Poole Hospital, Poole (11) (Dr S Ragab (PI), J Dube)

Russell’s Hall Hospital, Dudley (11) (Dr S Kausar (PI), Dr A Gujjar, D M Abdullah, D Kaur)

Queen's Hospital, Romford (10) (Dr N Gadapa (PI), Dr S Choudhary, Dr N Nisar, G Fawehinmi, K Dunne, S King)

Salford Royal Hospital, Salford (10) (Dr A Kishore (PI), S Lee, T Marsden, M Slaughter, K Cawley, J Perez)

Doncaster Royal Infirmary, Doncaster (10) (Dr P Anderton (PI), Dr S Soussi, D Walstow, R Pugh)

Royal Liverpool Hospital, Liverpool (9) (Dr A Manoj (PI), G Fletcher, P Lopez)

Craigavon Area Hospital, Portadown (9) (Dr M McCormick (PI), Dr M Magee, Dr G Tallon, D McFarland, D
Cosgrove)

6
Norfolk and Norwich University Hospital, Norwich (9) (Dr N Shinh (PI), Dr K Metcalf, Dr A Kostyuk, S
McDonald, S Sayers)

Wrexham Maelor Hospital, Wrexham (8) (Dr W Sayed (PI), Dr S Abraham, G Szabo, G Crosbie)

Royal Victoria Hospital, Belfast (6) (Dr J McIlmoyle (PI), Dr P Fearon, K Courtney, S Tauro)

Royal Blackburn Hospital, Blackburn (6) (Dr A Singh (PI), Dr A Nair, S Duberley, S Philip, C Curley, W
Goddard)

York General Hospital, York (5) (Dr Luke Bridge (PI), Dr P Wilcoxson, Dr P Wanklyn, J Owen)

Torbay Hospital, Torquay (5) (Dr J France (PI), B Reed, A Foulds)

Nevill Hall Hospital, Abergavenny (5) (Dr B Richard (PI), L Parfitt)

St. Peter’s Hospital, Chertsey (4) (Dr B Affley (PI), Dr C Russo, M Dsouza, E Cruddas)

William Harvey Hospital, Ashford (3) (Dr D Hargroves (PI), J Rand)

Royal Gwent Hospital - The Grange, Newport (3) (Dr S Shekar (PI), Dr Y Bhat, G Marshall, M Nash)

New Cross Hospital, Wolverhampton (3) (Dr N Ahmad (PI), B O Okoko, R Evans, T Taylor)

Queen Elizabeth University Hospital, Glasgow (2) (Dr J Dawson (PI), E Colquhoun)

Withybush General Hospital, Haverford West (1) (Dr C James (PI), Dr C Aguirre, C MacPhee, J Phipps)

Sandwell General Hospital, West Bromwich (1) (Dr S Ispoglou (PI), A Hayes, R Evans)

7
Table e1: Direct oral anticoagulant type initiated, dose, and classification of participants who were non-
guideline (over) dosed or non-guideline (under) dosed according to UK National Institute for Health and Care
Excellence guidance
Early (n=1,814) Delayed (n=1,807) Total (N=3,621)
n (%) n (%) n (%)
Apixaban (any dose) 1,142 (63·0) 1,106 (61·2) 2,248 (62·1)
Apixaban 5 mg twice daily 955 (52·7) 915 (50·6) 1,870 (51·6)
guideline dosed 929 (97·2) 874 (95·5) 1,803 (96·4)
non-guideline (over) dosed 26 (2·7) 41 (4·5) 67 (3·6)
Apixaban 2·5 mg twice daily 187 (10·3) 191 (10·6) 378 (10·4)
guideline dose 151 (80·7) 139 (72·8) 290 (76·7)
non-guideline (under) dosed 36 (19·3) 52 (27·2) 88 (23·3)
Dabigatran (any dose) 38 (2·1) 31 (2·1) 69 (1·9)
Dabigatran 150 mg twice daily 28 (1·5) 20 (1·1) 48 (1·3)
guideline dosed 27 (96·4) 18 (90·0) 45 (93·8)
non-guideline (over) dosed 1 (3·6) 2 (10·0) 3 (6·2)
Dabigatran 110 mg twice daily 10 (0·6) 11 (0·6) 21 (0·6)
guideline dosed 7 (70·0) 10 (90·9) 17 (81·0)
non-guideline (under) dosed 3 (30·0) 1 (9·1) 4 (19·0)
Edoxaban (any dose) 537 (29·6) 508 (28·1) 1,045 (28·9)
Edoxaban 60 mg once daily 345 (19·0) 331 (18·3) 676 (18·7)
guideline dosed 315 (91·3) 300 (90·6) 615 (91·0)
non-guideline (over) dosed 30 (8·7) 31 (9·4) 61 (9·0)
Edoxaban 30 mg once daily 192 (10·6) 177 (9·8) 369 (10·2)
guideline dosed 166 (86·5) 151 (85·3) 317 (85·9)
non-guideline (under) dosed 26 (13·5) 26 (14·7) 52 (14·1)
Rivaroxaban (any dose) 78 (4·3) 87 (4·8) 165 (4·6)
Rivaroxaban 20 mg once daily 58 (3·2) 59 (3·3) 117 (3·2)
guideline dosed 52 (89·7) 55 (93·2) 107 (91·5)
non-guideline (over) dosed 6 (10·3) 4 (6·8) 10 (8·5)
Rivaroxaban 15 mg once daily 20 (1·1) 28 (1·6) 48 (1·3)
guideline dosed 17 (85·0) 20 (71·4) 37 (77·1)
non-guideline (under) dosed 3 (15·0) 8 (28·6) 11 (22·9)
Did not commence DOAC 19 (1·0) 75 (4·2) 94 (2·6)

Participants were classed as receiving the guideline DOAC dose when the dose received was in line with the UK
National Institute for Health and Care Excellence guidance1 (reduced dose recommended when: for apixaban,
two out of three of age ≥80, body weight ≤60 kg or serum creatinine ≥133 micromol/L; for dabigatran, either
age ≥80 or creatinine clearance 30-50 ml/min; for edoxaban, either body weight ≤60 kg or creatinine clearance
30-50 ml/min; for rivaroxaban, creatinine clearance 30-50 ml/min). Dosage decisions were made at the
discretion of the physicias responsible for the care of each participant at trial sites.

1 Management | Anticoagulation - oral | CKS | NICE. https://cks.nice.org.uk/topics/anticoagulation-

oral/management/ (accessed Oct 2, 2024).

8
Table e2: Baseline characteristics of participants excluded from the analysis and those included in the modified
intention to treat population

Excluded from analysis Modified intention to

treat (mITT) population
(n=27) (n=3621)

Mean (SD) Mean (SD)

Age 78·0 (10·4) 78·0 (9·9)
n (%) n (%)
Sex, male 14 (51·9) 1,981 (54·7)
Anticoagulant 13 (48·1) 1,325 (36·6)
Warfarin 1 (3·7) 134 (3·7)
Direct oral anticoagulant (DOAC) 12 (44·4) 1,191 (32·9)
Intravenous thrombolysis treatment 3 (11·1) 798 (22·0)
Endovascular treatment 0 (0) 266 (7·3)
Hypercholesterolemia 11 (40·7) 1,188 (32·8)
Diabetes type 1 or 2, known prior to stroke or 7 (25·9) 768 (21·2)
diagnosed during admission
Hypertension 21 (77·8) 2,434 (67·2)
Chronic kidney disease 4 (14·8) 543 (15·0)
Dementia or cognitive impairment 1 (3·7) 248 (6·8)
Smoking status
Current smoker 1 (3·7) 273 (7·5)
Ex smoker 11 (40·7) 1,019 (28·1)
Never smoked 14 (51·9) 1,916 (52·9)
Not Known 1 (3·7) 410 (11·3)
Current alcohol intake >14 units per week 2 (7·4) 402 (11·1)
Myocardial infarction 4 (14·8) 336 (9·3)
Coronary revascularisation 4 (14·8) 229 (6·3)
Congestive heart failure 1 (3·7) 383 (10·6)
History of angina 2 (7·4) 262 (7·2)
Peripheral arterial disease 1 (3·7) 78 (2·2)
Previous ischaemic stroke 5 (18·5) 537 (14·8)
Previous intracranial haemorrhage 1 (3·7) 63 (1·7)
Atrial fibrillation known prior to stroke 16 (64·0) 1,838 (50·8)
Type of Atrial fibrillation
Paroxysmal 8 (29·6) 966 (26·7)
Persistent 16 (59·3) 2,561 (70·7)
Atrial Flutter 1 (3·7) 92 (2·5)
Missing 2 (7·4) 2 (0·1)
Previous hospitalisation for extracranial 1 (3·7) 68 (1·9)
haemorrhage
Stroke severity (NIHSS) at Admission
0-4 11 (40·7) 1,485 (41·0)
5-10 12 (44·4) 1,228 (33·9)
11-15 1 (3·7) 437 (12·1)
16-21 1 (3·7) 317 (8·8)
>21 0 (0) 137 (3·8)
Missing 2 (7·4) 17 (0·5)
Stroke severity (NIHSS) Randomisation
0-4 19 (70·4%) 2,083 (57·5%)
5-10 7 (25·9%) 1,010 (27·9%)
11-15 0 (0%) 282 (7·8%)
16-21 0 (0%) 178 (4·9%)
>21 1 (3·7%) 68 (1·9%)
Median (IQR) Median (IQR)
Stroke severity (NIHSS) at Admission 5·0 (3-7) 5·0 (3-10)
Stroke severity (NIHSS) Randomisation 3·0 (1-5) 4·0 (2-7)
SD (Standard deviation), IQR (Interquartile range)

9
Table e3: First occurrence of all primary and secondary outcome events during follow-up in the NIHSS >21 subgroup

Early (n=33) Delayed (n=35)

n (%) n (%) Adjusted risk Difference (95% CI) p-Value
Primary outcome* 1 (3·0) 2 (5·7) 0.027 (-0.070 to 0.123) 0.596
Recurrent ischemic stroke 0 (0) 0 (0) - -
Symptomatic intracranial haemorrhage 1 (3·0) 2 (5·7) 0.027 (-0.070 to 0.123) 0.596
Systemic embolism 0 (0) 0 (0) - -
Unclassifiable stroke 0 (0) 0 (0) - -
All-cause mortality 10 (30·3) 13 (37·1) 0.072 (-0.080 to 0.224) 0.362
Primary outcome and mortality 10 (30·3) 14 (40·0) 0.092 (-0.071 to 0.256) 0.270
Major extracranial bleeding 0 (0) 1 (2·9) - -
Non-major extracranial bleeding 3 (9·1) 0 (0) - -
All major bleeding (major extracranial 1 (3.0) 3 (8.6) 0.055 (-0.054 to 0.165) 0.352
bleeding and intracranial bleeding)
Venous thrombo-embolism 0 (0) 0 (0) - -

*The primary outcome was a composite of ischaemic stroke, unclassifiable stroke, symptomatic intracranial haemorrhage, or systemic embolism at 90 days

10
Figure e1: Time-to-event plot for all-cause mortality according to allocated treatment

Proportion with all-cause mortality (%)

11
Figure e2: Time-to-event plot for the primary outcome or all-cause mortality according to allocated treatment

Proportion with the primary outcome or

all-cause mortality (%)

12
Figure e3: Time-to-event plot for systemic embolism or recurrent ischaemic stroke according to allocated treatment

Proportion with systemic embolism

or recurrent ischaemic stroke (%)

13
Figure e4: Time-to-event plot for symptomatic intracranial haemorrhage (ICH) according to allocated treatment

14
Figure e5: Time-to-event plot for recurrent ischaemic stroke according to allocated treatment

15
Figure e6: Time-to-event plot for systemic embolism according to allocated treatment

with systemic embolism (%)

with systemic embolism
proportion
Proportion
Cumulative

16



     

OPTIMAS

OPtimal TIMing of Anticoagulation after acute ischaemic Stroke: a

randomised controlled trial

Version 5.0
Date 22 Jul 2021
Sponsor University College London (UCL)
Comprehensive Clinical Trials CTU/2017/300
REC # 19/SC/0021 (all nations), 20/SS/0069 (Scotland)
NIHR UKCRN identifier 40836
IRAS identifier 249552 (all nations), 279613 (Scotland)
ISRCTN 17896007

Authorisation: Chief Investigator

Name Professor David Werring
Role Chief Investigator
Signature

Date




Authorisation: Sponsor/CCTU Director Representative

Name Professor Nicholas Freemantle
Role UCL CCTU Director
Signature

Date




Authorisation: Senior Operations Staff

Name Marisa Chau
Role Clinical Project Manager
Signature

Date




Authorisation: Senior Statistician

Name Professor Nicholas Freemantle
Role Statistical Oversight
Signature

Date






     

Table of Contents
Table of Contents .................................................................................................................................... 2
1 Administrative information............................................................................................................. 7
1.1 Compliance ............................................................................................................................. 7
1.2 Sponsor ................................................................................................................................... 7
1.3 Structured trial summary ........................................................................................................ 8
1.4 Roles and responsibilities...................................................................................................... 13
Protocol contributors .................................................................................................... 13
Role of trial sponsor and funders .................................................................................. 13
Trial team ...................................................................................................................... 14
Trial Management Group .............................................................................................. 14
Trial Steering Committee .............................................................................................. 15
Independent Data Monitoring Committee ................................................................... 15
Event Validation Committee ......................................................................................... 16
Independent Event Adjudication Committee ............................................................... 16
2 Abbreviations ................................................................................................................................ 17
3 Glossary ......................................................................................................................................... 18
4 Introduction .................................................................................................................................. 22
4.1 Background and Rationale .................................................................................................... 22
Explanation for choice of comparator .......................................................................... 24
4.2 Objectives.............................................................................................................................. 24
4.3 Trial Design............................................................................................................................ 24
5 Methods ........................................................................................................................................ 26
5.1 Site Selection ......................................................................................................................... 26
Study Setting ................................................................................................................. 26
Site/Investigator Eligibility Criteria ............................................................................... 26
Principal Investigator’s (PI) Qualifications and Agreements ..................................... 26
Resourcing at site ...................................................................................................... 26
Site research staff ..................................................................................................... 27
5.2 Site approval and activation ................................................................................................. 27
5.3 Participants ........................................................................................................................... 27
Eligibility Criteria ........................................................................................................... 27



     

Participant selection ................................................................................................. 28

Participant Inclusion Criteria ..................................................................................... 28
Participant Exclusion Criteria .................................................................................... 29
Co-enrolment guidance ............................................................................................ 30
Screening procedures and pre-randomisation investigations ...................................... 30
Obtaining consent ..................................................................................................... 30
Screening Procedures ............................................................................................... 36
5.4 Interventions ......................................................................................................................... 37
Products ........................................................................................................................ 38
Treatment Schedule ...................................................................................................... 38
Dispensing ..................................................................................................................... 38
Dose Modifications and Interruptions ...................................................................... 39
Accountability ............................................................................................................... 39
Compliance and Adherence to the allocated treatment .............................................. 39
Concomitant Care ......................................................................................................... 39
Overdose of Trial Medication ....................................................................................... 39
Protocol Treatment Discontinuation ............................................................................ 39
5.5 Outcomes .............................................................................................................................. 40
Primary Outcome .......................................................................................................... 40
Secondary Outcomes .................................................................................................... 40
Outcome measures ....................................................................................................... 41
Event Adjudication Committee ................................................................................. 41
Definition of outcome events ................................................................................... 42
Scales, assessments and questionnaires................................................................... 44
5.6 Participant timeline............................................................................................................... 45
Enrolment and Randomisation ..................................................................................... 45
Discharge from acute (or hyperacute) stroke unit ....................................................... 45
Study follow-up ............................................................................................................. 47
Withdrawal.................................................................................................................... 48
Participant transfers...................................................................................................... 48
Loss to follow-up ........................................................................................................... 48
5.7 Sample size............................................................................................................................ 49
5.8 Recruitment and retention ................................................................................................... 49



     

Recruitment .................................................................................................................. 49
Retention....................................................................................................................... 50
5.9 Assignment of intervention .................................................................................................. 51
Allocation ...................................................................................................................... 51
Sequence generation ................................................................................................ 51
Allocation concealment ............................................................................................ 51
Allocation implementation ....................................................................................... 51
Blinding ......................................................................................................................... 51
Emergency unblinding .................................................................................................. 51
5.10 Data collection, management ............................................................................................... 51
Data collection methods ............................................................................................... 51
Data management ........................................................................................................ 52
Non-adherence and non-retention............................................................................... 53
5.11 Trial Closure .......................................................................................................................... 53
5.12 Analysis and statistical methods ........................................................................................... 54
Statistical analysis plan ................................................................................................. 54
Statistical methods – outcomes .................................................................................... 54
Additional analyses – subgroup .................................................................................... 55
Analysis population and missing data ........................................................................... 55
Economic evaluations ................................................................................................... 56
Health Economic Analysis Plan (HEAP) ..................................................................... 56
Within-trial analysis .................................................................................................. 57
5.13 Data monitoring .................................................................................................................... 58
Data Monitoring Committee ......................................................................................... 58
Interim Analyses............................................................................................................ 58
Data Monitoring for Harm ............................................................................................ 58
Safety reporting ........................................................................................................ 58
Other notifiable adverse events ............................................................................... 59
Urgent safety measures ............................................................................................ 59
Procedures to follow in the event of female participants becoming pregnant........ 59
Investigator responsibilities relating to safety reporting.......................................... 60
5.13.3.5.1 Seriousness assessment ................................................................................. 60
5.13.3.5.2 Severity or grading of Adverse Events............................................................ 61



     

5.13.3.5.3 Causality ......................................................................................................... 62

5.13.3.5.4 Expectedness .................................................................................................. 62
SAE Notifications ....................................................................................................... 62
5.13.3.6.1 Notifications by the Investigator .................................................................... 62
5.13.3.6.2 CCTU responsibilities ...................................................................................... 64
Quality Assurance and Control ..................................................................................... 64
Risk Assessment ........................................................................................................ 64
Central Monitoring at CCTU ...................................................................................... 64
On-site Monitoring.................................................................................................... 65
5.13.4.3.1 Direct access to participant records ............................................................... 65
Trial Oversight ........................................................................................................... 65
Trial Team.................................................................................................................. 65
Trial Management Group .......................................................................................... 65
Independent Trial Steering Committee .................................................................... 65
Independent Data Monitoring Committee ............................................................... 65
Trial Sponsor ............................................................................................................. 66
6 Ethics and Dissemination .............................................................................................................. 66
6.1 Ethics Committee Approval .................................................................................................. 66
6.2 Competent Authority approvals ........................................................................................... 66
6.3 Other approvals .................................................................................................................... 66
6.4 Protocol amendments .......................................................................................................... 66
6.5 Consent or assent ................................................................................................................. 66
Consent or assent in ancillary studies ........................................................................... 67
6.6 Confidentiality ....................................................................................................................... 67
6.7 Declaration of Interests ........................................................................................................ 67
6.8 Indemnity .............................................................................................................................. 67
6.9 Finance .................................................................................................................................. 68
6.10 Archiving ............................................................................................................................... 68
6.11 Access to data ....................................................................................................................... 68
6.12 Ancillary and post-trial care .................................................................................................. 68
6.13 Publication policy .................................................................................................................. 68
Trial results .................................................................................................................... 68
Authorship..................................................................................................................... 68



     

Reproducible research .................................................................................................. 68

7 Ancillary studies ............................................................................................................................ 68
8 Protocol Amendments .................................................................................................................. 69
Amendment 1 – Summary of Changes to Protocol v1.0 dated 14 Nov 2018 ................................... 69
Amendment 2 – Summary of Changes to Protocol v2.0 dated 20 Feb 2019.................................... 69
Amendment 3 – Summary of Changes to Protocol v3.0 dated 09 Sep 2019.................................... 69
Amendment 4 – Summary of Changes to Protocol v4.0 dated 12 Feb 2020.................................... 69
9 References .................................................................................................................................... 71
10 Appendix 1: Trial documentation for when patients lack capacity .............................................. 75



     

OPTIMAS

1 Administrative information
This document was constructed using the Comprehensive Clinical Trials Unit (CCTU) at UCL Protocol
template Version 5. It describes the OPTIMAS trial, sponsored by UCL and co-ordinated by CCTU.

It provides information about procedures for entering participants into the trial, and provides
sufficient detail to enable: an understanding of the background, rationale, objectives, trial population,
intervention, methods, statistical analyses, ethical considerations, dissemination plans and
administration of the trial; replication of key aspects of trial methods and conduct; and appraisal of
the trial’s scientific and ethical rigour from the time of ethics approval through to dissemination of the
results. The protocol should not be used as an aide-memoire or guide for the treatment of other
patients. Every care has been taken in drafting this protocol, but corrections or amendments may be
necessary. These will be circulated to registered investigators in the trial. Sites entering participants
for the first time should confirm they have the correct version of the study protocol through a member
of the trial team at CCTU.

CCTU supports the commitment that its trials adhere to the SPIRIT guidelines. As such, the protocol
template is based on an adaptation of the Medical Research Council CTU protocol template (2012)
and the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement
for protocols of clinical trials [1]. The SPIRIT Statement Explanation and Elaboration document [2] can
be referred to, or a member of CCTU Protocol Review Committee can be contacted for further detail
about specific items.

1.1 Compliance
The trial will be conducted in compliance with the approved protocol, the Declaration of Helsinki
(2008), the principles of Good Clinical Practice (GCP), the Human Tissue (Quality and Safety for Human
Application) Regulations 2007, the UK Data Protection Act 2018, and the National Health Service (NHS)
UK Policy Framework for Health and Social Care. Agreements that include detailed roles and
responsibilities will be in place between participating sites and CCTU.

The PI or delegate must document and explain any deviation from the approved protocol, and
communicate this to the trial team at CCTU as soon as they become aware of the event, as per Sponsor
requirements.

Participating sites will inform CCTU as soon as they are aware of a possible serious breach of
compliance with GCP or the protocol, so that CCTU can fulfil its requirement to report the breach if
necessary. For the purposes of this protocol, a ‘serious breach’ is one that is likely to affect to a
significant degree:

• The safety or physical or mental integrity of the subjects in the trial, or

• The scientific value of the trial.

1.2 Sponsor
UCL is the trial sponsor and has delegated responsibility for the overall management of the OPTIMAS
trial to CCTU. Queries relating to UCL sponsorship of this trial should be addressed to the CCTU
Director or via the Trial Team.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 7 of 75



     

OPTIMAS

1.3 Structured trial summary

Primary Registry and ClinicalTrials.gov: NCT03759938
Trial Identifying Number

Date of Registration in 03 October 2018

Primary Registry

Secondary Identifying R& D No 18/0316

Numbers CCTU No. CTU/2017/300
Funder: BHF Clinical Study no. CS/17/6/33361
IRAS: 249552 (all nations), 279613(Scotland)
REC: 19/SC/0021 (all nations), 20/SS/0069 (Scotland)
ISRCTN: 17896007
NIHR UKCRN Portfolio: 40836
Source of Monetary or British Heart Foundation (BHF)
Material Support

Sponsor University College London with sponsor responsibilities delegated to

CCTU.

Contact for Public [email protected] or

Queries
[email protected]

Contact for Scientific Professor David Werring (Chief Investigator)

Queries Professor of Clinical Neurology,
Department of Brain Repair and Rehabilitation
Stroke Research Centre
UCL Queen Square Institute of Neurology
First Floor
Russell Square House
10-12 Russell Square
London WC1B 5EH
Tel (office): +44 (0)20 3108 6255
Email (academic): [email protected]
Email (NHS): [email protected]

Public Title OPTIMAS: OPtimal TIMing of Anticoagulation after acute ischaemic

Stroke

Scientific Title OPtimal TIMing of Anticoagulation after acute ischaemic Stroke: a

randomised controlled trial

Countries of United Kingdom

Recruitment

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 8 of 75



     

OPTIMAS

Health Condition(s) or Patients with acute ischaemic stroke and atrial fibrillation (AF) (including
Problem(s) Studied paroxysmal, persistent or permanent AF, or atrial flutter).

Intervention(s) Intervention: early initiation of any direct oral anticoagulant (DOAC) at

a dose licensed for stroke prevention in AF, within four days (96hrs) of
onset of acute ischaemic stroke

Control: standard initiation of any DOAC at a dose licensed for stroke

prevention in AF, no sooner than day 7 and no later than day 14 after
the onset of acute ischaemic stroke (i.e. between 144hrs and 336hrs
from onset).

Participants will be randomised 1:1 to the intervention or control. The

exact timing of initiating treatment within each group is at the discretion
of the treating clinician.

Key Inclusion and Inclusion Criteria:

Exclusion Criteria 1. Aged 18 years or over
2. Clinical diagnosis of acute ischaemic stroke
3. AF (including paroxysmal, persistent or permanent AF, or atrial
flutter), confirmed by any of:
a. 12-lead ECG recording
b. Inpatient ECG telemetry
c. Other prolonged ECG monitoring technique (e.g. Holter
monitor)
d. Documentation of a diagnosis of AF detected before or after
the acute ischaemic stroke in medical records (e.g. primary
care records, letter from secondary care)
4. Eligibility to commence DOAC in accordance with approved
prescribing recommendations and SmPC confirmed by treating
physician
5. Uncertainty on the part of the treating physician regarding early
versus standard initiation of DOAC.

Exclusion Criteria:
1. Contraindication to anticoagulation:
a. Known coagulopathy or current or recent anticoagulation with
vitamin K antagonist (VKA) leading to INR ≥1.7 at
randomisation.
b. Thrombocytopenia (platelets < 75 x 109/L)
c. Other coagulopathy or bleeding tendency (based on clinical
history or laboratory parameters) judged to contraindicate
anticoagulation by treating clinician
2. Contraindication to early anticoagulation

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 9 of 75



     

OPTIMAS

a. Known presence of haemorrhagic transformation with

parenchymal haematoma occupying >30% of the infarct
volume and exerting significant mass effect (i.e. PH2) (NB: HI1,
HI2 and PH1 are not considered contraindications)
b. Presence of clinically significant intracranial haemorrhage
unrelated to qualifying infarct
c. Any other contraindication to early anticoagulation as judged
by the treating clinician
3. Contraindication to use of DOAC:
a. Known allergy or intolerance to both factor Xa inhibitor and
direct thrombin inhibitor
b. Definite indication for VKA treatment e.g. mechanical heart
valve, valvular AF (determined by the local investigator, but
usually defined as moderate to severe mitral valve disease, a
prosthetic valve, or both), antiphospholipid syndrome
c. Severe renal impairment with creatinine clearance (Cockcroft
& Gault formula) <15 mL/min (i.e. 14 mL/min or less)
d. Liver function tests ALT > 2x ULN
e. Cirrhotic patients with Child Pugh score equating to grade B or
C
f. Patient is taking medication with significant interaction with
DOAC, including:
• Azole antifungals (e.g. ketoconazole, itraconazole)
• HIV protease inhibitors (e.g. ritonavir)
• Strong CYP3A4 inducers (e.g. rifampicin, phenytoin,
carbamazepine, phenobarbital or St. John's Wort)
• Dronedarone
4. Pregnant or breastfeeding women
5. Presence on acute brain imaging of non-stroke pathology judged
likely to explain clinical presentation (e.g. mass lesion, encephalitis)
6. Inability for patient to be followed up within 90 days of trial entry
7. Patient or designated representative(s) (according to relevant
legislation for each nation) refusal to consent to study procedures,
including the site informing GP and healthcare professional
responsible for anticoagulation care of participants
8. Any other reason that the PI considers would make the patient
unsuitable to enter OPTIMAS.

Note that current DOAC treatment is NOT an exclusion criterion, as long

as the treating physician considers it appropriate to restart (or continue)
according to the timings specified in the OPTIMAS trial protocol;
continuation of the DOAC would be recorded as a start time of zero
hours.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 10 of 75



     

OPTIMAS

Study Type Interventional:

1. Randomised controlled trial
2. Prospective, partially blinded study: participants and physicians
treating the patient at the time of randomisation will not be blinded,
but all outcomes will be assessed blinded to treatment allocation.
Sites must make every effort to ensure that outcome assessors are
unaware of treatment allocation.
Date of First Enrolment April 2019

Target Sample Size 3478

Primary Outcome(s) Composite outcome of the combined incidence of:

1. Stroke of any cause (i.e. recurrent symptomatic ischaemic
stroke, symptomatic intracranial haemorrhage (sICH)including
extradural, subdural, subarachnoid and intracerebral
haemorrhage, and haemorrhagic transformation of the
qualifying infarct), and unclassifiable stroke syndromes)
2. Systemic arterial embolism
at 90 days from randomisation.

Key Secondary Efficacy outcomes:

Outcomes 1. All-cause mortality
2. Incidence of vascular death
(All secondary 3. Incidence of recurrent ischaemic stroke
outcomes are within 90 4. Incidence of systemic arterial embolism
days of randomisation 5. Incidence of venous thromboembolism (deep vein thrombosis
unless stated otherwise) [DVT], pulmonary embolism [PE], cerebral venous thrombosis [CVT])
6. Functional status (assessed by the mRS scale)
7. Cognitive ability (assessed by the MoCA questionnaire)
8. Quality of life at 90 days (assessed by EQ-5D 5 level [EQ-5D-5L])
9. Patient reported outcomes (assessed by the PROMIS-10)
10. Ongoing anticoagulation
11. Time to event for overall survival
12. Time to first incidence of composite primary outcome and overall
survival
13. Time to first incidence of composite primary outcome (recurrent
ischaemic stroke, systemic arterial embolism, sICH or unclassifiable
stroke syndromes)
14. Time to first incidence of composite of the ischaemic components of
the primary outcome (ischaemic stroke and systemic embolism)
15. Time to first incidence of sICH
16. Time to first incidence of ischaemic stroke
17. Time to first incidence of systemic arterial embolism
18. Length of hospital stay for stroke-related care

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 11 of 75



     

OPTIMAS

19. Health and Social Care Resources usage (assessed by a study-specific

questionnaire: HSCR).

Safety outcomes:
20. Incidence of sICH classified according to site: intracerebral
haemorrhage (within the brain parenchyma); subdural
haemorrhage; extradural haemorrhage; subarachnoid
haemorrhage; and haemorrhagic transformation of a brain infarct.
21. Incidence of major extracranial bleeding
22. Incidence of all major bleeding (intracranial and extracranial)
23. Incidence of clinically relevant non-major bleeding

Other secondary outcomes:

24. Ongoing anticoagulation at 90 days

Exploratory outcomes:
25. Individual cognitive domain sub-scores (measured using the MoCA
questionnaire).

Exploratory outcomes Individual cognitive domain sub-scores (measured using the MoCA
questionnaire)

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 12 of 75



     

OPTIMAS

1.4 Roles and responsibilities

These membership lists are correct at the time of writing; please see terms of reference
documentation in the Trial Master File (TMF) for current lists.

Protocol contributors
Name Affiliation Role
Professor Gary Ford University of Oxford Steering Committee Chair
Professor David Werring UCL Chief Investigator
Dr Hannah Cohen UCL Co-applicant
Professor Stefan Engelter University Hospital Basel, Co-applicant
Switzerland
Dr Martin James University of Exeter Co-applicant
Professor Gregory Lip University of Liverpool Co-applicant
Professor Bo Norrving Lund University, Sweden Co-applicant
Professor Nikola Sprigg University of Nottingham Co-applicant
Professor Roland Veltkamp Imperial College Co-applicant
Professor John Camm St George’s Medical School Cardiology expertise
Professor Caroline Doré UCL CCTU Professor of Clinical Trials and
Statistics
Dr Jonathan Best UCL Clinical Training Fellow and Data
Manager
Dr Marta Campos UCL CCTU Clinical Project Manager
Emilia Caverly UCL CCTU Clinical Project Manager
Dr Iwona Zaczyk UCL CCTU Trial Manager
Kate Bennett UCL CCTU Trial Statistician
Dr Macey Murray UCL CCTU Trial Manager
Rachael Hunter UCL Senior Health Economist
Ekaterina Kuznetsova UCL CCTU Health Economist

Role of trial sponsor and funders

Name Affiliation Role
UCL Comprehensive UCL Trial development and
Clinical Trials Unit implementation (including conduct
(UCL CCTU) and analysis)
British Heart Foundation BHF Sole funder of the trial
(BHF)

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 13 of 75



     

OPTIMAS

Trial team
Name Affiliation Role
Professor David Werring UCL Chief Investigator
Emilia Caverly UCL CCTU Clinical Project Manager
Norin Ahmed UCL CCTU Trial Statistician
Marisa Chau UCL CCTU Trial Manager
Maryam Balogun UCL CCTU Trial Manager
Robert Fenner UCL CCTU Data Manager
Dr Jonathan Best UCL Clinical Training Fellow and Data
Manager
Liz Arram UCL Stroke Research Coordinator
Ekaterina Kuznetsova UCL CCTU Health Economist

Trial Management Group

Name Affiliation Role
Professor David Werring UCL Chief Investigator
Professor Hannah Cohen UCL Consultant Haematologist and
Professor of Haematology
Professor Martin James University of Exeter Consultant Stroke
Physician/Associate Professor
Professor Gregory Lip University of Liverpool Professor of Cardiovascular
Medicine
Professor Nikola Sprigg University of Nottingham Professor of Stroke Medicine
Professor Nick Freemantle UCL CCTU Professor of Clinical Epidemiology
& Biostatistics Director
Dr Jonathan Best UCL Clinical Training Fellow and Data
Manager
Rachael Hunter UCL Senior Health Economist
Ekaterina Kuznetsova UCL CCTU Health Economist
Emilia Caverly UCL CCTU Clinical Project Manager
Norin Ahmed UCL CCTU Trial Statistician
Marisa Chau UCL CCTU Trial Manager
Maryam Balogun UCL CCTU Trial Manager
Liz Arram UCL Stroke Research Coordinator
Robert Fenner UCL CCTU Data Manager

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 14 of 75



     

OPTIMAS

Trial Steering Committee

Name Affiliation Role
Professor Gary Ford University of Oxford Independent Chair
Dr Christopher Price University of Newcastle Independent member
Rosamund Yu UCL Independent member; patient
representative
Professor Amanda Farrin Professor of Clinical Trials & Independent member, statistician
Evaluation of Complex
Interventions, University of
Leeds, UK
Professor David Werring UCL Chief Investigator, non-
independent member
Professor Stefan Engelter University Hospital Basel, Non-independent member
Switzerland
Professor Bo Norrving Lund University, Sweden Non-independent member
Professor Hannah Cohen UCL Observer
Professor Martin James University of Exeter Observer
Professor Gregory Lip University of Liverpool Observer
Professor Nikola Sprigg University of Nottingham Observer
Professor Nick Freemantle UCL CCTU Observer
Shannon Amoils BHF Observer
Dr Jonathan Best UCL Observer
Rachael Hunter UCL Observer
Emilia Caverly UCL CCTU Observer
Norin Ahmed UCL CCTU Observer
Marisa Chau UCL CCTU Observer
Maryam Balogun UCL CCTU Observer
Liz Arram UCL Observer
Robert Fenner UCL CCTU Observer

Independent Data Monitoring Committee

Name Affiliation Role
Dr John Bamford University of Leeds Independent Chair
Professor John Camm St George’s Medical School Cardiology expertise
Professor Tim Clayton The London School of Hygiene Statistician
and Tropical Medicine
Professor Karin Klijn Radboud University, Nijmegen Stroke neurology expertise
Dr Ander Cohen King’s College London Haematology expertise

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 15 of 75



     

OPTIMAS

Event Validation Committee

Name Affiliation Role
Professor David Werring UCL Chair
Dr Jonathan Best UCL Clinical Training Fellow and Data
Manager
Liz Arram UCL Stroke Research Coordinator

Independent Event Adjudication Committee

Name Affiliation Role
Dr Liz Warburton Consultant in stroke Chair
medicine Cambridge
University Hospitals
NHS Foundation Trust
Dr Alastair Webb Consultant Neurologist Member
at Oxford University
Hospitals NHS
Foundation Trust
Dr Craig Smith Professor of Stroke Member
Medicine at University
of Manchester

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 16 of 75



     

OPTIMAS

2 Abbreviations
AE Adverse Event ITT Intention to Treat
AF Atrial fibrillation MDT Multidisciplinary team
AR Adverse Reaction mRS Modified Rankin Scale
ASU Acute stroke unit MHRA Medicines and Healthcare products
CA Competent Authority Regulatory Agency
CCTU Comprehensive Clinical Trials Unit MoCA The Montreal Cognitive Assessment
CI Chief Investigator MRI Magnetic resonance imaging
CRF Case Report Form NAE Notifiable Adverse Event
CSRI Client Service Receipt Inventory NHS National Health Service
CT Computed tomography NHS IEP NHS Imaging Exchange Portal
CTA Clinical Trial Authorisation NIHSS National Institute of Health Stroke
Scale
CTCAE Common Terminology Criteria for
NOAC Non-vitamin K antagonist oral
Adverse Events
anticoagulants; DOAC and NOAC are
CV Curriculum Vitae
interchangeable terms
CVT Cerebral venous thrombosis Non-CTIMP Trials that do not involve an
DOAC Direct Oral Anticoagulant Investigational Medicinal Product
DVT Deep vein thrombosis OAC Oral Anticoagulant
EC Ethics Committee PE Pulmonary embolism
EU European Union PI Principal Investigator
EAC Event Adjudication Committee PIS Participant Information Sheet
ECASS European Cooperative Acute Stroke PROMIS - Patient-Reported Outcomes
Study 10 Measurement Information System
EQ-5D-5L EuroQol EQ-5D 5 level QA Quality Assurance
HSCIC Health & Social Care Information QC Quality Control
Centre QMMP Quality Management and Monitoring
HEAP Health Economic Analysis Plan Plan
HES Hospital Episode Statistics R&D Research and Development
ICH GCP International Conference on REC Research Ethics Committee
Harmonisation Good Clinical Practice SAE Serious Adverse Event
GDPR General Data Protection Regulation SAP Statistical Analysis Plan
GP General Practitioner SAR Serious Adverse Reaction
HASU Hyperacute stroke unit sICH Symptomatic intracranial
HDU High-dependency unit haemorrhage
HSCR Health and Social Care Resources SmPC Summary of Product Characteristics
questionnaire SSA Site Specific Approval
ICF Informed consent form TIA Transient ischaemic attack
ICH Intracerebral haemorrhage TMF Trial Master File
IDMC Independent Data Monitoring TMG Trial Management Group
Committee TMT Trial Management Team
INR International Normalized Ratio ToR Terms of Reference
IQCODE Informant Questionnaire on Cognitive TSC Trial Steering Committee
Decline in the Elderly
UCL University College London
ISF Investigator Site File
USM Urgent Safety Measure
ISTH International Society on Thrombosis
and Haemostasis VKA Vitamin K antagonist

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 17 of 75



     

OPTIMAS

3 Glossary
Acute ischaemic stroke An episode of neurological dysfunction caused by
cerebral, spinal, or retinal infarction due to interruption of
the relevant blood supply, typically by a thrombus (blood
clot)
Anticoagulants Blood-thinning medication

Apixaban A factor Xa inhibitor indicated for stroke prevention in

non-valvular atrial fibrillation, at a standard dose of 5mg
BD, reduced to 2.5mg BD in certain patients.
Atrial fibrillation (AF) An abnormal heart rhythm (tachyarrhythmia)
characterised by irregular atrial contraction, which
increases the risk of stroke and blood clots. On the
electrocardiogram (ECG), AF is described by the absence
of consistent P waves; instead there are rapid oscillations
or fibrillatory waves that vary in size, shape and timing
and are generally associated with an irregular ventricular
response when atrioventricular (AV) conduction is intact.
Subtypes (all of which are eligible for OTPIMAS) include
paroxysmal, persistent and permanent AF.
Atrial flutter An abnormal heart rhythm closely related to AF in which
the atria, but not ventricles, contract very rapidly but
regularly.

Clinically relevant non-major Clinically relevant non-major bleeding was defined as

bleeding overt bleeding not meeting the criteria for major
bleeding but associated with medical intervention,
unscheduled contact (visit or telephone) with a physician,
interruption or discontinuation of study treatment, or
associated with any other discomfort such as pain or
impairment of activities of daily life.

Computed tomography (CT) A diagnostic imaging test using x-rays to create detailed
images of internal organs including the brain.

Dabigatran A direct thrombin inhibitor indicated for stroke

prevention in non-valvular atrial fibrillation, at a standard
dose of 150mg BD, reduced to 110mg BD in certain
patients.

Deep vein thrombosis A blood clot that develops in the large veins, usually in the
(DVT) legs.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 18 of 75



     

OPTIMAS

Direct Oral Anticoagulants (DOACs) Specific oral anticoagulant drugs acting directly on
components of the coagulation pathway, including the
factor Xa inhibitors rivaroxaban, apixaban, and edoxaban,
and the direct thrombin inhibitor dabigatran.

Edoxaban A factor Xa inhibitor indicated for stroke prevention in

non-valvular atrial fibrillation at a standard dose of 60mg
OD, reduced to 30mg OD in certain patients.

Endarterectomy The surgical removal of plaque from a narrowed artery

(usually the carotid) to restore blood flow and prevent
strokes.

EQ-5D-5L A standardized instrument developed by the EuroQol

Group as a measure of health-related quality of life that
can be used in a wide range of health conditions and
treatments.

Haemorrhagic transformation Bleeding occurring within infarcted brain tissue following

ischaemic stroke. Severity classified radiologically (ECASS-
2 classification) as:
• HI1: scattered small petechiae, no mass effect
• HI2: confluent petechiae, no mass effect
• PH1: haematoma within infarcted tissue, occupying
<30% infarct zone, no significant mass effect
• PH2: haematoma occupying 30% or more of the
infarcted tissue, with obvious mass effect

International Normalised Ratio (INR) A blood test measuring how quickly a person’s blood clots

Intracranial haemorrhage Bleeding within the skull. This includes intracerebral

haemorrhage (within the brain matter) as well as
subarachnoid, subdural and extradural haemorrhage
(outside the brain substance). It also includes
haemorrhagic transformation of a brain infarct.

Infarct An area of cell death due to an inadequate blood supply.

Informant Questionnaire on The Informant Questionnaire for Cognitive Decline in the

Cognitive Decline in the Elderly Elderly is a structured interview based on informant
(IQCODE) responses that is used to assess for possible dementia. In
OPTIMAS it will be used to screen for pre-stroke dementia.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 19 of 75



     

OPTIMAS

Major bleeding Major bleeding is defined as clinically overt bleeding

associated with any of the following: fatal outcome,
involvement of a critical anatomic site (intracranial, spinal,
ocular, pericardial, articular, retroperitoneal, or
intramuscular with compartment syndrome), fall in
haemoglobin concentration of at least 20 g/L or
transfusion of 2 or more units of red blood cells.
Minor bleeding Bleeding events that do not meet the criteria of major or
clinically relevant non-major bleeding are defined as
minor.
Modified Rankin Scale (mRS) Modified Rankin Scale measures functional ability (the
degree of disability and dependence) following a stroke.

Montreal Cognitive Assessment The Montreal Cognitive Assessment is a questionnaire

(MoCA) widely used as a screening assessment for detecting
cognitive impairment.

Magnetic resonance imaging (MRI) Magnetic resonance imaging is a type of scan that uses
strong magnetic fields and radio waves to produce
detailed images of the inside of the body.

National Institute of Health Stroke The NIHSS is a standardised clinical method for assessing
Scale (NIHSS) the severity of a stroke. The severity of stroke is classified
as: 0-4, 5-10, 11-15, 16-21, >21.

Nearest relative The Adults with Incapacity (Scotland) Act 2000 uses the
hierarchy of relationships defined in the Mental Health
(Scotland) Act 1984 as the definition of nearest relative. In
decreasing order of closeness, these are Spouse; Child;
Father or mother; Brother or sister; Grandparent;
Grandchild; Uncle or aunt; Nephew or niece.

Patient-Reported Outcomes The PROMIS Global-10 is an assessment tool that allows

Measurement Information System measurements of symptoms, functioning, and healthcare-
(PROMIS – 10) related quality of life (HRQoL) for a wide variety of chronic
diseases and conditions.

Rivaroxaban A factor Xa inhibitor licensed for stroke prevention in

non-valvular atrial fibrillation at a standard dose of 20mg
OD, reduced to 15mg OD in certain patients.

Symptomatic intracranial Bleeding within the cranial vault causing clinical

haemorrhage (sICH) symptoms or signs, typically a focal neurological deficit,
headache, seizure or change in level of consciousness

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 20 of 75



     

OPTIMAS

Transient ischaemic attack (TIA) Transient focal neurological symptoms due to inadequate
blood supply to part of the brain, lasting less than 24hrs
and typically less than an hour.

Warfarin A vitamin K antagonist oral anticoagulant licensed for

stroke prevention in atrial fibrillation.

Welfare guardian A person appointed by court to take action and make

decisions on behalf of an adult with incapacity, in relation
to that adult's personal welfare; under the Adults with
Incapacity (Scotland) Act.

Welfare attorney A power of attorney is an authority given by an individual

(known as the Granter) to another person(s) (known as the
Attorney/s) to deal with aspects of the Granter's affairs,
under the Adult with Incapacity (Scotland) Act. In the case
of Welfare Attorney, the Granter gives authority to deal
with their personal welfare.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 21 of 75



     

OPTIMAS

4 Introduction
4.1 Background and Rationale
Importance of atrial fibrillation and associated strokes. Atrial fibrillation (AF) has a lifetime risk of 1
in 4 in European populations [3], and increases the risk of ischaemic stroke 4-5 fold [4]. About 1 in 5
strokes are caused by AF [5] - over 20,000 strokes per year in the UK. In AF-associated acute ischaemic
stroke, the risk of early recurrence (within 7-14 days) is high, between 0.4% and 1.3% per day [6-10].
AF-associated ischaemic strokes are more often disabling or fatal than other types of stroke, with
longer hospital stays and higher costs [11], so preventing early recurrence is a key clinical challenge.
Anticoagulation is extremely effective for long term AF stroke prevention [12], but safety and benefit
in acute stroke has not been established. Early anticoagulation (i.e. in the first few days) might increase
the risk of symptomatic intracranial haemorrhage (ICH), including haemorrhagic transformation of the
infarct (estimated at ~1% per day [13]), leading to clinical uncertainty about when to start
anticoagulation. Recent studies reported an 8-10% risk of recurrent ischaemic stroke and a 2-4% risk
of symptomatic intracranial haemorrhage within 90 days of AF-associated ischaemic stroke [14, 15].
Direct (non-vitamin K antagonist [VKA]) oral anticoagulants (DOACs) - apixaban, dabigatran, edoxaban
or rivaroxaban - have a 50% lower risk of intracranial haemorrhage compared to VKA. DOACs might
allow safe and earlier OAC after acute ischaemic stroke in patients with AF, providing net benefit by
reducing ischaemic stroke recurrence without increased ICH risk [12]. The OPtimal TIMing of
Anticoagulation after acute ischaemic Stroke (OPTIMAS) clinical trial aims to test this hypothesis.

Current guidelines do not provide clear recommendations on the timing of OAC after acute AF-related
stroke: US guidelines suggest that commencing OAC within 14 days is reasonable [16] while European
Society of Cardiology guidelines recommend starting anticoagulation according to infarct size at 1, 3,
6 or 12 days based only on expert consensus [17]. Current UK guidelines for anticoagulation state that
“delay for an arbitrary 2-week period is recommended” for “disabling” stroke and that anticoagulation
can be started “no later than 14 days” for other strokes, at the prescriber’s discretion [18]. The
American College of Chest Physicians guideline (2012) recommended that “oral anticoagulation
should generally be initiated within 1 to 2 weeks after stroke onset.” Although a recent observational
study (n=1029) suggested that anticoagulation at 4-14 days after cardioembolic stroke might give the
best outcome, it had limitations including mixed treatment protocols with low molecular weight
heparin (LMWH) and warfarin as well as DOACs, and insufficient statistical power to determine the
benefit of earlier anticoagulation. The authors concluded that a randomised trial of early DOACs was
needed [14]. There is considerable uncertainty about the optimum timing of anticoagulation in AF-
associated acute ischaemic stroke; data from the CROMIS-2 study (www.ucl.ac.uk/cromis-2;
ClinicalTrials.gov NCT02513316; CI David Werring), illustrate the wide range of timing of
anticoagulation after AF-associated acute ischaemic stroke: of 1,355 patients, OAC was started early
(0-4 days) in 358 (26%) patients and later (or not at all) in 997 (74%) patients [19]. A recent survey of
121 UK stroke physicians [20] found that 95% of responders agreed there was uncertainty regarding
timing of OAC initiation after AF-related ischaemic stroke; only 36% followed the ‘1-3-6-12’ European
Society of Cardiology (ESC) guidelines recommendation. Uncertainty was greater in cases of moderate
stroke than in cases of TIA, mild or severe stroke. 88% of responders would be willing to participate in
a clinical trial of early vs. later initiation of OAC after stroke. Direct-acting oral anticoagulant (DOAC)
were the preferred OAC of choice.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 22 of 75



     

OPTIMAS

Previous observational and randomised studies of anticoagulation in patients with acute ischaemic
stroke and AF. A meta-analysis of 7 randomised trials of unfractionated heparin (UFH), LMWH or
heparinoids (n=4624) started <48 hours, vs. aspirin or placebo, found that early anticoagulation was
associated with non-significantly reduced incidence of recurrent ischaemic stroke, but with increased
intracranial bleeding (especially with UFH), and no reduction in death or disability [10]. Since these
trials (which were not confined to AF patients) the landscape of anticoagulation has been transformed
by DOACs, which are at least as effective as warfarin for AF-related stroke prevention, but with only
about half the risk of intracranial bleeding [12]. DOACs have other potential advantages over VKAs,
including: their rapid onset of action (hours rather than days); not requiring “bridging” anticoagulation
with heparin or heparinoids; simpler dosing; more predictable anticoagulant effects; and no need for
routine anticoagulation monitoring. As a result, if given early, DOACs might have substantial clinical,
quality of life and economic benefits, by contrast with previous neutral trials of UFH, LMWH and
heparinoids [10]. Indeed, recent observational studies suggest early anticoagulation with DOACs
might be safe [14, 15 and 21]. For example, in the RAF study (n=1029) [14], patients who received a
DOAC had low risks of symptomatic intracranial bleeding (2.1%) and ischaemic events (4.3%); while
SAMURAI‐NVAF reported improved outcome and no early ICH with DOAC started at a median of 4
days (IQR 2-6 days, n=1192, median NIHSS=8, IQR 2-18) [21]. The Pre-TIMING observational study of
249 patients with AF-associated acute ischaemic stroke treated with OAC (<5 days) reported in-
hospital recurrent ischaemic stroke in 4.4%, and symptomatic ICH in 3.1% [22]. Data from CROMIS-2
(n=1,355 patients, mean age 76 (SD 10), 580 (43%) female) found that OAC was started early in 358
(26%) patients and later (or not at all) in 997 (74%) patients. The event rate within 90 days was 48/997
(5%) in the late-OAC group (2 ICHs, 18 ischaemic strokes or TIAs and 31 deaths) vs 7/358 (2%) in the
early-OAC group (5 ischaemic strokes or TIAs and 2 deaths) [19]. A single centre observational study
(n=204) in AF-associated ischaemic stroke/TIA early anticoagulation (≤7 days) found that early DOACs
was safe, with no ICH [23]. A recent pooled analysis of 4912 participants patients with AF and recent
cerebral ischemia DOAC treatment commenced early (median 5 days) after recent cerebral ischemia
related to AF was associated with reduced risk of poor clinical outcomes compared to VKA, mainly
attributed to lower risks of ICH [55]. These data strongly support the testing early administration of
DOACs in patients with acute ischaemic stroke and AF in a large randomised controlled trial.

Novelty of OPTIMAS and the need for the trial now. None of the large trials of DOACs included any
patients within 7 [24] or 14 days [25, 26] of acute stroke, so cannot provide information on the relative
risk and benefit of oral anticoagulation soon after stroke. A small trial (Triple AXEL) randomised 195
patients with AF-associated acute ischaemic stroke to rivaroxaban or warfarin <5 days and found
similar rates of symptomatic/asymptomatic MRI-defined recurrent ischaemia (~30%) or intracranial
bleeding (~30%) at 4 weeks, with reduced hospital stay for rivaroxaban [27]. Together with the
observational data, the available evidence [56] indicates that early DOACs are a highly promising but
unproven treatment for acute AF-associated ischaemic stroke which is increasing dramatically with
our ageing population, thus making it a key UK priority and emerging healthcare and socio-economic
challenge [28, 29]. If early DOAC treatment is safe and effective, this could have important implications
for treatment efficacy, safety, patient quality of life, and health economics. The safety and efficacy of
early DOACs in acute ischaemic stroke in patients with AF can only be established by a large
randomised controlled trial; OPTIMAS is designed to fill this important gap in scientific evidence.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 23 of 75



     

OPTIMAS

OPTIMAS aims to obtain new data on early DOAC treatment to change standard practice in the acute
stroke care pathway, reduce hospital stays, and improve quality of life for patients with AF and acute
ischaemic stroke.

Explanation for choice of comparator

The comparator (“standard” OAC) reflects usual UK practice regarding timing of anticoagulation based
on: current UK guidelines regarding OAC after acute AF-associated ischaemic stroke (Intercollegiate
Stroke Working Party Guideline 2016) which recommend delaying anticoagulation for 14 days for
“disabling” stroke and by up to 14 days for “non-disabling” stroke [18]; a review of available guidelines
internationally [56]; and our survey of current practice for anticoagulation after recent cerebral
ischemia with AF [20].

4.2 Objectives
Primary objective: OPTIMAS will investigate whether early initiation of DOAC treatment, within 4 days
(96hrs) of onset, in patients with acute ischaemic stroke and AF (including paroxysmal, persistent or
permanent AF, or atrial flutter) is as effective as, or better than, standard initiation of DOAC treatment,
no sooner than day 7 (>144hrs) and no later than day 14 (<336hrs) after onset, in preventing stroke
of any cause (i.e. recurrent ischaemic stroke, sICH and unclassifiable stroke) and systemic arterial
embolism.

Main hypothesis to be tested: that early DOAC treatment (≤4 days [96 hours]) will not substantially
increase, and might reduce, the incidence of recurrent stroke (including ischaemic stroke, sICH and
unclassifiable stroke) and systemic arterial embolism in patients with AF presenting with acute
ischaemic stroke, compared to standard DOAC initiation no sooner than day 7 (>144hrs) and no later
than day 14 (<336hrs) after onset.

Secondary objectives:
To establish whether clinical stroke severity, brain imaging factors detected on CT or MRI scans (e.g.
large vessel occlusion, infarct size, cerebral small vessel disease, haemorrhagic transformation), or
other factors (including baseline characteristics, e.g. prior antithrombotic treatment) influence the
outcome after early compared with late DOAC treatment in acute ischaemic stroke patients with AF.

To establish whether early anticoagulation reduces hospital stay and the cost-effectiveness of early
DOAC compared to standard DOAC over 90 days from a health and social care cost perspective.

To establish whether early anticoagulation leads to improved patient functional outcomes, as

assessed by mRS, at 90 days.

To establish whether early anticoagulation increases the incidence of major and clinically relevant
bleeding up to 90 days.

4.3 Trial Design

OPTIMAS is a large, prospective, partially blinded randomised controlled trial of early (within ≤4 days
[96hrs]) or standard (between day 7 and day 14 after stroke onset) initiation of anticoagulation after
stroke in patients with AF, using any licensed dose of a DOAC. The trial will use a non-inferiority

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 24 of 75



     

OPTIMAS

gatekeeper approach to test for non-inferiority of early anticoagulation followed by a test for
superiority, if non-inferiority is established.

Figure 1: Trial Diagram 1

Eligible patients identified from HASU, ASU or

PRESCREENING

HDU at participating hospitals

1
Participant consent
SCREENING

Screening of potentially eligible

participants in sufficient time to start early
DOAC treatment

Patients enrolled and randomised into trial

(n=3478)
RANDOMISATION &
INTERVENTON

Intervention: Control:
Early initiation of licensed oral dose of a Standard initiation of licensed dose of a
DOAC (within 4 days [96 hours] of acute DOAC (between day 7 [>144hrs] and day 14
ischaemic stroke onset) [<336hrs] after acute ischaemic stroke onset)

Outcomes at 90 days from randomisation

FOLLOW-UP

END OF TRIAL

1
Or, if the patient lacks capacity: informed consent by legal representative (Scotland); consultee advice
supporting participation (England, Wales); or MDT decision in individual patient’s best interest (Common Law)
in Northern Ireland (see Section 5.3.2.1 for detailed guidance).

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 25 of 75



     

OPTIMAS

5 Methods
5.1 Site Selection
The trial sponsor has overall responsibility for site and investigator selection and has delegated this
role to CCTU.

Study Setting
The trial will be run at selected stroke services throughout the UK, including their associated
hyperacute stroke units, acute stroke units, and high-dependency units. The target for the number of
recruiting sites is ≥100.

Site/Investigator Eligibility Criteria

Once a site has been assessed as being suitable to participate in the trial, the CCTU trial team will
provide the site with a copy of this protocol and all relevant documentation needed for site set-up.

To participate in the OPTIMAS trial, investigators and trial sites must fulfil a set of criteria that have
been agreed by the OPTIMAS trial team as follows:

• A named clinician is willing and appropriate to take Principal Investigator responsibility

• Anticipated ability of the stroke unit to recruit patients
• Suitably trained staff are available to recruit participants, collect and enter data and collect
samples as required
• The site must be able to store and dispense DOACs appropriately
• The site must have access to either an MRI or CT scanner for the diagnosis of acute ischaemic
stroke
• Clinicians at the site must use DOACs to treat acute ischaemic stroke in patients with AF and
support their site’s participation in the OPTIMAS study
• Sites must make every effort to ensure that outcome assessors are unaware of treatment
allocation at the 90-day follow-up visit.

Trial sites meeting these eligibility criteria and that are accepted as suitable by the CCTU trial team
will be issued with the OPTIMAS documentation to use when applying for Site-Specific Approval or
local institutional approval as applicable.

Principal Investigator’s (PI) Qualifications and Agreements

The investigator(s) must be willing to sign an Investigator Agreement to comply with the trial protocol
(confirming their specific roles and responsibilities relating to the trial, and that their site is willing and
able to comply with the requirements of the trial). This includes confirmation of appropriate
qualifications, by provision of a CV, familiarity with the appropriate use of any investigational
products, agreement to comply with the principles of GCP, to permit monitoring and audit as
necessary at the site, and to maintain documented evidence of all staff at the site who have been
delegated significant trial related duties.

Resourcing at site
The investigator(s) should be able to demonstrate potential for recruiting the required number of
suitable subjects within the agreed recruitment period (i.e. the investigator(s) regularly treat(s) the

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 26 of 75



     

OPTIMAS

target population). They should also have an adequate number of qualified staff and facilities available
for the foreseen duration of the trial to enable them to conduct the trial properly and safely, including
the conduct of the 90-day follow-up visit by a staff member who is unaware of the treatment
allocation at the time of the follow-up visit. Unless unavoidable, this staff member should have had
no previous involvement with the research subject, particularly at the time of randomisation.

Sites will be expected to complete a delegation of responsibilities log and provide staff contact details.

The site should have sufficient data management resources to allow prompt data return to CCTU.

Site research staff

Medical staff members of the clinical trial team at sites will have the appropriate qualifications to
manage patients with acute stroke. Each member of the trial team at each site will have their roles
within the trial, as delegated by the PI, documented in the OPTIMAS site delegation log. The CVs and
GCP certificates of the PI and the lead research nurse(s) will be collected by CCTU to document their
qualifications and relevant experience before a site can be activated. All other staff will document the
availability of their signed CV and appropriate training documentation on the site delegation log. The
PI is responsible for ensuring all staff have the appropriate qualifications and training to perform trial-
related tasks before they are delegated trial roles.

Sites will be trained by CCTU staff on all trial-related procedures and assessments prior to initial
activation and following substantial amendments if needed. Site staff training on the study tests and
questionnaires will be self-directed on-line training. All trial training will be recorded in the OPTIMAS
site delegation log.

Only suitably trained and qualified members of the clinical trial team will perform study assessments.

5.2 Site approval and activation

The trial manager or delegate will notify the PI in writing of the plans for site activation. On receipt of
the signed Clinical Trial Site Agreement, Investigator Agreement, approved delegation of
responsibilities log, staff contact details, and any other documents required by CCTU site activation
process, written confirmation will be sent to the site PI. The Trial Manager or delegate will be
responsible for issuing the site activation letter once all required documents and approvals are in
place. Sites will not be permitted to recruit any patients until a letter for activation has been issued.

The site must conduct the trial in compliance with the protocol as agreed by the Sponsor and given a
favourable opinion by the Research Ethics Committee (REC).

A list of activated sites may be obtained from the OPTIMAS Trial Manager.

5.3 Participants

Eligibility Criteria
Patients aged 18 years or more admitted to hospital with an acute ischaemic stroke, who also have AF
(including paroxysmal, persistent or permanent AF, or atrial flutter) and are eligible to commence a
DOAC in the judgement of their treating physician, should be considered for inclusion in the trial. The
detailed inclusion and exclusion criteria are listed below.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 27 of 75



     

OPTIMAS

Note that:
• Patients with paroxysmal, persistent or permanent AF (or atrial flutter) are eligible provided
that the treating clinician intends to start long-term anticoagulation.
• Prior use of a DOAC or VKA, including at the time of the qualifying stroke, does not exclude
participation.
• Current DOAC treatment is NOT an exclusion criterion, as long as the treating physician
considers it appropriate to restart (or continue) according to the timings specified in the
OPTIMAS trial protocol. Continuation of the DOAC would be recorded as a start time of zero
hours.
• Only a clinical diagnosis of acute ischaemic stroke is required for participation, as brain
imaging may be normal in the first few hours after ischaemic stroke onset. There are no formal
imaging requirements for inclusion, though it is expected that all patients will have undergone
at least one form of brain imaging (usually CT) to exclude intracranial haemorrhage. Where
possible, we encourage MR imaging to define lesion location and anatomy, and repeat
imaging (with CT or MRI) to assess for haemorrhagic transformation prior to anticoagulation,
in accordance with ESC recommendations [17].
• A definite decision made by the time of randomisation for a patient to undergo surgery
requiring interruption or delay of anticoagulation within the first week of stroke (typically
expected to be carotid endarterectomy or decompressive hemicraniectomy) excludes a
patient from participation in the study. When a patient is included in the study and a decision
is subsequently made for him or her to undergo such surgery, they will remain in the study,
with the variable resulting dosing interruption recorded in their medical notes and the
OPTIMAS Medication Log. This will not be recorded as a protocol breach.

Participant selection
There will be NO EXCEPTIONS (waivers) to eligibility requirements at the time of randomisation.
Questions about eligibility criteria should be addressed PRIOR to attempting to randomise the participant.

The eligibility criteria for this trial have been carefully considered and are the standards used to ensure
that only medically appropriate participants are entered. Participants not meeting the criteria should
not be entered into the trial for their safety and to ensure that the trial results can be appropriately
used to make future treatment decisions for other people with similar diseases or conditions. It is
therefore vital that exceptions are not made to these eligibility criteria.

Participants will be considered eligible for enrolment in this trial if they fulfil all the inclusion criteria
and none of the exclusion criteria as defined below.

Participant Inclusion Criteria

1. Aged 18 years or over
2. Clinical diagnosis of acute ischaemic stroke
3. AF (including paroxysmal, persistent or permanent AF, or atrial flutter), confirmed by any of:
a. 12-lead ECG recording
b. Inpatient ECG telemetry
c. Other prolonged ECG monitoring technique (e.g. Holter monitor)

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 28 of 75



     

OPTIMAS

d. Documentation of existing diagnosis of AF in medical records (e.g. primary care records, letter
from secondary care)
4. Eligibility to commence DOAC in accordance with approved prescribing recommendations and
SmPC confirmed by treating physician
5. Uncertainty on the part of the treating physician regarding early versus standard initiation of
DOAC

Participant Exclusion Criteria

1. Contraindication to anticoagulation:
a. Known coagulopathy or current or recent anticoagulation with vitamin K antagonist (VKA)
leading to INR ≥1.7 at randomisation.
b. Thrombocytopenia platelets < 75 x 109/L
c. Other coagulopathy or bleeding tendency (based on clinical history or laboratory parameters)
judged to contraindicate anticoagulation by treating clinician
2. Contraindication to early initiation of anticoagulation:
a. Known presence of haemorrhagic transformation with parenchymal haematoma occupying
>30% of infarct volume and exerting significant mass effect (i.e. ECASS-2 classification PH2)
(NB: HI1, HI2 and PH1 are not considered contraindications)
b. Presence of clinically significant intracranial haemorrhage unrelated to qualifying infarct
c. Any other contraindication to early anticoagulation as judged by treating clinician
3. Contraindication to use of DOAC:
a. Known allergy or intolerance to both factor Xa inhibitor and direct thrombin inhibitor
b. Definite indication for VKA treatment e.g. mechanical heart valve, valvular AF (determined by
the local investigator, but usually defined as moderate to severe mitral valve disease, a
prosthetic valve, or both), antiphospholipid syndrome.
c. Severe renal impairment creatinine clearance (Cockcroft & Gault formula) <15 mL/min (i.e. 14
mL/min or less)
d. Liver function tests ALT > 2 x ULN
e. Cirrhotic patients with Child Pugh score equating to grade B or C
f. Patient taking medication with significant interaction with DOAC, including:
• Azole antifungals (e.g. ketoconazole, itraconazole)
• HIV protease inhibitors (e.g. ritonavir)
• Strong CYP3A4 inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital or St.
John's Wort)
• Dronedarone
4. Pregnant or breastfeeding women
5. Presence on acute brain imaging of non-stroke pathology judged likely to explain clinical
presentation (e.g. mass lesion, encephalitis)
6. Inability for patient to be followed up for 90 days after trial entry
7. Patient or designated representative(s) (according to relevant legislation for each nation) refusal
to consent to study procedures, including the site informing GP and healthcare professional
responsible for anticoagulation care of participants
8. Any other reason that the PI considers would make the patient unsuitable to enter OPTIMAS.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 29 of 75



     

OPTIMAS

Co-enrolment guidance
Participants will not be excluded from this trial by previous participation in the trial, as long as they
have completed the 90-day follow-up. This will be confirmed with the patient or their legal
representative at the time of consent. Co-enrolment should be discussed with the OPTIMAS team.
Co-enrolment in observational studies will usually be accepted but co-enrolment in any other trial
including an intervention which could affect the primary outcome at 90 days requires the permission
of both the OPTIMAS Chief Investigator and the Chief Investigator of the other trial.

Screening procedures and pre-randomisation investigations

Obtaining consent
Informed consent must be obtained and documented for a patient and eligibility confirmed to be
randomised into the trial. In most cases, this will be written informed consent provided by the patient.
However, in some cases, due to the effects of acute stroke, the patient may lack capacity to provide
consent, or possess capacity to consent but be physically unable to provide written consent. Provisions
for these patients are discussed below.

As the intervention arm of the trial is early DOAC treatment, eligible patients will be approached as
soon as this is deemed appropriate by the treating clinical team. Patients should be approached in
sufficient time to allow randomisation and implementation of early DOAC treatment if allocated to
the intervention group. Ideally, this should be within 72hrs of stroke onset.

If the time of stroke onset is not known, it should be estimated clinically if at all possible, using all
available evidence. If insufficient evidence is available to do this, the onset time should be taken as
the time the patient was first found to have stroke symptoms, so long as this is not more than 24hrs
after the time the patient was last known to be well. If this interval is more than 24 hours, the patient
is not eligible.

The patient will be given sufficient time to read and understand the Patient Information Sheet (PIS)
and the opportunity to inquire about details of the trial and to decide whether or not to participate in
the trial. All questions about the trial should be answered to the satisfaction of the patient. Due to the
time-sensitive nature of intervention, once the patient has decided to take part in the trial the
Informed Consent Form (ICF) should be completed, eligibility confirmed, and the patient randomised,
as soon as possible.

The study will be discussed with the patient in a way appropriate to their level of understanding, using
an appropriate PIS (full or short). The discussion will include an assessment of the patient’s capacity
by a suitably experienced and qualified research team member in accordance with the law of the
relevant part of the UK. If the patient possesses capacity and wishes to participate in the study, they
will be asked to complete the corresponding consent form. Once the consent form is signed, eligibility
confirmed, the patient will be randomly allocated to one of the study arms.

During the consent process, it will be made completely and unambiguously clear that the patient is
free to decline to participate in any or all aspects of the trial, at any time, and for any reason, without
incurring any penalty or affecting the patient’s treatment.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 30 of 75



     

OPTIMAS

If a patient has capacity and is willing to provide verbal consent, but is physically unable to sign the
consent form, a witness independent of the trial team will be identified and asked to sign the witness
signature field in the consent form, to attest to the patient’s verbal consent to participate.

The full PIS will be provided to all patients in the first instance however a short PIS will be offered if
they have capacity but struggle to understand complex and long-form information or request a
focussed summary of the key points regarding the trial. An Easy Access PIS which uses pictures to aid
understanding will be given together with the short PIS to patients with aphasia or otherwise struggle
with verbal or written language.

The ICF corresponding to the version of the PIS (short or full) provided to the patient will be signed.

Because of Covid-19, there may be restrictions put in place to protect the safety of the participant and
members of the public in visiting the hospital. For OPTIMAS, there may be rare occasions where an
eligible participant is identified after they have been discharged from the acute hospital and therefore
the research team is unable to approach them to obtain written consent. If this is the case, the site’s
research team can obtain verbal consent over the telephone from the participant, which must be
documented on the relevant OPTIMAS Telephone Consent record (participants with capacity). When
sites are phoning the participant, the research staff will explain over the phone what the study involves
if the participant is recruited. A witness (ideally independently from the trial team) will join the
research staff and listen to this telephone call to ensure the verbal consent obtained is valid. This
witness will also need to sign the OPTIMAS Telephone Consent record. Once this verbal consent is
obtained, the participant can proceed with trial-related activities. The PIS and relevant consent form
can subsequently be emailed or posted to the participant, where they will post back a partially signed
wet-inked copy back to the research team. Sites will then countersign, make a photocopy and post
back the photocopy to the participant. Please note: Sites do not have to wait till a signed consent form
is posted back to start trial-related activities. Once verbal consent is obtained, the trial-related
activities can start.

If a patient lacks capacity to consent to participation in the trial, their participation may still be sought.
The inclusion of patients who lack capacity in OPTIMAS will increase the scientific validity and
generalisability of the study, by avoiding bias associated with excluding more severely affected,
aphasic or cognitively impaired patients, maximising its potential benefit to stroke patients in the
future. As only patients in whom there is uncertainty regarding the timing of anticoagulation will be
included, patients lacking capacity will not be exposed to excessive risk in taking part.

The consent process for patients who lack capacity will be aligned with relevant legislation: for England
and Wales the Mental Capacity Act (MCA) 2005 [30]; for Scotland the Adults with Incapacity Act (AWIS)
2000 [31]; for Northern Ireland, the Common Law principle of best interest [32]; and the Declaration
of Helsinki [33] (see Table 1). It is the local recruiting clinical trial research team’s responsibility to
ensure compliance with these requirements. Only research team members with suitable experience
and training will take consent for such patients, and their experience and qualification to do this will
be recorded in the OPTIMAS delegation log.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 31 of 75



     

OPTIMAS

A patient will only be concluded to lack capacity once all practicable adjustments to help them decide
have been taken without success, in accordance with the MCA 2005, AWIS 2000 or other applicable
legislation.

In the case of a patient lacking capacity, an appropriate representative (as described in Table 1) will
be identified. Firstly, a personal legal representative should be approached. This is a person who can
be asked to give consent (Scotland only) or give advice on whether an adult lacking capacity would
wish to participate in a clinical trial, in accordance with their presumed wishes. This will be a
guardian/welfare attorney, or nearest relative if there is no guardian/welfare attorney. This person is
independent of the trial and knows the participant sufficiently to advise on their presumed wishes;
Table 1 describes the types of representatives and their roles in the UK [34]. Please note that the
arrangements for patients lacking capacity in Northern Ireland differ from those for patients in the
other UK nations as close relatives/close friends cannot give advice or consent; only the multi-
disciplinary team (MDT) involved in the direct care of the patient can make the decision for or against
trial participation in the individual best interests of the patient following discussion with a close
relative or close friend if available [35].

Because of Covid-19, there may be restrictions put in place to protect the members of the public in
visiting the hospital. Where this is the case, an appropriate representative (as described in Table 1)
may be unable to enter the hospital and therefore not available to obtain written consent. During this
pandemic, sites instead can obtain verbal consent over the telephone from the appropriate
representative, which must be documented on the relevant OPTIMAS Telephone Consent record
(participants who lack capacity). When sites are phoning the appropriate representative, the research
staff will explain over the phone what the study involves if the patient is recruited. A witness (ideally
independently from the trial team) will join the research staff and listen to this telephone call to ensure
the verbal consent obtained is valid. This witness will also need to sign the OPTIMAS Telephone
Consent record. Once this verbal consent is obtained, the participant can proceed with trial-related
activities. The PIS and relevant consent or declaration form can subsequently be emailed or posted to
the representative, where they will post back a partially signed wet-ink copy back to the research
team. Sites will then countersign, make a photocopy and post back the photocopy to the
representative. Please note: Sites do not have to wait till a signed consent/declaration form is posted
back to start trial-related activities. Once verbal consent is obtained, the trial-related activities can
start. It must be clearly explained to a potential representative that taking this role is entirely
voluntary. In addition to being asked to consider what the patient would want, and to set aside their
personal views when making the decision, they must be informed about the following, in accordance
with the HRA guidance [36]:

In England and Wales:

- They are being asked to advise on the views and feelings they believe the patient would have
towards participation in the trial.
- They are free to decide whether they wish to provide this advice or not.

In Scotland:
- They are being asked to give consent on behalf of the incapacitated adult.
- They are free to decide whether they wish to make this decision or not.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 32 of 75



     

OPTIMAS

In Northern Ireland:
- The close relative or close friend may be approached and their views sought but the final decision
in the individual best interest of the patient must be made by the MDT in charge of the holistic
care of the patient. It is up to the MDT to determine if any potential individual benefit to the
patient outweighs any risk of being involved in the trial.

Table 1: Representatives for patients lacking capacity

Country Who should be asked Their role What is

provided by the
representative?
England and Consultee: Can be asked to advise Advice to the
Wales • A personal consultee involved the researcher on what researcher.
in the person's care, interested the participant’s wishes
in their welfare and must be and feelings would be The researcher
willing to help. They must not makes the
if they were able to
be a professional or paid care decision on
worker. They will probably be a consent for whether or not
family member, but could be themselves, and on the patient will
another person. whether they should participate
• A nominated (professional) take part. The based on this
consultee may be consulted if consultee does not give advice.
no personal consultee can be consent in law.
identified; they are
independent of the trial.
Scotland Personal Legal representative: Can be asked to give Informed
• Welfare Guardian, or consent on behalf of an consent.
• Welfare Attorney. adult who lacks the
• If there are no capacity to do so
guardian/welfare attorney, themselves.
then Nearest relative
Northern Ireland Multi-disciplinary team (MDT) Will be asked to Unanimous
(prior to MCA comprising all professionals consider the individual decision that
2016 normally involved in clinical best interests of the participation is
in the individual
implementation) decisions or holistic care of the adult who lacks
patient’s best
patient; depending on the capacity to do so interests.
patient’s needs this may include: themselves. They will
• Consultant make a unanimous and
• Nurse clearly recorded
• Pharmacist decision in the
• Allied health professional patient’s individual
• Social worker. best interest for
NB: A close relative or close inclusion into the
friend of the patient can inform study. This decision
the MDT of the patient’s likely needs to be
views but cannot provide consent

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 33 of 75



     

OPTIMAS

Country Who should be asked Their role What is

provided by the
representative?
on behalf of the patient, the final documented in the
decision in the individual best medical record
interests of the patient lies with
the MDT in charge of the holistic
care of the patient

The representative must be given sufficient information, in an understandable form, about their role
to enable them to make an informed decision. The representative will receive the same information
about the study that a patient with capacity would receive (i.e. full PIS) and have the opportunity to
discuss this with the study team. Where possible, the representative will be encouraged to
communicate with the patient to ascertain their wishes and feelings. If the potential representative is
willing to take on the role and concludes that the patient without capacity would have wished to take
part in the study, they will be asked to sign an appropriate form to record the advice or consent to
take part in the study has been given on his or her behalf (refer to Appendix 1: Trial documentation
for when patients lack capacity). If consent is provided, this remains valid in law unless the patient
recovers capacity. If consent is not provided, this must be respected. If the patient objects to any of
the interventions or part of the trial or has made advance decisions or statements contrary to trial
participation, even though agreement is given by their representative, they must not be enrolled into
the trial.

Following provision of advice or consent, the representative should remain involved in the patient’s
participation in the study. They should be aware that the participant can be withdrawn from the trial
if at any time the representative is of the opinion that the participant would not have wished to
continue. Also, the participant will be withdrawn if they indicate that they no longer wish to take part
in the trial. If this occurs in Scotland, the participant will be withdrawn from the study. Outside of
Scotland, the participant will be withdrawn unless the researcher has reasonable grounds to think that
withdrawal of treatment will cause a significant risk to the participant’s health. Samples and data
already collected will be retained.

If a participant recovers capacity, they will be informed about the trial and asked to decide whether
or not they want to continue in the trial. The Recovered Capacity cover letter and the appropriate
format of the Patient Information Sheet will be provided, and they will be offered the opportunity to
discuss any questions or concerns they may have with the research team. If the participant wishes to
continue in the study the participant will sign the Informed Consent Form. A Reconsent CRF will also
need to be completed. If they wish to withdraw, this must be respected. Data already collected will
be retained.

Because of Covid-19, if a patient regains capacity and is not required to routinely come back into the
hospital, to minimise unnecessary travel, reconsent can be obtained over the phone from the
participant, in which case the relevant OPTIMAS Telephone consent record (participant with capacity)
must be completed. When sites are phoning the participant, the research staff will explain over the

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 34 of 75



     

OPTIMAS

phone what the study involves if the participant is recruited. A witness (ideally independently from
the trial team) will join the research staff and listen to this telephone call to ensure the verbal consent
obtained is valid. This witness will also need to sign the OPTIMAS Telephone Consent record. Once
verbal consent is obtained, the participant can continue with trial related activities. The PIS and
relevant consent form must be posted or emailed to the participant where they will post back a
partially signed wet-ink copy back to the research team. Sites should then countersign, make a
photocopy and post back the photocopy to the participant.

If a participant loses capacity having previously provided informed consent, their consent becomes
invalid. Agreement to remain in the study must be sought from the participant’s representative
according to the procedures (including procedures during Covid-19) described above for patients
lacking capacity. A patient who, while having capacity, previously declined to participate in the trial,
but subsequently loses their capacity, will not be reconsidered for inclusion in the trial.

For all participants, consent will be re-sought if new information becomes available that affects the
participant’s consent in any way. This will be documented in a revision to the appropriate format of
the Patient Information Sheet and the participant will be asked to sign an updated corresponding
consent form. These will be approved by the REC prior to their use. A copy of the approved consent
form is available from the OPTIMAS trial team.

Please see the study consent process flowchart below (Figure 2).

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 35 of 75



     

OPTIMAS

Figure 2: Process of informed consent2

*only applicable when the participant regains capacity during the trial

Screening Procedures
Written informed consent must be obtained BEFORE any trial-specific procedures are performed or
any samples are taken for the trial. (Please see Section 5.3.2.1 for obtaining consent processes during
Covid-19). The only procedures that may be performed in advance of written informed consent being

2
In patients lacking capacity, seek informed consent by legal representative (Scotland) or seek consultee advice
(England, Wales) or decision in individual best interest from MDT in Northern Ireland (Common Law).

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 36 of 75



     

OPTIMAS

obtained are those that would be performed on all patients in the same situation as usual standard of
care.

Interventions and assessments prior to randomisation:

- 12-lead ECG
- Blood tests: creatinine, ALT, platelets, INR
- Blood pressure
- Weight
- Estimated pre-stroke modified Rankin Score (mRS)
- National Institute of Health Stroke Scale (NIHSS)
- Urine pregnancy test (βhCG) (women of child-bearing potential only)
- Cognitive Patient Questionnaire (IQCODE)
- Quality of Life questionnaire (EQ-5D-5L).

If the participant is considered obese (BMI >30) or morbidly obese (BMI >40), then the estimated or
reported height should be obtained to allow creatinine clearance calculation using the Cockcroft Gault
formula (calculator available at http://www.baspath.co.uk/calculations/creatinine_clearance.htm).

5.4 Interventions
After eligibility has been confirmed, participants satisfying the inclusion/exclusion criteria will be
randomised using a secure online randomisation system (refer to section 5.6.1). Patients will be
randomised in a 1:1 ratio to intervention or control arms of the study. Participants and their physicians
will not be blinded to study arm allocation.

The intervention is early initiation of a licensed dose of any DOAC (currently, dabigatran, apixaban,
rivaroxaban and edoxaban), within four days (96hrs) or less after acute ischaemic stroke.

The control is initiation of a DOAC no earlier than day 7 and no later than day 14 after stroke onset
(note that days are defined here as 24hr periods, rather than calendar days – i.e. day 7 begins 144hrs
after stroke onset and day 14 ends 336hrs after stroke onset). This reflects current standard, guideline-
based practice in the United Kingdom. Our standard treatment arm is also in line with current ESC
guidelines for moderately severe stroke (NIHSS 8-15) [17].

The exact timing of anticoagulation within the period specified for the allocated study arm is at the
discretion of the treating physician, as is the choice of DOAC. Apart from the timing of DOAC initiation,
the DOAC should be prescribed in accordance with usual clinical practice and the relevant SmPC.

The DOAC will be supplied from normal hospital stock, using local hospital prescriptions.

If, following DOAC prescription, any safety concerns arise regarding continuation of treatment, the
treating clinician should take appropriate action in accordance with usual clinical practice. Any
resulting medical decisions should be documented in the participant’s medical notes and relevant
CRFs.

The clinical responsibility for DOAC treatment remains with the PI and treating team, which will be
recorded in the Delegation Log.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 37 of 75



     

OPTIMAS

The OPTIMAS trial team can request details regarding pharmacy procedures and review the process if
any concern arises.

Products
Any of the DOACs listed below may be used for treatment in either study arm. A standard dosage
should be used unless the participant satisfies the criteria in the relevant SmPC for a reduced dosage,
in which case the reduced dosage should be used.

1. Dabigatran; standard dosage 150mg BD, reduced dosage (if indicated) 110mg BD.
2. Apixaban; standard dosage 5mg BD, reduced dosage (if indicated) 2.5mg BD.
3. Edoxaban; standard dosage 60mg OD, reduced dosage (if indicated) 30mg OD.
4. Rivaroxaban; standard dosage 20mg OD, reduced dosage (if indicated) 15mg OD.

Treatment Schedule
Following randomisation to a study arm, the exact timing and dosage of DOAC will be determined by
the treating clinician, who, together with his or her clinical team, will ensure the DOAC is prescribed
and administered at a clinically appropriate time point within the designated interval for the allocated
study arm. Neither the prescribing nor administering clinician needs to be a member of the study team
or named on the study delegation log, but the PI for a study site should ensure that prior to site
activation there is agreement amongst local senior medical staff to support the implementation of the
study and respect treatment group allocation unless a clinical reason not to do so arises.

Once treatment is initiated, this will continue at the hospital site until the participant is discharged.
After discharge, DOAC treatment management should be continued by the new treating team (for
example, GP, local anticoagulant clinic, or rehabilitation ward staff) unless, in their judgement, a
contraindication arises.

The DOAC selected, dosage, date and time of starting will be recorded in the participant’s medical
notes and the relevant CRFs.

In the event that administration of the first DOAC dose is delayed such that it is given at >4 days (96hrs)
after stroke onset in the intervention arm, or before day 7 (<144hrs) or after day 14 (>336hrs) in the
control arm, the participant’s data will be included in the analysis according to the intention-to–treat
principle. The incident will be logged as a major protocol deviation and the reason should be clearly
explained in the participant medical notes and CRFs.

Dispensing
Medication will be prescribed by the local treating team, who need not be named on the trial
delegation log, and dispensed by the local hospital pharmacy according to established local practice.
Handling and management will be subject to the standard procedures of the pharmacy and staff will
be appropriately trained. No trial-specific clinical trial labelling is required. Labels for dispensing will
comply with the site’s routine procedures for dispensing medication. The pharmacy team should
ensure adequate hospital stocks for enrolled participants. In the unlikely event of temperature
excursion or recall of any medications used in OPTIMAS, the site should follow the standard
procedures of the local pharmacy and inform the OPTIMAS team (for more details, refer to the
Pharmacy Management plan).

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 38 of 75



     

OPTIMAS

Dose Modifications and Interruptions

Any dose interruptions or modifications made should be in accordance with individual SmPCs, and
recorded with reasons, in the participant medical notes and CRFs.

Accountability
There will not be any study specific accountability logs. All DOACs used in this trial will be supplied
from normal hospital stock and from community pharmacies thereafter, where dispensing records will
be kept as per normal practice, including the name of DOAC, number of tablets dispensed, batch
number and expiry date (if applicable). For more details refer to the Pharmacy Management Plan.

Any unused DOAC will be disposed of as per local standard procedures.

Compliance and Adherence to the allocated treatment

Non-compliance with study treatment during the hospital stay, regardless of study arm, is not
expected as the DOAC will be administered by stroke unit nurses and recorded in medication charts.

Once the participant is discharged, monitoring of adherence will rely on self-reporting by the
participant to their GP or other local treating clinician where DOAC adherence will be supervised as in
routine clinical practice. At their 90-day follow-up visit, the participant will be asked to confirm
whether treatment has been continuous and ongoing, and whether any dose modifications or
interruptions occurred since discharge and this will be recorded on the study CRF.
To increase the likelihood of participants’ compliance the following steps will be taken:

• The randomising clinician will be encouraged to emphasise the importance of adhering to the
allocated DOAC policy
• A letter will be sent to the participant’s GP shortly after enrolment to inform them the participant
has been enrolled in OPTIMAS and is taking a DOAC. This will allow the GP to support medication
adherence as required, following discharge from the hospital.

Concomitant Care
Treatment of any other conditions, should be given as per standard care. Any medications should be
recorded in the Medication Log CRF on a regular basis to ensure all information is up to date.

Overdose of Trial Medication

It is not expected that overdose of the trial medication will occur while the participant is in hospital,
as medication will be administered and monitored by the treating clinical team.
At discharge, the participant should be advised on how to continue taking the trial medication and
instructed to seek immediate medical treatment if they have taken an overdose of DOAC.

Protocol Treatment Discontinuation

In consenting to the trial, participants are consenting to trial treatments, trial follow-up and data
collection. However, an individual participant may stop treatment early or be stopped early for any of
the following reasons:

• Unacceptable treatment toxicity or adverse event, as defined in 5.13.3.1 (Safety Reporting)

• Inter-current illness that prevents further treatment.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 39 of 75



     

OPTIMAS

Treatment MUST be discontinued (and the reason(s) documented in the medical notes and relevant
CRF) in the event of the following:
• Any change in the participant’s condition that in the clinician’s opinion justifies the
discontinuation of treatment
• Withdrawal of consent for treatment by the participant
• Pregnancy (section 5.13.3.4).

As participation in the trial is entirely voluntary, the participant may choose to discontinue trial
treatment at any time without penalty or loss of benefits to which they would otherwise be entitled.
Although not obliged to give a reason for discontinuing their trial treatment, a reasonable effort
should be made to establish this reason, whilst remaining fully respectful of the participant’s rights.

Participants who discontinue protocol treatment, for any of the above reasons, should remain in the
trial for the purpose of follow up and data analysis, unless they explicitly refuse to continue to provide
data. Any data collected up until the time of withdrawal will be retained and may be used for the
purpose of data analysis.

5.5 Outcomes
Sites must make every effort to ensure that all outcome data (for primary and secondary outcomes)
are collected by an assessor who is not aware of treatment allocation. All outcomes will be collected
at 90-day follow-up.

Primary Outcome
The primary outcome is a composite of the combined incidence of stroke of any causes (i.e. recurrent
ischaemic stroke, symptomatic intracranial haemorrhage (including haemorrhagic transformation of
the infarct), and strokes that cannot be classified as ischaemic or haemorrhagic due to insufficient
data, and systemic arterial embolism at 90 days of randomisation. All stroke and systemic arterial
embolism outcomes will be verified by an adjudication committee (blinded to the treatment
allocation; see section 5.5.3.1) convened by the OPTIMAS Trial Management Group with reference to
outcome event CRFs and supporting brain imaging. Sites may be requested to provide additional
anonymised information if required.

Secondary Outcomes
Efficacy outcomes:
1. All-cause mortality
2. Incidence of vascular death
3. Incidence of recurrent ischaemic stroke
4. Incidence of systemic arterial embolism
5. Incidence of venous thromboembolism (deep vein thrombosis [DVT], pulmonary embolism [PE],
cerebral venous thrombosis [CVT])
6. Functional status (assessed by the mRS scale)
7. Cognitive ability (assessed by the MoCA questionnaire)
8. Quality of life at 90 days (assessed by EQ-5D 5 level [EQ-5D-5L])
9. Patient reported outcomes (assessed by the PROMIS-10)

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 40 of 75



     

OPTIMAS

10. Ongoing anticoagulation

11. Time to event for overall survival
12. Time to first incidence of composite primary outcome (recurrent ischaemic stroke, systemic
arterial embolism, sICH or unclassifiable stroke syndromes) plus overall survival
13. Time to first incidence of the composite primary outcome (recurrent ischaemic stroke, systemic
arterial embolism, sICH or unclassifiable stroke syndromes)
14. Time to first incidence of composite of the ischaemic components of the primary outcome
(ischaemic stroke and systemic embolism)
15. Time to first incidence of sICH
16. Time to first incidence of ischaemic stroke
17. Time to first incidence of systemic arterial embolism
18. Length of hospital stay for stroke-related care
19. Health and social care resources (assessed by a study-specific questionnaire; HSCR).

Safety outcomes:
20. Incidence of sICH, classified according to site: intracerebral haemorrhage (within the brain
parenchyma); subdural haemorrhage; extradural haemorrhage; subarachnoid haemorrhage; and
haemorrhagic transformation of the acute brain infarct.
21. Incidence of major extracranial bleeding
22. Incidence of all major bleeding (intracranial and extracranial)
23. Incidence of clinically relevant non-major bleeding

Other secondary outcomes:

24. Ongoing anticoagulation at 90 days

Exploratory outcomes:
25. Individual cognitive domain sub-scores (measured using the MoCA questionnaire).

Outcome measures

Event Adjudication Committee

Two groups will be convened to review reported outcome events: an Internal Event Validation
Committee (EVC) and an Independent Event Adjudication Committee (EAC).

The EVC will be made up of clinicians from the OPTIMAS TMG, who will perform an initial review of all
primary outcome event reports as they are reported, including associated imaging data when relevant,
to ensure that the outcome event data provided is complete and of sufficient quality to allow event
adjudication, and to allow further information to be requested from sites if needed. The EVC will also
periodically meet to adjudicate trial secondary outcome events. It will be blinded to treatment
allocation in all its activities.

The EAC will comprise independent experts with relevant therapeutic area expertise and clinical trial
experience, who have been trained on the study protocol including specific details of primary outcome
events. The EAC will meet periodically to review all primary outcome event reports, and supporting
imaging when relevant, blinded to treatment allocation.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 41 of 75



     

OPTIMAS

The membership of the EVC and EAC, including the requirements for committee membership,
frequency of meetings, activities (including trial data review) and authority will be described in the
Terms of Reference.

Definition of outcome events

For the purposes of event adjudication, the definitions of the outcome events are as follows:
• Recurrent ischaemic stroke: a neurological deficit of acute onset, lasting at least 24hrs, judged by
the treating clinician to have no other likely cause than cerebral infarction, with or without
radiological or pathological supporting evidence, but unrelated to any persistent or delayed
effects of the qualifying stroke.
• Symptomatic intracranial haemorrhage (sICH): a focal neurological deficit, headache, seizure, or
change in level of consciousness, judged by the treating clinician to be due to (and, where
applicable, anatomically referable to) the presence of extravascular blood, demonstrated
radiologically or pathologically, within the cranial vault (skull). sICH may be classified by aetiology,
distribution and extension as follows:
o Aetiology:
▪ Spontaneous: arising unrelated to preceding trauma or infarction
▪ Haemorrhagic transformation (HT): bleeding arising from previously infarcted brain
tissue
▪ Traumatic: arising following, and judged causally-related to, trauma
o Distribution:
▪ Extradural: bleeding originates between dura mater and overlying skull
▪ Subdural: bleeding originates between arachnoid and dura mater
▪ Subarachnoid: bleeding originates between pia and arachnoid mater
▪ Intracerebral: bleeding originates within brain parenchyma
▪ Intraventricular: bleeding originates from within the ventricles (usually from the choroid
plexus)
o Extension:
▪ Intraventricular: bleeding originates from outside of the ventricles but extends into them
▪ Subarachnoid: bleeding originates from outside of the subarachnoid space, but extends
into it
o Note that haemorrhagic transformation by definition arises from within infarcted brain
parenchyma i.e. is classified as intracerebral haemorrhage. It is also classified radiologically as
haemorrhagic infarction (HI) or parenchymal haemorrhage (PH), each with two grades of
severity (ECASS-2 classification [37]):
▪ HI1: scattered small petechiae, no mass effect
▪ HI2: confluent petechiae, no mass effect
▪ PH1: haematoma within infarcted tissue, occupying <30% infarct zone, no significant
mass effect
▪ PH2: haematoma occupying 30% or more of the infarcted tissue, with obvious mass effect
• Unclassifiable stroke: This is defined as a clinical event reported by a site as either a recurrent
ischaemic stroke or symptomatic intracranial haemorrhage which, in the opinion of the study
Event Adjudication Committee, could be explained by either event type but cannot be classified

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 42 of 75



     

OPTIMAS

as one or the other with confidence. Typically, this will be when no brain imaging has been
performed.
• Systemic arterial embolism
o Clinical findings (symptoms, signs or laboratory investigations) consistent with acute loss of
blood flow to a peripheral artery (i.e. those other than the arteries supplying the brain or
heart), accompanied by evidence of embolism from vascular imaging, angiography, surgical
specimens or autopsy.
• Deep vein thrombosis
o Clinical symptoms or signs consistent with deep vein thrombosis (swelling, oedema, erythema,
pain, superficial venous distension) with corresponding evidence of thrombosis within
relevant deep vein of limb (most commonly lower limb, but may also occur in upper limbs) on
ultrasonography/other vascular imaging or examination of pathological specimen following
surgery or autopsy.
• Pulmonary embolism
o Clinical symptoms or signs consistent with PE (breathlessness, chest pain, tachycardia,
hypoxia, hypotension) with evidence of thromboembolism to pulmonary arterial supply,
confirmed by vascular imaging (CTPA), nuclear medicine (V/Q), or pathological examination
following surgery or autopsy.
• Cerebral venous thrombosis
o Clinical symptoms or signs consistent with cerebral venous sinus thrombosis (headache,
seizure, focal neurological deficit or change in level of consciousness), with evidence of
thrombosis within cerebral veins or venous sinuses demonstrated on imaging or at autopsy.
• Vascular death
o Death resulting from myocardial infarction, heart failure, cardiac arrhythmia, sudden cardiac
death (including sudden unexpected death for which no evidence of a non-vascular cause is
present), arterial dissection, ischaemic stroke, non-traumatic intracranial haemorrhage, non-
traumatic extracranial haemorrhage, systemic arterial embolism, DVT, PE or cerebral venous
sinus thrombosis. The diagnosis of these conditions should be made with reference to the
above definitions where applicable, and to contemporary diagnostic criteria where not. The
evidence for the death being ‘vascular’ should be provided in the CRF. Death resulting from a
direct complication of one of these conditions or their accepted treatment is also regarded as
‘vascular’ if the chain of causation is made clear in the CRF.
• Major extracranial bleeding [38]
o Clinically overt bleeding originating outside the cranial vault (skull) associated with any of the
following:
▪ Fatal outcome, and/or
▪ Involvement of a critical anatomic site (spinal, ocular, pericardial, articular,
retroperitoneal, or intramuscular with compartment syndrome), and/or
▪ Fall in haemoglobin concentration of at least 20 g/L or transfusion of 2 or more units of
red blood cells.
• Clinically-relevant non-major bleeding [39]
o Overt bleeding not meeting the criteria for major bleeding but associated with:
▪ Medical intervention, and/or

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 43 of 75



     

OPTIMAS

▪ Unscheduled contact (visit or telephone) with a physician, and/or

▪ Interruption or discontinuation of study treatment, and/or
▪ Any other discomfort such as pain or impairment of activities of daily life.

Scales, assessments and questionnaires

The following scales and questionnaires will be used:

1. mRS: The Modified Rankin Scale measures the degree of disability and dependence following
a stroke. The scale consists of 7 category descriptions, where 0 means no symptoms and 6
means death. The assessment is carried out by asking the participant or their carer about their
activities of daily living [40-42].
2. NIHSS: The NIHSS is a standardised clinical method for assessing the severity of a stroke. The
severity of stroke is classified as: 0-4, 5-10, 11-15, 16-21, >21 [43-45].
3. IQCODE: The Informant Questionnaire for Cognitive Decline in the Elderly is a structured
interview based on informant responses that is used to assess for possible dementia. It is used
to screen for pre-stroke dementia, and will be used in OPTIMAS for this purpose [46]. It must
be used to estimate cognitive change up to the point immediately prior to the stroke, and
must not include cognitive change occurring after the stroke
4. MoCA: The Montreal Cognitive Assessment is a questionnaire widely used as a screening
assessment for detecting cognitive impairment. It assesses different cognitive domains:
attention and concentration, executive functions, memory, language, visuo-constructional
skills, conceptual thinking, calculations, and orientation. An abbreviated version of the MoCA
assessing attention, verbal learning, memory, executive functions/language and orientation
can be performed over the phone [47-48].
5. EQ-5D-5L: Quality of life will be assessed and recorded on the EuroQoL EQ-5D-5L
questionnaire. The EQ-5D 5-Level version comprises a descriptive system and the EQ visual
analogue scale (EQ VAS). The EQ-5D-5L descriptive system comprises the following 5
dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each
dimension has 5 levels: no problems, slight problems, moderate problems, severe problems,
and extreme problems. The EQ VAS records the respondent’s self-rated health on a vertical,
visual analogue scale where the endpoints are labelled ‘Best imaginable health state’ and
‘Worst imaginable health state’. Where possible, this will be completed by the participant. In
instances in which the participant struggles with giving answers on their own, the participant’s
next-of-kin or a friend who knows the participant well will be asked to complete the EQ-5D-
5L proxy version. The proxy is asked to rate how they think the participant would rate their
own health-related quality of life, if the participant were able to communicate it. In case a
proxy is not available, the research team member who is looking after the participant will
complete it on their behalf [49] to their best ability.
6. PROMIS Global-10 - The PROMIS Global-10 is an assessment tool that allows measurements
of symptoms, functioning, and healthcare-related quality of life (HRQoL) for a wide variety of
chronic diseases and conditions. The PROMIS Global-10 short form consists of 10 items that
assess general domains of health and functioning including overall physical health, mental
health, social health, pain, fatigue, and overall perceived quality of life [50].

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 44 of 75



     

OPTIMAS

7. Health and Social Care Resources (HSCR) – A study-specific questionnaire designed to capture
the community Health and Social Care Resources by participants at 90 days follow-up. It will
include questions about staying in a community hospital, rehabilitation center or nursing
home, including length of stay; use of the community NHS services including number of
visits/contacts; use of social services (e.g. Home Care worker, food at home service, social
worker), including the number of visits/contacts and out-of-pocket payments; adaptations at
home; and unpaid help from friends and relatives [51].

5.6 Participant timeline

Enrolment and Randomisation

Table 2 specifies the assessments and interventions that are required before enrolment. The eligibility
of the participant will be confirmed from screening data and clearly documented in participant
medical notes and the study CRF. Details of the participant’s medical history and current clinical
condition will be recorded in participant’s notes. After participant eligibility has been confirmed by
the PI or clinical delegate, enrolment can occur, and the participant will be randomly allocated to early
or standard timing of anticoagulation via the Sealed Envelope website. Randomisation should occur
in sufficient time to receive a DOAC within 96hrs of stroke onset if randomised to the intervention arm

On the day of randomisation, delegated staff at site will enter the participant’s initials, date of birth,
NHS number (which will be AES-256 encrypted), date of consent, eligibility criteria fulfilment, and site
details into the Sealed Envelope randomisation website, which will then allocate the randomised
treatment. The treatment allocation will not be concealed from the site staff as this is an open-label
trial. Usernames and passwords for Sealed Envelope will be provided to trained site staff during the
site activation procedure (refer to Randomisation Plan).

The randomisation confirmation (printed from the website or email confirmation) with the allocated
timing for administering a DOAC will be filed in participant medical notes, and the Investigator Site
File in the appropriate sections. The DOAC will be started as per participant’s allocated treatment arm.
(Refer to section 5.4.3, Dispensing).

Discharge from acute (or hyperacute) stroke unit

At discharge, patients will receive counselling on their anticoagulant in accordance with usual clinical
practice at the site, which may include being issued with an anticoagulant alert card if this is
established local practice. Patients should receive a copy of the manufacturer's patient information
leaflet and be made aware of the need to seek prompt medical attention in the event of new
neurological or bleeding symptoms. Any anticoagulation-related complication should be managed
according to applicable local and national guidelines. [52]

It is the treating clinician’s responsibility to ensure the participant/carer understands the potential
bleeding risks when taking DOAC and that they are aware what action they should take. In addition,
participants should be advised on what action to take if they miss a dose or take an overdose of the
DOAC. Counselling should be documented in line with usual clinical practice.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 45 of 75



     

OPTIMAS

Table 2: Trial schedule of interventions and assessments

Intervention/assessment Screening and Treatment period Discharge (from Follow-up
enrolment at acute stroke unit acute stroke unit)
ideally within
90 days from
72hrs and no
Time randomisation
later than 96 hrs
(+21 days)
of stroke onset
Obtain informed consent X
ECG (12-lead, plus copy taken of any other ECG
recording or medical record used to confirm AF X
diagnosis)
Blood tests (including creatinine, ALT,
X
platelets, INR)
Blood Pressure X
Weight X
Estimated pre-stroke Modified Rankin score
X
(mRS)
Current Modified Rankin score (mRS) X
National Institute of Health Stroke Scale
X
(NIHSS)
Urine pregnancy test (βhCG) (women of child
X
bearing potential only3)
Cognitive Patient Questionnaire (IQCODE) X
Quality of Life questionnaire (EQ-5D-5L)4 X X
Concomitant medications X X X
CRF completion X X X
Confirmation of eligibility X
Randomisation via Sealed Envelope website5 X
First Administration of DOAC X
Assessment of response to DOAC treatment X X X
and need for additional/altered treatment6
Assessment of serious adverse events (SAEs) X X X
Reminder card given to participant X
Cognitive Patient Questionnaire (MoCA) X
Patient reported outcomes questionnaire
X
(PROMIS-10)
Health and Social Care Resources
X
questionnaire (HSCR)

3 Women of child-bearing potential excludes women who are postmenopausal or permanently sterilised (e.g. tubal occlusion,

hysterectomy, bilateral salpingectomy).

4 If patient cannot self-complete the questionnaire, a proxy (carer, close family or friend) can complete the Proxy 2 version

of the EQ-5D-5L.
5 Randomisation should occur in sufficient time to receive a DOAC within 96hrs of stroke onset if randomised to the

intervention arm.
6 If there are any changes to the medication, a medication log CRF should be completed.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 46 of 75



     

OPTIMAS

Study follow-up
Participants will be followed up for 90 days from randomisation. The follow-up visit must be conducted
by a blinded assessor who is unaware of the treatment allocation at the time of the follow-up visit,
and, unless unavoidable, has not previously been involved with the research participant, especially at
the time of randomisation. To allow for scheduling logistics and participant availability, the follow-up
may be conducted up to 21 days after 90 days, but data should be collected with reference to 90 days
from randomisation – that is, any events occurring after 90 days but before the follow-up appointment
should be discounted. Ideally, the date of follow-up should be arranged and a follow-up reminder
card, with research team contact details, given prior to discharge.

Follow-up should occur face-to-face, and should be arranged by the local research team, making every
effort to contact the participant, their carer, or next-of-kin. If face-to-face follow-up cannot occur, a
telephone consultation is acceptable (e.g. during a pandemic or if the patient is unable to travel).In
this case, telephone-MoCA (i.e. the MOCA with visuospatial and picture naming components omitted)
should replace the usual MoCA. Any outcome scales which can be performed over the phone should
be, and any remaining scales sent by post.

If the 90-day follow-up appointment is missed, the participant or their next of kin should be contacted
immediately by the local research team to arrange another. At least three attempts should be made
to do this.

In exceptional circumstances (e.g. during a pandemic) and with prior agreement if the site does not
have the capacity to collect the 90-day follow-up data (from either the participant or their
representative), the central study site (UCL Stroke Research Centre) can conduct the 90-day follow-up
on the site’s behalf.

If a patient cannot be followed up face-to-face despite at least three attempts, on separate occasions,
a follow-up questionnaire should be sent by the local research team to the patient’s GP (followed by
a telephone reminder if required). If not returned within 14 days, the patient’s GP should be
contacted, preferably by telephone, to follow this up. If the participant is alive and judged able to
undertake questionnaire follow-up, the participant will be sent a postal questionnaire (followed by a
telephone reminder if required); this can also be completed by a carer if the patient has difficulties
with language or capacity, or does not speak English. If not returned within 14 days, the participant
should be contacted, preferably by telephone, to follow this up.

The central study site (UCL Stroke Research Centre) should be informed of all patients for whom a GP
or participant questionnaire is sent, and updated when a reply is received.

To provide support with GP or participant follow-up, the central study site (UCL Stroke Research
Centre) will provide advice (including by telephone) on outcome events.

If, after all reasonable attempts to obtain follow-up data from the participant and their GP, no follow-
up data can be obtained, the reason for this should be logged in the follow-up CRF and the central
study site (UCL Stroke Research Centre) should be informed.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 47 of 75



     

OPTIMAS

If the follow-up information cannot be obtained by face-to-face visit, or by postal or telephone

questionnaires, the central study site (UCL Stroke Research Centre, including the Chief Investigator
and team) will make a final attempt to obtain missing follow up data for the primary and secondary
outcomes.

If a participant attends follow-up, but is unsure of any of the objective outcome measures (i.e. those
relating to events and current medication), their GP should be contacted by site staff to obtain or
verify this information, which may be via telephone or via submission of the study GP questionnaire,
as judged most appropriate by the local study team.

NHS Hospital Episode Statistics (HES; for England-based participants) and the equivalent in the other
three UK nations: Wales (Patient Episode Database for Wales); Scotland (Scottish Morbidity Record),
and Northern Ireland (Hospital Inpatient System), will be used where possible to obtain follow-up data
on all participants including those for whom follow-up data cannot be obtained in person or by
telephone / postal questionnaires. Information on outcome events and hospital admissions will be
sought. Participants will provide consent to their GP being contacted and the use of their NHS hospital
records as part of the study consent procedures at enrolment.

Withdrawal
If a participant discontinues trial treatment or wishes to be withdrawn, they should be encouraged
and facilitated to continue follow-up for 90 days as close as possible to the follow-up schedule defined
in the protocol, even though they are no longer receiving the trial treatment. If, however, the
participant no longer consents to be followed up, this must be respected, and the participant should
be withdrawn from follow-up. The CCTU should be informed of the withdrawal in writing using the
appropriate OPTIMAS CRF. Data already collected will be kept and included in analyses according to
the intention-to-treat principle for all participants.

Participants who stop trial follow-up early will not be replaced. Any participants who drop out of the
trial will continue to be treated in accordance with usual clinical practice.

Participant transfers
If a participant moves from the area making continued follow up at their consenting centre
inappropriate, every effort should be made for them to be followed at another participating trial
centre. Written consent should be taken at the new centre and then a copy of the participant’s CRFs
should be provided to the new centre. Responsibility for the participant remains with the original
consenting centre until the new consent process is complete.

Loss to follow-up
Every effort will be made to obtain follow-up data on all participants. This may require tracing
participants via their NHS number using relevant NHS IT systems once approvals for access has been
granted. Additionally, we will apply for access to data held by NHS Digital and its equivalent in the
other UK nations; the datasets will include Hospital Episode Statistics (HES), Patient Episode Database
for Wales (PEDW); Scottish Morbidity Record (SMR), and Hospital Inpatient System (HIS). We will
assess the feasibility of using these data sources to collect data on subsequent stroke admissions and
other stroke-related acute care hospital use.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 48 of 75



     

OPTIMAS

The patient information sheet will include information that data will be collected using their NHS
number and participants will be asked to give their consent freely.

Participants will only be deemed “lost to follow-up” if all avenues outlined here and in section 5.6.6
have been exhausted.

5.7 Sample size

Our planned sample size is 3478 for the composite outcome of recurrent ischaemic stroke, systemic
arterial embolism symptomatic intracranial haemorrhage, or unclassifiable stroke within 90 days of
the index stroke. Power calculations are based on an expected reduction in the event rate of the
composite outcome from 11.5% in the control group to 8% in the intervention group (a percentage
reduction of 30%). Alongside a favourable safety profile, this would be a clinically meaningful benefit
likely to influence clinical guidelines and practice. The assumed overall composite event rate of 11.5%
in the control group and the hypothesised effect size are based on the Virtual International Stroke
Trials Archive (VISTA) of randomised trials in patients with acute stroke and AF [23]. Sample size
calculations used a power of 90%, significance level of 5% and were inflated by 10% for loss to follow-
up or other methodological challenges. Sample size calculations were performed with Stata 15 using
a continuity adjusted chi-squared and assuming a 1:1 randomisation ratio.

Using the non-inferiority gatekeeper approach requires the specification of a non-inferiority margin.
A non-inferiority margin of 3% for the proportion of those experiencing the primary outcome has been
identified as being clinically acceptable. If there is truly no difference between the control group and
the intervention group, an evaluable sample size of 3478 will have over 80% power to establish non-
inferiority (of the intervention), i.e. that the upper limit of a one-sided 97.5% confidence interval (or
equivalently a 95% two-sided confidence interval) will exclude a difference in favour of the standard
group of more than 3%. This would be equivalent to the upper bound of the confidence interval for
the odds ratio being below 1.32.

It is possible that these assumptions may need to be revised in the light of accruing data, in particular
the overall rate of primary events, and they will be reviewed by the IDMC during the recruitment
period, such that adjustments can be made if necessary.

5.8 Recruitment and retention

Recruitment
Process for identifying eligible participants: Potential participants will be screened for eligibility and
recruited by stroke-trained research staff. (The procedure for this has been discussed in section 5.3.2.
Screening procedures and pre-randomisation investigations). Recruitment will be monitored monthly
and staff at centres will be encouraged and supported to identify suitable patients. Recruitment rates
will be reported regularly over the course of the OPTIMAS recruiting period to the TMG, TSC and
British Heart Foundation (BHF). Any concerns regarding the rate of recruitment will be discussed as
soon as possible with the relevant trial committees and appropriate strategies will be implemented if
recruitment falls below an acceptable level.

Stop/amend/go decision: The trial will have two phases: the internal pilot phase will consist of the 12
months following randomisation of the first participant, after which a stop/amend/proceed decision

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 49 of 75



     

OPTIMAS

will be made before proceeding to the main phase of the trial if the decision is to amend/proceed. The
progression criteria for the end of the internal pilot phase are as follows:

(A) Recruitment rate

(1) If the predicted recruitment period is 44 months or less, proceed to main trial.

(2) If the predicted recruitment period is between 44 months and 56 months, consider and introduce
ways to reduce this, e.g.: (a) increase the number of centres; (b) address training needs at sites; and
(c) assess whether the eligibility criteria could be widened. Then proceed to main trial as amended.

(3) If the predicted recruitment period is more than 56 months, and no obvious solutions exist after
consideration by the Trial Steering Committee, discuss further options with the trial funder including
funding extension or extending the trial beyond the UK.

(B) Consent rate

(1) If consent rate in eligible participants is 50% or more, proceed to main trial.

(2) If consent rate is between 30% and 50% in eligible participants, consider information collected on
the reasons why eligible participants do not want to participate to identify any aspects amenable to
change. Then proceed to main trial as amended.

(3) If consent rate is less than 30% in eligible participants, consider information collected on the
reasons why eligible participants do not want to participate.

(C) Completeness of primary outcome data

(1) If primary outcome data are available for over 90% of randomised participants scheduled to have
completed 90-day follow-up, proceed to main trial.

(2) If primary outcome data are available for 70-90% of randomised participants, use the information
captured on reasons for missing data to identify whether any aspects are amenable to change;
proceed to main trial as amended.

(3) If primary outcome data are available for less than 70% of randomised participants and no obvious
solutions exist after consideration by the Trial Steering Committee, abandon the plan for the main
trial.

Retention
The importance of follow-up appointments will be explained to participants (and their next of kin) at
enrolment, so that participants fully understand the commitments required by OPTIMAS. The research
teams will be encouraged to contact participants in good time prior to 90 day follow–up visits to
encourage attendance and maximise engagement and retention. Participants will be given a reminder
card on discharge from hospital to increase the rate of follow up.

If participants do not attend for the 90-day follow-up visit or telephone consultation, a member of the
local trial team will contact them immediately to arrange a further appointment. To aid sites with
follow-up, the contact details of participants who do not attend a 90-day follow-up visit will be

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 50 of 75



     

OPTIMAS

provided to the central study site at the UCL Stroke Research Centre. The arrangements for follow-up
are detailed in section 5.6.3.

5.9 Assignment of intervention

Allocation
Participants will be randomised 1:1 to receive early or standard timing of starting DOAC treatment.

Sequence generation
An independent online randomisation service (www.sealedenvelope.com) will be used to minimise
allocation bias within the trial. Stratification by stroke severity (baseline NIHSS) comprising five strata
will be carried out using random permuted blocks with randomly varying block lengths to ensure that
balance across randomisation groups will be achieved. The strata cut-offs for NIHSS will be as follows:
0-4, 5-10, 11-15, 16-21, >21 [45].

Allocation concealment
The allocation will be concealed prior to assignment to prevent allocation bias. This will be facilitated
by the use of random block lengths. After allocation, allocation concealment (blinding) at site is not
possible as the treatment being allocated is the timing of first DOAC dose. However, sites must make
every effort to ensure that the 90-day follow-up visit is conducted by an assessor blinded to treatment
allocation. The committee adjudicating outcome events will remain blinded.

Allocation implementation
The responsibility for enrolling participants and randomising them into study arms lies with the PI and
other trained clinicians (including research practitioners) named on the delegation log. Once a
participant has been allocated to a study arm, the prescription for the DOAC may be completed by
any prescribing-qualified member of the treating team. The PI at each site should work with the clinical
teams to ensure that DOACs are prescribed within the appropriate window for each arm of the study.
Randomisation will be carried out at each recruiting centre by the research nurse or delegated
individual using the online randomisation service provided by Sealed Envelope.

Blinding
It is not practical to blind either the participant or randomising physicians to treatment timing once
allocated but sites should ensure that outcome data are collected by an assessor who is unaware of
the treatment allocation, In addition, all outcomes will be adjudicated by a committee blinded to
treatment allocation.

Emergency unblinding
Not applicable.

5.10 Data collection, management

Data collection methods

Data will be collected at the time-points indicated in the Trial Schedule (Table 2).

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 51 of 75



     

OPTIMAS

CRFs must be kept current to reflect the participant’s status at each phase during the course of the
trial.

The preferred method of data collection is direct online entry of data into electronic Case Report
Forms (CRFs) by the site staff onto the central database, stored on servers based at UCL by members
of the OPTIMAS trial team working within each research site. Data may be entered onto paper CRFs
prior to entry onto the database (but this is not an essential step). Staff will receive training on data
collection and entry (refer to CRF Completion Guide).

Data collection, data entry and queries raised by a member of the OPTIMAS trial team will be
conducted in line with the CCTU and trial specific Data Management Plan.

The UCL CCTU will act as custodian for the trial data. The following guidelines will be strictly adhered
to:

• Participant data will be pseudonymised.

• All anonymised data will be stored on a password protected CCTU computer.
• All trial data will be stored in compliance with the EU General Data Protection Regulation
(GDPR), and the UK Data Protection Act 2018 (and subsequent amendments) and archived in
line with the Sponsor’s Archiving SOP and ethical approval.

Safety Report Forms will be sent encrypted by email to the CCTU as detailed in section 5.13.3.1, Safety
Reporting (also refer to Safety Management Plan).

Data management
Data will be entered in the approved OPTIMAS database by a trained member of the team at sites and
protected using established CCTU procedures.

Coded data: Participants will be given a unique trial Participant Identification Number (PIN). Data will
be entered under this identification number onto the central database stored on the servers based at
CCTU. The database will be password protected and only accessible to members of the OPTIMAS trial
team at site and CCTU, and external inspectors if requested. Site staff only have access to data from
their site. The servers are protected by firewalls and are patched and maintained according to best
practice. The physical location of the servers is protected by CCTV and security door access.

Members of the trial team at CCTU have developed the database and coding frames. The database
software provides a number of features to help maintain data quality, including: maintaining an audit
trail, allowing custom validations on all data, allowing users to raise data query requests, and search
facilities to identify validation failure/ missing data.

After completion of the trial, the database will be retained on the servers of UCL for on-going analysis
of secondary outcomes.

Contact details of participants will be provided to the central study team at the UCL Stroke Research
Centre, if needed, to assist with follow-up. These will be securely stored on a password-protected
computer or in a locked filing cabinet. Members of the trial team at CCTU will not have access to this

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 52 of 75



     

OPTIMAS

information. The contact details will be destroyed after all efforts have been made to obtain follow-
up information, and within 12 months of the participant’s enrolment into the trial.

Neuroimaging data will be transferred to the Stroke Research Centre at UCL for analysis. The preferred
method is electronic secure transfer via a web-based interface based at UCL, though transfer by CD or
other storage media is acceptable. The process is outlined in the OPTIMAS Imaging Manual. All data
should be pseudonymised prior to transfer.

The identification, screening and enrolment logs, linking participant identifiable data to the
pseudonymised PIN, will be held locally by the trial site. This will either be held in written form in a
locked filing cabinet or electronically in password-protected form on hospital computers. Logs
containing identifiable data should not be transferred to the CCTU. Relevant summarised screening
data will be sent to the CCTU for the Stop/Amend/Go decision (see section 5.8.1). After completion of
the trial the identification, screening and enrolment logs will be stored securely by the sites for 5 years
unless otherwise advised by CCTU.

Non-adherence and non-retention

Withdrawal of consent will be documented in the Cessation of Trial Treatment or Withdrawal CRF.
Once consent has been withdrawn trial treatment will cease but follow up should continue if possible.
The trial team, if possible, will record reasons for treatment discontinuation.

Participants who are randomised but withdraw before the intervention will undergo standard clinical
care according to local protocols.

5.11 Trial Closure

The trial is expected to take approximately 5 years but this may need to be revised in the light of
unexpected changes in circumstances (e.g. Covid-19). The End of the Trial is defined as the date when
all data have been received, cleaned and all queries resolved at all sites.

The REC which gave a favourable opinion of the research will be notified by CCTU within 90 days of
trial ending. If the trial is closed early, notification should occur within 15 days along with justification
for early closure.

A site will be “closed’’ once the following criteria are fulfilled: all trial-related activities at that site are
reconciled and/or are complete; all outstanding data queries have been resolved; all necessary trial
documentation has been provided to the participating site for inclusion in the ISF; following the Trial
manager or delegate at the CCTU arranging for a close-out visit or teleconference/webinar as
appropriate. The close-out process will be documented accordingly. Any outstanding actions resulting
from the close-out visit will need to be completed and documented within an agreed timeframe. The
responsibility for completing the outstanding actions will lie with both the local research staff and the
Trial Manager or delegate. A letter confirming that close down is complete will be sent to the site PI
from CCTU.

The end of trial report is due within 12 months of the Declaration of End of Trial and in the UK is
submitted to the REC and funding body. The CI or delegate is responsible for ensuring reports to

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 53 of 75



     

OPTIMAS

funding bodies are completed correctly and on time. The submission of these reports may be
facilitated by CCTU.

5.12 Analysis and statistical methods

Statistical analysis plan

A detailed statistical analysis plan, including a full specification of the analysis principles and details,
will be drafted as early as possible and finalised prior to the first substantive analysis, following
approval by the Trial Steering Committee and review by the Independent Data Monitoring Committee.
The primary analysis will be conducted following the intention to treat (ITT) principle where all
randomised participants are analysed in their allocated group, whether or not they receive their
randomised treatment plan.

All statistical tests will use a 2-sided p-value of 0.05, unless otherwise specified, and all confidence
intervals presented will be 95% and two-sided.

Statistical methods – outcomes

Baseline characteristics will be summarised by treatment using appropriate descriptive statistics;
means and standard deviations for approximately normally distributed variables, medians and
interquartile ranges for non-normally distributed variables and counts (percentages) for categorical
variables.

Primary outcome
The primary outcome is the difference in event rates, according to treatment, of the composite
endpoint of all causes of stroke (i.e. recurrent ischaemic stroke, symptomatic intracranial
haemorrhage (including haemorrhagic transformation of the infarct), unclassifiable stroke syndromes,
or systemic arterial embolism in the 90 days following randomisation.

Since we are using a gatekeeper approach, the first stage of the analysis of the primary outcome will
be to establish non-inferiority. If the non-inferiority condition is met, such that early initiation of DOAC
is found to be as effective as standard initiation in preventing the primary outcome event, further
inspection of the results will test for superiority of the intervention compared to control.

Since the primary outcome has a binary classification, mixed effects logistic regression will be used to
determine whether there is any difference in the risk of a primary outcome event due to treatment,
by inclusion of a binary covariate indicating treatment. The results will be adjusted for the stratifying
variable stroke severity, which will be included as an additional covariate in the model. Sites will be
included as random effects. Should there be any issues with model convergence, standard logistic
regression will be used. In this case it will not be possible to account for variability between sites. The
model coefficient due to treatment will give an estimate of the difference in log odds, or equivalently
(exponentiated to give) an estimate of the odds multiplier, i.e. the change in odds of a negative
outcome on the composite endpoint due to early treatment with DOAC, conditional on stroke severity.
The adjusted odds ratio, together with the 95% confidence interval will be presented. If the upper
bound of the 95% confidence interval is less than 1.32, regardless of the estimated odds ratio, the
intervention will be deemed non-inferior. If, however, the upper bound of the confidence interval is

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 54 of 75



     

OPTIMAS

less than 1, the intervention will be deemed superior and the null hypothesis of no difference between
the groups will be rejected.

Secondary and exploratory outcomes

Secondary and exploratory outcomes will be handled similarly. All secondary outcomes will be
adjusted for the stratifying variable stroke severity and sites will be included as random effects. Binary
secondary outcomes will be analysed using mixed effects logistic regression models, continuous
secondary outcome measures will be analysed using a mixed effects linear regression model, and
time-to-event outcomes using Kaplan-Meier plots and Cox proportional hazards models where
covariate adjustment is necessary. Ordered categorical outcomes such as the mRS will be analysed
using a mixed effects ordinal logistic regression model.

Adverse events will be summarised in terms of the number of (serious) adverse events and the number
of participants with any (serious) adverse events in each randomised group and compared using
Fisher’s exact test mid P value. The difference (in the number of serious adverse events in each
randomised group) and 95% CI will be presented.

Additional analyses – subgroup

Results of the primary outcome will be presented by stratum, i.e. according to the levels of stroke
severity, the only stratifying variable used in the randomisation process. An interaction between the
subgroup and treatment will be added to the primary analysis model to investigate whether the
treatment effect differs according to the levels of stroke severity (NIHSS 0-4, 5-10, 11-15, 16-21, >21).
As the trial has not been powered to detect this, this should be considered a supportive analysis.

Further hypothesis generating, supportive subgroup analyses will be undertaken for the following
groups (the details of the subgroup cut-offs for groups 4 and 5 will be confirmed at a later date, before
the completion of the full statistical analysis plan):

1. Age (<75 years vs ≥75 years)

2. Sex
3. Geographical location of participants (within England, Wales, Scotland and Northern Ireland)
4. Neuroimaging features including infarct location, size and haemorrhagic transformation
5. Severity of cerebral small vessel disease
6. Pre-stroke antithrombotic (including oral anticoagulant) use
7. Baseline characteristics including renal function, hypertension, diabetes mellitus

Additionally, within the Stroke Research Centre, we will undertake exploratory analyses using
advanced brain imaging analysis and high dimensional modelling methods (including “machine
learning”) incorporating neuroimaging and clinical variables. The exact details of the exploratory
outcomes will be completed later, once the availability of imaging data can be assessed and before
the statistical analysis plan is finalised.

Analysis population and missing data

The main analysis will be conducted following the intention-to-treat principle in accordance with the
randomised allocation. Missing data on the primary outcome is expected to be less than 10% based

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 55 of 75



     

OPTIMAS

on previous studies in this area. The primary outcome is achieved or not at 90 days during which time
the participant population is expected to maintain close ties with health services during the stroke
rehabilitation period. Missing covariate data are not anticipated since covariates must be recorded to
allocate treatment. All participants with outcome data will be included in the analysis. The primary
analysis is likelihood based and therefore robust to the assumption of missing-at-random, and missing
observations in primary and secondary outcomes will not be imputed, but should substantial missing
data be encountered, the reasons for missingness will be investigated using logistic regression of
covariates on an indicator of missingness to help inform the interpretation of the trial results.

Trial outcomes will be harmonised as far as possible with other ongoing randomised trials of the timing
of DOAC in AF-associated acute ischaemic stroke, including TIMING (NCT02961348), ELAN
(NCT03148457), and START (NCT03021928). We will explore the possibility of pooled analyses with
these and other suitable trial datasets as appropriate.

Economic evaluations
The aim of the economic evaluation is to calculate the mean incremental cost per quality adjusted life
year (QALY) gained of early initiation of DOAC compared to late initiation of DOAC over 90 days from
a health and social care cost perspective. The cost of DOAC will not be included in the analysis given
that we assume it will be the same between the two arms, only differing by time of initiation.

QALYs will be calculated based on EQ-5D-5L completed at baseline and 90 days. Where possible
participants will self-complete the EQ-5D-5L. If this is not possible the EQ-5D-5L will be completed by
proxies (Proxy 2 questionnaire), ideally the person who acted as the main carer or a close family
member or friend. In case a proxy is not available, the clinical team member who is looking after the
participant will complete it on their behalf to the best of their ability. In all instances the CRF will note
if the EQ-5D-5L is self or proxy completed.

Date of death collected as part of the primary outcome will also be used to calculate QALYs.

Health and Social Care Resources will come from a number of sources including:

• Stroke Unit discharge/transfer CRF: health care resource use and length of stay for the index
admission, transfer or discharge destination, and social care allocation and if the participant
has been given early supported discharge.
• Participant (EQ-5D-5L) /proxy (EQ-5D-5L Proxy 2) completed at 90-day follow-up.
• Trial-specific questionnaire of community health and social care resources (HSCR) following
hospital discharge and any other stroke related home help completed at 90-day follow-up.
• We will assess the feasibility of using Hospital Episode Statistics (HES) to collect data on
subsequent stroke admissions and other stroke related acute care hospital use.

Health Economic Analysis Plan (HEAP)

A full HEAP will be developed for the within-trial analysis and will be subject to approval by the Trial
Steering Committee. The primary analysis will be a within-trial intention-to-treat analysis. There will
be no economic modelling conducted as part of the trial.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 56 of 75



     

OPTIMAS

Covariates to include in analysis models will be agreed based on discussion with the statistician and
the trial team. In the first instance they will include the stratification variable and stroke severity. A
random effects variable for site will also be included.

Final decisions on imputation of missing data will be discussed with the trial team and trial statistician
as part of the development of the HEAP. Given that the key resource data will be completed by trial
sites as part of the discharge/transfer CRF it is likely that we will not impute any health care resource
use or cost data.

Cost-effectiveness will primarily be evaluated using cost-effectiveness acceptability curves generated

from bootstrapped results to calculate the probability that early initiation of DOAC is cost-effective
compared to late initiation for a range of values of willingness to pay for a QALY gained. Incremental
cost-effectiveness ratios will be reported where appropriate i.e. where a decision rule is required.

We will conduct sensitivity analyses to test the impact of any assumptions made. A sub-group analysis
of participants with Proxy 2 reported versus self-completed EQ-5D-5L will also be conducted.

A secondary analysis will be conducted where we will calculate the cost-effectiveness of early
compared to late initiation of DOAC at 90 days using the mRS to calculate QALYs.

Within-trial analysis
QALYs will be calculated as the area under the curve based on baseline and 90-day responses to the
EQ-5D-5L. For participants that have died within 90 days from randomisation QALYs will be calculated
as a straight line from baseline EQ-5D-5L to the time of death which will be imputed as 0.

Of particular importance will be length of stay and hence any cost savings associated with the index
admission. Working closely with the trial statistician, we will report statistics on length of stay. Length
of stay for the index admission will be costed from the NHS cost perspective using NHS reference costs.
Cost differences for early versus late initiation of DOAC will be calculated using an appropriate general
linear model (GLM) based on the distribution of the data and Akaike Information Criteria.

We will report descriptive statistics, including percentages, means and standard deviations, for all
Health and Social Care Resources at 90 days by early versus late DOAC initiation. Mean total costs and
standard errors by intervention group will be reported for secondary care, community health care,
social care and nursing home care costs. Costs will be calculated based on national published sources.
95% Confidence intervals for differences in costs between the two groups will be based on the
bootstrapped results.

To account for the correlation between costs and QALYs coefficients for calculating CEACs will be
calculated using seemingly unrelated regression. 1,000 replications will be stored based on
bootstrapping.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 57 of 75



     

OPTIMAS

5.13 Data monitoring

Data Monitoring Committee

An Independent Data Monitoring Committee (IDMC) constituting a minimum of 3 independent
members who will each provide expert knowledge/advice on different aspects notably clinical
expertise on stroke, cardiology, conduct of clinical trials and statistical analysis of trial data.

IDMC members will convene at scheduled time points throughout the duration of the trial to review
interim trial data and safety data. Recommendations will be made by the IDMC to the Trial Steering
Committee (TSC) regarding continuation/stopping of the trial based on safety data.

Further details of the roles and responsibilities of the IDMC including membership, relationships with
other committees, decision-making processes, and description of stopping rules and/or guidelines
where applicable are described in detail in the OPTIMAS IDMC Terms of Reference (ToR) and are
available from the CCTU trial team.

Interim Analyses
No formal interim analysis is planned within the RCT, but regular reports concerning participant safety
and key efficacy outcomes will be prepared for the IDMC as agreed in the ToR. The IDMC will describe
its processes separately in its ToR.

Data Monitoring for Harm

All serious adverse events will be recorded by site staff and reported to CCTU as detailed in sections
5.13.3.5. A trained member of the trial team will report the events, according to the reporting
timelines detailed. Adverse events are expected within this cohort and, as the safety profile of the
interventions is well established, non-serious adverse events will be recorded in the participant
medical notes but will not be collected by the CCTU.

Safety reporting
Definitions of harm of the EU Directive 2001/20/EC Article 2 based on the principles of ICH GCP apply
to this trial (see Table 3).

Table 3: Adverse Event Definitions

Adverse Event (AE) Any untoward medical occurrence in a study participant, which
does not necessarily have a causal relationship with the study
intervention.
Adverse Reaction (AR) Any untoward and unintended response that has occurred due
to the intervention.
Serious Adverse Event (SAE) or Any AE or AR that at any dose:
Serious Adverse Reaction (SAR) • results in death
• is life threatening*
• requires hospitalisation or prolongs existing
hospitalisation**
• results in persistent or significant disability or incapacity
• is a congenital anomaly or birth defect
• or is another important medical condition***

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 58 of 75



     

OPTIMAS

* The term life threatening here refers to an event in which the patient is at risk of death at the
time of the event; it does not refer to an event that might hypothetically cause death if it was more
severe (e.g. a silent myocardial infarction)
** Hospitalisation is defined as an in-patient admission, regardless of length of stay, even if the
hospitalisation is a precautionary measure for continued observation. Hospitalisation for pre-
existing conditions (including elective procedures that have not worsened) does not constitute an
SAE
*** Medical judgement should be exercised in deciding whether an AE or AR is serious in other
situations. Important AEs or ARs that may not be immediately life threatening or result in death or
hospitalisation, but may seriously jeopardise the participant by requiring intervention to prevent
one of the other outcomes listed in the table (e.g. a secondary malignancy, an allergic
bronchospasm requiring intensive emergency treatment, seizures or blood dyscrasias that do not
require hospitalisation, or development of drug dependency).

In addition to the definition above, Adverse Events (AEs) include but are not limited to the following:

• An exacerbation (i.e. increase in the frequency or intensity) of a pre-existing illness episodic

event or symptom (initially recorded at the screening/baseline visit), that is detected after
randomisation
• Occurrence of a new illness, episodic event or symptom, that is detected after randomisation

AEs do NOT include:

• Medical or surgical procedures: the condition that leads to the procedure is the AE
• Pre-existing disease or a condition present before treatment that does not worsen
• Hospitalisation where no untoward or unintended response has occurred e.g. elective
cosmetic surgery
• Overdose of medication without signs or symptoms.

Other notifiable adverse events

Not applicable.

Urgent safety measures

An Urgent Safety Measure (USM) is described as an action that the sponsor or investigator may take
in order to protect the study participants against any immediate hazard to their health or safety. This
is a procedure, which is not defined by the study protocol that can be put in place with immediate
effect without needing to gain prior authorisation by a study sponsor however, study sponsor must
be notified immediately, and the reason why measure has been taken should be clearly explained.
The sponsor will notify the REC immediately by telephone and in writing within 3 days.

Procedures to follow in the event of female participants becoming pregnant

Pregnancy is not considered as an SAE. If a female participant becomes pregnant, the investigator
should be informed and the pregnancy should be recorded on the Pregnancy log and in the participant

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 59 of 75



     

OPTIMAS

medical notes. The clinician responsible for participant’s care will take appropriate actions.
Participants who become pregnant will be withdrawn from the trial.

Investigator responsibilities relating to safety reporting

Adverse Events:

All AEs should be recorded in the participant’s medical notes as per usual clinical practice however
they will not be collected by the CCTU.

Serious Adverse Events:

All SAEs should be notified to CCTU:

• SAEs related to the time at which the DOAC was administered (rather than DOAC
administration in general) are classed as Serious Adverse Reactions (SARs). They should be
reported immediately and no later than 24 hours after the investigator becoming aware of
the event, on the ‘SAR form’.

SAEs unrelated to the time the DOAC was administered are exempt from expedited reporting. They
should be recorded on a ‘SAEs Unrelated to Study Intervention Log’. Please see the ‘Safety reporting
diagram’ below (figure 3).

5.13.3.5.1 Seriousness assessment

When an AE or AR occurs, the PI or delegates responsible for the care of the participant must first
assess whether or not the event is serious using the definition given in Table 3.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 60 of 75



     

OPTIMAS

Figure 3: Safety reporting

5.13.3.5.2 Severity or grading of Adverse Events

The severity of SAEs and/or SARs in this trial should be graded using the Common Terminology Criteria
for Adverse Events (CTCAE), version 5 [54].

Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention
not indicated.

Grade 2: Moderate; minimal, local or non-invasive intervention indicated; limiting age-appropriate

instrumental activities of daily living (ADL)*7.

Grade 3: Severe or medically significant but not immediately life-threatening; hospitalisation or

prolongation of hospitalisation indicated; disabling; limiting self-care ADL8.

7
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.
8
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 61 of 75



     

OPTIMAS

Grade 4: Life-threatening consequences; urgent intervention indicated.

Grade 5: Death related to AE

5.13.3.5.3 Causality
The PI or delegates must assess the causality of all serious adverse events or reactions in relation to
the time the DOAC was administered using the definitions in Table 4.

If there are reasonable grounds to believe that, had the DOAC been started at 7-14 days rather than
0-4 days or vice versa, this adverse event would have been avoided entirely, then the event should be
considered related to trial intervention.

Table 4: Causality definitions

Relationship Description

Unrelated There is no evidence of any causal relationship

Related There is clear evidence to suggest a causal relationship

to the time the DOAC was administered and other
possible contributing factors can be ruled out (i.e. they
resulted from administration of any research
procedures)

If due to SAR (related to the timing of the trial intervention), treatment is discontinued, interrupted
or the dose modified, refer to the relevant sections of the protocol for more details.

5.13.3.5.4 Expectedness
The sponsor will assess the expectedness of the event. If information on expectedness is provided by
the investigator this should also be taken into consideration by the sponsor. SARs which are also
outcome events (e.g. symptomatic ICH) will be considered expected unless there are exceptional
reasons to believe they are not, as the OPTIMAS trial is designed to assess the incidence of these
events and the balance of benefit and risk associated with early DOAC administration. The incidence
of outcome events will be monitored throughout the trial by the IDMC, who will take action if concerns
regarding an excess of outcome events in either treatment group arise. If a SAR is assessed as being
unexpected it should be reported to REC within 15 days (refer to Notifications section 5.13.3.6).

SAE Notifications

5.13.3.6.1 Notifications by the Investigator

Investigators should notify CCTU of all SAEs occurring from the time of randomisation until 90 days
after randomisation as follows:

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 62 of 75



     

OPTIMAS

• SARs (that is, SAEs related to the time the DOAC was administered)

CCTU must be notified of all SARs (related to the time the DOAC was administered), immediately (i.e.
within 24 hours) after the site staff becomes aware of the event.

The SAR form must be completed by the PI or delegate who will provide the grading and causality for
the event. In the absence of the responsible investigator, the SAR form should be completed and
signed by a member of the site trial team and emailed as appropriate within the timeline. The
responsible investigator should check the SAR form at the earliest opportunity, make any changes
necessary, sign and then email to CCTU. Detailed written reports should be completed as appropriate.
Systems will be in place at the site to enable the PI or delegate to check the form for clinical accuracy
as soon as possible.

The minimum criteria required for reporting a SAR are:

• the participant identification number,

• month and year of birth,
• name of reporting investigator, and
• information to confirm seriousness and causality.

Any further information regarding the event that is unavailable at the time of the first report should
be sent as soon as it becomes available.

The SAR form must be completed and sent by email to the trial team at CCTU in an encrypted format
to:

[email protected]

Participants must be followed up until clinical recovery is complete and laboratory results have
returned to normal or baseline values, or until the event has stabilised. Follow-up should continue
after completion of 90 days follow up if necessary. Every effort will be made to resolve SARs related
to the time the DOAC was administered by the end of the study. Follow-up SAR forms should be
completed and emailed to CCTU as further information becomes available. Additional information
and/or copies of test results etc., may be provided separately. The participant must be identified by
participant identification number, month and year of birth and initials only. The participant’s name
should not be used on any correspondence and should be redacted and replaced with trial identifiers
on any test results.

If the SAR is also an outcome event (refer to section 5.5.3.2 Definition of outcome events), both the
SAR form and Outcome Event Form should be completed (see Figure 3).

• SAEs unrelated to the time the DOAC was administered

SAEs unrelated to the time the DOAC was administered are exempt from expedited reporting. They
should be recorded on a ‘SAEs Unrelated to Study Intervention Log’. For database entry timelines refer
to ‘CRF Completion Guide’.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 63 of 75



     

OPTIMAS

If the unrelated to the time the DOAC was administered SAE is also an outcome event (see section
5.5.3.2), both the ‘SAEs Unrelated to Study Intervention Log’ AND Outcome Event Form should be
completed (see Figure 3).
For further guidelines, refer to Safety Management Plan.
Important information:

This is a non-CTIMP study looking at the timing (i.e. strategy) of drug delivery and is not investigating
drug safety and efficacy per se. Therefore any Serious Adverse Reactions related to standard use of
any of the DOACs should be reported to the MHRA via the Yellow Card scheme
(https://yellowcard.mhra.gov.uk/) by the PI or treating physician as they would for patients being
prescribed these medications in the usual way.

5.13.3.6.2 CCTU responsibilities

A medically qualified member of staff will be appointed as the sponsor clinical reviewer (usually the
Chief Investigator (CI) or a medically qualified delegate) and will perform a clinical review of all SAR
reports received.
CCTU is undertaking the duties of trial sponsor and is responsible for the reporting of all SAEs occurring
to a research participant where in the opinion of the CI the event was related and unexpected, to the
REC within 15 days of the CI becoming aware of the event.
CCTU will keep investigators informed of any safety issues that arise during the course of the trial.
CCTU will submit progress report to REC annually, starting 12 months after the date of the favourable
opinion.

Quality Assurance and Control

Risk Assessment
The Quality Assurance (QA) and Quality Control (QC) considerations for the OPTIMAS trial are based
on the standard CCTU Quality Management Policy that includes a formal Risk Assessment, and that
acknowledges the risks associated with the conduct of the trial and proposals of how to mitigate them
through appropriate QA and QC processes. Risks are defined in terms of their impact on: the rights
and safety of participants; project concept including trial design, reliability of results and institutional
risk; project management; and other considerations.

QA is defined as all the planned and systematic actions established to ensure the trial is performed
and data generated, documented and/or recorded and reported in compliance with the principles of
GCP and applicable regulatory requirements. QC is defined as the operational techniques and activities
performed within the QA system to verify that the requirements for quality of the trial related
activities are fulfilled.

Central Monitoring at CCTU

CCTU staff will review Case Report Form (CRF) data for errors and missing key data points. The trial
database will also be programmed to generate reports on errors and error rates. Essential trial issues,

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 64 of 75



     

OPTIMAS

events and outputs, including defined key data points, will be detailed in the OPTIMAS trial Data
Management Plan.

On-site Monitoring
The frequency, type and intensity of routine and triggered on-site monitoring will be detailed in the
OPTIMAS Quality Management and Monitoring Plan (QMMP). The QMMP will also detail the
procedures for review and sign-off of monitoring reports.

5.13.4.3.1 Direct access to participant records

Participating investigators must agree to allow trial related monitoring, including audits and REC
review, by providing access to source data and other trial related documentation as required.
Participant consent for this must be obtained as part of the informed consent process for the trial.

Trial Oversight
Trial oversight is intended to preserve the integrity of the trial by independently verifying a variety of
processes and prompting corrective action where necessary. The processes reviewed relate to
participant enrolment, consent, eligibility, and allocation to trial groups; adherence to trial
interventions and policies to protect participants, including reporting of harms; completeness,
accuracy and timeliness of data collection; and will verify adherence to applicable policies detailed in
the Compliance section of the protocol. Independent trial oversight complies with the CCTU trial
oversight policy.

In multi-site trials, this oversight is considered and described both overall and for each recruiting
centre by exploring the trial dataset or performing site visits as described in the OPTIMAS QMMP.

Trial Team
The Trial Team (TT) will be set up to assist with developing the design, co-ordination and day-to-day
operational issues in the management of the trial, including budget management. The membership,
frequency of meetings, activity (including trial conduct and data review) and authority will be covered
in the QMMP.

Trial Management Group

A Trial Management Group (TMG) will be set up to assist with developing the design, co-ordination
and management of the trial. The membership, frequency of meetings, activity (including trial conduct
and data review) and authority will be covered in the TMG terms of reference.

Independent Trial Steering Committee

The Independent Trial Steering Committee (TSC) is the independent group responsible for oversight
and strategic management of the trial in order to safeguard the interests of trial participants. The TSC
provides advice to the CI, CCTU, the funder and sponsor on all aspects of the trial through its
independent Chair. The membership, frequency of meetings, activity (including trial conduct and data
review) and authority will be covered in the TSC terms of reference.

Independent Data Monitoring Committee

The Independent Data Monitoring Committee (IDMC) is the only oversight body that has access to
accumulating comparative data. The IDMC is responsible for safeguarding the interests of trial

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 65 of 75



     

OPTIMAS

participants, monitoring the accumulating data and making recommendations to the TSC on whether
the trial should continue as planned. The membership, frequency of meetings, activity (including
review of trial conduct and data) and authority will be covered in the IDMC terms of reference

Trial Sponsor
The role of the sponsor is to take on responsibility for securing the arrangements to initiate, manage
and finance the trial. UCL is the trial sponsor and has delegated the duties as sponsor to CCTU via a
signed letter of delegation.

6 Ethics and Dissemination

6.1 Ethics Committee Approval
Before initiation of the trial at any clinical site, the protocol, all informed consent forms and any
material to be given to the prospective participant will be submitted to the relevant REC for approval.
Any subsequent amendments to these documents will be submitted for further approval.

6.2 Competent Authority approvals

The UK Competent Authority, the MHRA, has defined the trial as a non-Clinical Trial of an
Investigational Medicinal Product as the DOACs are being used in accordance to their MAs, so a CTA
is not required.

6.3 Other approvals

The protocol will be submitted by those delegated to do so to the relevant R&D department of each
participating site or to other local departments for approval as required in each country. A copy of the
local R&D confirmation (or other relevant approval as above) and of the Participant Information Sheet
(PIS) and consent form on local headed paper must be forwarded to the CCTU before participants are
randomised to the trial.
The protocol has received formal review and methodological, statistical, clinical and operational input
from the CCTU Protocol Review Committee.

6.4 Protocol amendments

The sponsor will ensure that essential documents - namely the trial protocol, patient information
sheets, consent forms, GP letters and submitted supporting documents - have been approved by the
REC, and HRA prior to any participant recruitment. The protocol and all agreed substantial
amendments will be documented and submitted for ethical approval prior to implementation.
Approved protocol amendments will be communicated by the OPTIMAS Trial Team at CCTU to all
investigators.

6.5 Consent or assent

In this trial, there will be subpopulation of potential patients who may be unable to consent for
themselves but these patients should not be excluded from the trial. Special arrangements are in place
to ensure that the interests of such patients are protected as outlined in section 5.3.2 Screening
Procedures and Pre-randomisation Investigations.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 66 of 75



     

OPTIMAS

Consent or assent in ancillary studies

At present the OPTIMAS trial does not include any sub-study, which requires additional patient
consent.

6.6 Confidentiality
All data will be collected and stored in line with GDPR.

Any paper copies of personal trial data will be kept at the participating site in a secure location with
restricted access. Only non-identifiable data will be kept at the CCTU office with only authorised CCTU
staff members having access. Only staff working on the trial will have password access to this
information.

Confidentiality of participant’s personal data is ensured by not collecting participant names on CRFs
that will be sent to CCTU and storing the data in a pseudonymised fashion at CCTU. At trial enrolment,
the participant will be issued a patient identification number and this will be the primary identifier for
the participant, with secondary identifiers of month and year of birth and initials only. The NHS
number will be collected and encrypted with AES-256 at randomisation through Sealed Envelope, and
will only be decrypted securely within UCL’s Data Safe Haven; this is to allow for linkage to HES data.
Any identifiable personal data (such as participant contact details) will only be provided to the Stroke
Research Centre for follow-up purposes.

The participant's consent form will carry their name and signature but these will be kept at the trial
site (participant's hospital) and not with the participant's data at CCTU. The participant consent forms
will only be accessed by CCTU staff for purposes of monitoring the consent procedure at the site.

6.7 Declaration of Interests

The investigators named on the protocol have no financial or other competing interests that impact
on their responsibilities towards the scientific value or potential publishing activities associated with
the trial.

6.8 Indemnity
UCL holds insurance to cover participants for injury caused by their participation in the clinical trial.
Participants may be able to claim compensation if they can prove that UCL has been negligent.
However, as this clinical trial is being carried out in a hospital, the hospital continues to have a duty of
care to the participant in the clinical trial. UCL does not accept liability for any breach in the hospital’s
duty of care, or any negligence on the part of hospital employees. This applies whether the hospital is
an NHS Trust or not.

Participants may also be able to claim compensation for injury caused by participation in this clinical
trial without the need to prove negligence on the part of UCL or another party. Participants who
sustain injury and wish to make a claim for compensation should do so in writing in the first instance
to the Chief Investigator, who will pass the claim to UCL’s insurers, via the Sponsor’s office.

Hospitals selected to participate in this clinical trial shall provide clinical negligence insurance cover
for harm caused by their employees and a copy of the relevant insurance policy or summary shall be
provided to UCL, upon request.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 67 of 75



     

OPTIMAS

6.9 Finance
OPTIMAS is fully funded by a British Heart Foundation grant number (BHF Clinical Study no.
CS/17/6/33361).

6.10 Archiving
The investigators agree to archive and/or arrange for secure storage of OPTIMAS trial materials and
records for a minimum of 5 years after the close of the trial unless otherwise advised by the CCTU.

The Trial Manager or delegate will ensure that all actions have been completed and documented
before archiving.

6.11 Access to data

Requests for access to trial data will be considered, and approved in writing where appropriate, after
formal application to the TSC. Considerations for approving access are documented in the TSC ToR.

6.12 Ancillary and post-trial care

Ancillary and post-trial care will be standard medical care.

6.13 Publication policy

Trial results
The publication of results will comply with the UCL and CCTU Publication Policies and will include
submission to open access journals.

The results of the trial will be disseminated regardless of the direction of effect.

Authorship
The TMG will nominate a writing group, which will include members of the TMG and TSC, and will be
responsible for drafting manuscripts for publication. Individuals on the writing group will be named
on resulting publications which will be published on behalf of the OPTIMAS Investigators.

Reproducible research
The OPTIMAS Trial Protocol and Statistical Analysis Plan will be published and made available for public
access.

7 Ancillary studies
Sub-studies of circulating biomarkers, or DNA extraction and storage may be undertaken subject to
availability of appropriate funding and staff at participating sites.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 68 of 75



     

OPTIMAS

8 Protocol Amendments
Amendment 1 – Summary of Changes to Protocol v1.0 dated 14 Nov 2018
Version 1.0 was the first version submitted to REC and MHRA for review, and was amended to reflect
the MHRA’s categorisation of the trial as a non-CTIMP and the changes requested during the initial
REC meeting on 8 Jan 2019. The main changes were:

• Removal of reference to the MHRA, investigational medicinal products, and regulatory

requirements.
• Changes to safety reporting guidance as expedited reporting to the MHRA is not required.
• Clarification of consent procedures (including the use of the Easy Access PIS as an aide
memoire), and the inclusion of incapacitated patients according to national legislation.
• Clarification of the study follow up, use of GP questionnaires, and the completion of patient-
facing questionnaires by proxy.
• Clarification of the roles of the Internal Event Validation Committee and the Event
Adjudication Committee.

Amendment 2 – Summary of Changes to Protocol v2.0 dated 20 Feb 2019

Version 2.0 was revised to clarify follow-up procedures and include updated information on the IDMC.
Changes to the procedures for the inclusion of patients lacking capacity in Northern Ireland were also
requested by the REC in the initial approval letter (14 March 2019) as the Mental Capacity Act
(Northern Ireland) 2016 has not been implemented. Clarifications were made throughout the protocol
where relevant. The main changes were:

• Updated IDMC membership list

• Revised procedures for the inclusion of adult patients lacking capacity, including Northern
Ireland.
• Blinded assessor requirement for the 90-day follow-up
• Collection of recurrent stroke and outcome events and hospital admission records from NHS
Wales Informatics Service, Public Health Scotland, and the Northern Ireland Department of
Health, as well as from NHS Digital (England-based participants only).

Amendment 3 – Summary of Changes to Protocol v3.0 dated 09 Sep 2019

Version 3.0 was revised to clarify consenting processes for participants lacking capacity in Scotland.
As the this is a non-CTIMP study, only Personal Legal Representatives can be approached if the
participant lacks capacity to consent. In addition, there was also some staff changes and is reflected
in this protocol.

Amendment 4 – Summary of Changes to Protocol v4.0 dated 12 Feb 2020

Version 4.0 was revised to clarify the eligibility criteria and unclassifiable strokes, provide guidance to
unknown stroke onset time, changes to safety reporting definitions, updates to the definition of acute
ischaemic stroke, clarity of when INR should be performed, updated the secondary outcomes,
rebranding of ISD Scotland, reflect staff changes, and mitigation plans as a result of Covid-19. The
main changes were:

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 69 of 75



     

OPTIMAS

• Clarified that participants with paroxysmal, persistent or permanent AF, or atrial flutter, are
eligible to participate
• Clarified the primary outcome to incorporate unclassifiable stroke if there are insufficient data
• Provided further guidance when the stroke onset time is unknown
• Changed the safety definition of SAEs to only expedite reporting if the AE is related to the
timing of the DOAC administration (not DOAC administration in general)
• Updated the secondary outcomes
• Information Services Division (ISD) Scotland has now been rebranded as Public Health
Scotland
• Provided further clarity on when INR should be performed during screening
• Updated on acute ischaemic stroke definition
• Updated staff teams and committee members
• Formally added to the protocol mitigation plans during Covid-19 (NB: this has already been
submitted as non-substantial amendments when the pandemic started).

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 70 of 75



     

OPTIMAS

9 References
1. Chan AW, Tetzlaff JM, Altman DG et al. SPIRIT 2013 Statement: Defining Protocol Items for Clinical
Trials. Ann Intern Med 2013; 158:200-207.
2. Chan AW, Tetzlaff JM, Gotzsche PC, et al. SPIRIT 2013 explanation and elaboration: guidance for
protocols of clinical trials. BMJ 2013; 346: e7586.
3. Heeringa J, van der Kuip DA, Hofman A, et al. Prevalence, incidence and lifetime risk of atrial
fibrillation: the Rotterdam study. Eur Heart J 2006; 27: 949-953.
4. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for Stroke: the
Framingham Study. Stroke 1991; 22:983-988.
5. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation: a major contribution to stroke in the elderly:
The Framingham Study. Arch Intern Med 1987; 147:1561-1564.
6. Saxena R, Lewis S, Berge E, Sandercock PA, Koudstaal PJ. Risk of early death and recurrent stroke
and effect of heparin in 3169 patients with acute ischemic stroke and atrial fibrillation in the
International Stroke Trial. Stroke 2001; 32: 2333-2337.
7. Hart RG, Coull BM, Hart D. Early recurrent embolism associated with nonvalvular atrial fibrillation:
a retrospective study. Stroke 1983; 14:688-693.
8. CAST: randomised trial of early aspirin in 20,000 patients with acute stroke. CAST (Chinese Acute
Stroke Trial) Collaborative Group. Lancet 1997; 34: 1641-1649.
9. Berge E, Abdelnoor M, Nakstad PH, Sandset PM. Low molecular-weight heparin versus aspirin in
patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study.
HAEST Study Group. Heparin in Acute Embolic Stroke Trial. Lancet 2000; 355: 1205-1210.
10. Paciaroni M, Agnelli G, Micheli S, Caso V. Efficacy and safety of anticoagulant treatment in acute
cardioembolic stroke: a meta-analysis of randomized controlled trials. Stroke 2007; 38:423-430.
11. Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation. The Framingham Study.
Stroke 1996; 27, 1760-1764.
12. Freedman B, Potpara TS, Lip GYH. Stroke prevention in atrial fibrillation. Lancet 2016; 388: 806–
817.
13. Paciaroni M, Agnelli G, Corea F, et al. Early hemorrhagic transformation of brain infarction: rate,
predictive factors, and influence on clinical outcome: results of a prospective multicenter study.
Stroke 2008; 39: 2249-2256.
14. Paciaroni M, Agnelli G, Falocci N, et al. Early Recurrence and Cerebral Bleeding in Patients with
Acute Ischemic Stroke and Atrial Fibrillation: Effect of Anticoagulation and Its Timing: The RAF
Study. Stroke 2015; 46:2175-2182.
15. Abdul-Rahim AH, Fulton RL, Frank B, et al. Association of improved outcome in acute ischaemic
stroke patients with atrial fibrillation who receive early antithrombotic therapy: analysis from
VISTA. Eur J Neurol 2015; 22:1048-1055.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 71 of 75



     

OPTIMAS

16. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with
stroke and transient ischemic attack: a guideline for healthcare professionals from the American
Heart Association/American Stroke Association. Stroke 2014; 45:2160-2236.
17. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial
fibrillation developed in collaboration with EACTS. European Heart Journal 2016; 37: 2893-2962.
doi: 10.1093/eurheartj/ehw210.
18. Intercollegiate Stroke Working Party. National Clinical Guideline for Stroke 2016.
https://www.strokeaudit.org (accessed 17 Oct 2018).
19. Wilson D, Ambler G, Banerjee G, et al. Early versus late anticoagulation for ischaemic stroke
associated with atrial fibrillation: multicentre cohort study. J Neurol Neurosurg Psychiatry, in
press.
20. Munn D, Abdul-Rahim AH, Fischer U, Werring DJ, Robinson TG, Dawson J. A survey of opinion:
When to start oral anticoagulants in patients with acute ischaemic stroke and atrial fibrillation?
Eur Stroke J 2018. https://doi.org/10.1177/2396987318787124.
21. Toyoda K, Arihiro S, Todo K, et al. Trends in oral anticoagulant choice for acute stroke patients
with nonvalvular atrial fibrillation in Japan: The SAMURAI-NVAF Study. Int J Stroke 2015; 10:836-
842.
22. Terent A, Åsberg S, Oldgren J, et al. Antikoagulantia efter akut ischemisk stroke med
förmaksflimmer. Läkartidningen 2016; 113.
23. Seiffge DJ, Traenka C, Polymeris A, et al. Early DOAC after ischemic stroke: Risk of intracranial
hemorrhage and recurrent events. Neurology 2016; 87:1856-1860.
24. Easton JD, Lopes RD, Bahit MC, et al. Apixaban compared with warfarin in patients with atrial
fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of the ARISTOTLE
trial. Lancet Neurol 2012; 11:503-511.
25. Diener HC, Connolly SJ, Ezekowitz MD, et al. Dabigatran compared with warfarin in patients with
atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-
LY trial. Lancet Neurol 2010; 9:1157-1163. Erratum in: Lancet Neurol. 2011 10:27.
26. Hankey GJ, Patel MR, Stevens SR, et al. Rivaroxaban compared with warfarin in patients with atrial
fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF.
Lancet Neurol 2012; 11:315-22.
27. Hong KS, Lee JS, Kim YJ, et al. Trial of early anticoagulation with rivaroxaban versus warfarin in
patients with atrial fibrillation and acute cerebral ischemia. ESOC6-1426 Abstracts of ESOC 2016.
European Stroke Journal 1(1S):613–780 (2016)
28. Stroke Association. Atrial fibrillation. https://www.stroke.org.uk/take-action/atrial-fibrillation-af
(accessed 17 Oct 2018).
29. Yiin GS, Howard DP, Paul NL, et al. Age-specific incidence, outcome, cost, and projected future
burden of atrial fibrillation-related embolic vascular events: a population-based study. Circulation
2014; 130:1236-1244.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 72 of 75



     

OPTIMAS

30. Mental Capacity Act 2005.

http://www.legislation.gov.uk/ukpga/2005/9/pdfs/ukpga_20050009_en.pdf (accessed 17 Oct
2018).
31. Adults with Incapacity (Scotland) Act 2000.
https://www.legislation.gov.uk/asp/2000/4/pdfs/asp_20000004_en.pdf (accessed 17 Oct 2018).
32. Mental Capacity Act (Northern Ireland) 2016. https://www.legislation.gov.uk/nia/2016/18
(accessed 6 Feb 2019).
33. World Medical Association. WMA Declaration of Helsinki – ethical principles for medical research
involving human subjects. Revised 2013. https://www.wma.net/policies-post/wma-declaration-
of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/ (accessed 17 Oct
2018).
34. Medicines and Healthcare products Regulatory Agency (MHRA). Good Clinical Practice Guide.
London: TSO, 2012.
35. Northern Ireland Health and Social Care (HSC) Public Health Agency, Office for Research Ethics
Committees Northern Ireland (ORECNI). Briefing Note Regarding Research on Adults Lacking
Capacity Studies – Northern Ireland (Non-Clinical Trials of Investigational Medicinal Products
only). 15 March 2019 version 2.0. http://www.hscbusiness.hscni.net/services/1984.htm
(accessed 21 Aug 2019).
36. Health Research Authority. Consent and Participant Information Guidance. 19 September 2018.
http://www.hra-decisiontools.org.uk/consent (accessed 17 Oct 2018).
37. Larrue V, von Kummer RR, Müller A, Bluhmki E. Risk factors for severe hemorrhagic transformation
in ischemic stroke patients treated with recombinant tissue plasminogen activator: a secondary
analysis of the European-Australasian Acute Stroke Study (ECASS II). Stroke. 2001; 32:438-441.
38. Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and
Standardization Committee of the International Society on Thrombosis and Haemostasis.
Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-
surgical patients. J Thromb Haemost. 2005; 3:692-694.
39. Spyropoulos AC, Ageno W, Albers GW, Elliott CG, Halperin JL, Hiatt WR, Maynard GA, Steg PG,
Weitz JI, Suh E, Spiro TE, Barnathan ES, Raskob GE; MARINER Investigators. Rivaroxaban for
Thromboprophylaxis after Hospitalization for Medical Illness. N Engl J Med. 2018; 379:1118-1127.
doi: 10.1056/NEJMoa1805090.
40. Rankin L. Cerebral vascular accidents in patients over the age of 60. II. Prognosis. Scott Med J 1957;
2:200–215.
41. Banks JL, Marotta CA. Outcomes validity and reliability of the modified Rankin scale: implications
for stroke clinical trials: a literature review and synthesis. Stroke 2007; 38:1091-1096.
42. SITS Open. How to perform Modified Rankin Scale Assessments: Training, questions and scoring.
https://www.sitsinternational.org/media/1200/140611-sits-open-mrs-questions.pdf (accessed
17 Oct 2018).

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 73 of 75



     

OPTIMAS

43. Harrison JK, McArthur KS, Quinn TJ. Assessment scales in stroke: clinometric and clinical
considerations. Clin Interv Aging. 2013; 8: 201-211.
44. Kwah LK, Diong J. National Institutes of Health Stroke Scale (NIHSS). J Physiother. 2014; 60: 61.
45. Whiteley WN, Emberson J, Lees KR, et al. Risk of intracerebral haemorrhage with alteplase after
acute ischaemic stroke: a secondary analysis of an individual patient data meta-analysis. Lancet
Neurol 2016; 15: 925–33.
46. Burton L, Tyson SF. Screening for cognitive impairment after stroke: A systematic review of
psychometric properties and clinical utility. J Rehabil Med 2015; 47: 193–203.
47. Nasreddine ZS, Phillips NA, Bédirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief
screening tool for mild cognitive impairment. J Am Geriatr Soc 2005; 53:695-699.
48. Pendlebury ST, Welch SJ, Cuthbertson FC, Mariz J, Mehta Z, Rothwell PM. Telephone assessment
of cognition after transient ischemic attack and stroke: modified telephone interview of cognitive
status and telephone Montreal Cognitive Assessment versus face-to-face Montreal Cognitive
Assessment and neuropsychological battery. Stroke. 2013; 44: 227-229.
49. Rabin R, Gudex C, Selai C, Herdman M. From translation to version management: a history and
review of methods for the cultural adaptation of the EuroQol five-dimensional questionnaire.
Value Health. 2014; 17: 70-76.
50. Hays RD, Bjorner JB, Revicki DA, Spritzer KL, Cella D. Development of physical and mental health
summary scores from the patient-reported outcomes measurement information system (PROMIS)
global items. Qual Life Res. 2009; 18:873-880.
51. Winter Y, Wolfram C, Schaeg M et al. Evaluation of costs and outcome in cardioembolic stroke or
TIA. J Neurol 2009; 256:954–63
52. Makris M, Van Veen JJ, Tait CR, Mumford AD, Laffan M on behalf of the British Committee for
Standards in Haematology. Guideline on the management of bleeding in patients on
antithrombotic agents. Br J Haematol 2012; 160:35-46.
53. Abdul-Rahim AH, Fulton RL, Frank B, Tatlisumak T, Paciaroni M, Caso V, Diener HC, Lees KR; VISTA
collaborators. Association of improved outcome in acute ischaemic stroke patients with atrial
fibrillation who receive early antithrombotic therapy: analysis from VISTA. Eur J Neurol. 2015;
22:1048-1055. doi: 10.1111/ene.12577.
54. Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. 27 November 2017.
Bethesda, MD: National Cancer Institute, 2017.
55. Seiffge DJ, Paciaroni M, et al. Direct oral anticoagulants versus vitamin K antagonists after recent
ischemic stroke in patients with atrial fibrillation. Ann Neurol 2019;85:823-834.
56. Seiffge DJ, Werring DJ, et al. Timing of anticoagulation after recent ischaemic stroke in patients
with atrial fibrillation. Lancet Neurol 2019;18:117-126.

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 74 of 75



     

OPTIMAS

10 Appendix 1: Trial documentation for when patients lack capacity

Country Information to be provided Document to be signed

England and • Personal Consultee covering letter Personal consultee declaration form
Wales OR OR
Nominated Consultee covering letter Nominated consultee declaration
• Full Patient Information Sheet form

Scotland • Personal legal representative Personal legal representative

covering letter informed consent form
• Full Patient Information Sheet

Northern Ireland To close relative/close friend (where Close relative/close friend

(before MCA available): declaration form
2016 • Close relative or close friend AND
implementation) covering letter (Northern Ireland) MDT declaration form
• Full or short Patient Information
Sheet
To Multidisciplinary Team (MDT):
• MDT covering letter
• Full Patient Information Sheet

UCL CCTU OPTIMAS Trial

IRAS: 249552; REC: 19/SC/0021
Protocol Version 5.0, dated 22 July 2021 Page 75 of 75
Certificate Of Completion
Envelope Id: 3C136681A3FC40829FBD3CD0DB706952 Status: Completed
Subject: Please DocuSign: OPTIMAS Protocol_v5.0_22 Jul 2021_clean_CPM name change.pdf
Source Envelope:
Document Pages: 75 Signatures: 4 Envelope Originator:
Certificate Pages: 5 Initials: 0 Maryam Balogun
AutoNav: Enabled 90 High Holborn 2nd Floor London
EnvelopeId Stamping: Enabled , London WC1V 6LJ
Time Zone: (UTC) Dublin, Edinburgh, Lisbon, London [email protected]
IP Address: 144.82.114.192

Record Tracking
Status: Original Holder: Maryam Balogun Location: DocuSign
16 August 2021 | 10:22 [email protected]

Signer Events Signature Timestamp

Marisa Chau Sent: 16 August 2021 | 10:28
[email protected] Viewed: 17 August 2021 | 11:33
Clinical Project Manager Signed: 17 August 2021 | 11:33
UCL
Signature Adoption: Pre-selected Style
Security Level: Email, Account Authentication
(Optional) Using IP Address: 144.82.114.191

Electronic Record and Signature Disclosure:

Not Offered via DocuSign

David Werring Sent: 17 August 2021 | 11:33

[email protected] Viewed: 01 September 2021 | 09:43
Professor of clinical neurology Signed: 01 September 2021 | 09:44
University College London (Stroke Research Centre)
Signature Adoption: Uploaded Signature Image
Security Level: Email, Account Authentication
(Optional) Using IP Address: 144.82.48.45

Electronic Record and Signature Disclosure:

Accepted: 01 September 2021 | 09:43
ID: c140f68d-d4ce-445a-864d-b799de0ba197

Nick Freemantle Sent: 01 September 2021 | 09:44

[email protected] Viewed: 01 September 2021 | 11:26
Professor & Director Signed: 01 September 2021 | 11:26
Comprehensive Clinical Trials Unit (CCTU) at UCL
Signature Adoption: Pre-selected Style
Security Level: Email, Account Authentication
(Optional) Using IP Address: 86.175.67.205

Electronic Record and Signature Disclosure:

Accepted: 22 September 2020 | 10:02
ID: fe2ae0ae-56f3-4f05-b488-9f99b0266d69

In Person Signer Events Signature Timestamp

Editor Delivery Events Status Timestamp

Agent Delivery Events Status Timestamp

Intermediary Delivery Events Status Timestamp

Certified Delivery Events Status Timestamp

Carbon Copy Events Status Timestamp

Witness Events Signature Timestamp

Notary Events Signature Timestamp

Envelope Summary Events Status Timestamps

Envelope Sent Hashed/Encrypted 16 August 2021 | 10:28
Certified Delivered Security Checked 01 September 2021 | 11:26
Signing Complete Security Checked 01 September 2021 | 11:26
Completed Security Checked 01 September 2021 | 11:26

Payment Events Status Timestamps

Electronic Record and Signature Disclosure
 !


!"
  "
!


!

$
 
!

!
#


!

ELECTRONIC RECORD AND SIGNATURE DISCLOSURE

From time to time, Comprehensive Clinical Trials Unit (CCTU) at UCL (we, us or Company)
may be required by law to provide to you certain written notices or disclosures. Described below
are the terms and conditions for providing to you such notices and disclosures electronically
through the DocuSign system. Please read the information below carefully and thoroughly, and if
you can access this information electronically to your satisfaction and agree to this Electronic
Record and Signature Disclosure (ERSD), please confirm your agreement by selecting the
check-box next to ‘I agree to use electronic records and signatures’ before clicking
‘CONTINUE’ within the DocuSign system.

Getting paper copies

At any time, you may request from us a paper copy of any record provided or made available
electronically to you by us. You will have the ability to download and print documents we send
to you through the DocuSign system during and immediately after the signing session and, if you
elect to create a DocuSign account, you may access the documents for a limited period of time
(usually 30 days) after such documents are first sent to you. After such time, if you wish for us to
send you paper copies of any such documents from our office to you, you will be charged a
$0.00 per-page fee. You may request delivery of such paper copies from us by following the
procedure described below.

Withdrawing your consent

If you decide to receive notices and disclosures from us electronically, you may at any time
change your mind and tell us that thereafter you want to receive required notices and disclosures
only in paper format. How you must inform us of your decision to receive future notices and
disclosure in paper format and withdraw your consent to receive notices and disclosures
electronically is described below.

Consequences of changing your mind

If you elect to receive required notices and disclosures only in paper format, it will slow the
speed at which we can complete certain steps in transactions with you and delivering services to
you because we will need first to send the required notices or disclosures to you in paper format,
and then wait until we receive back from you your acknowledgment of your receipt of such
paper notices or disclosures. Further, you will no longer be able to use the DocuSign system to
receive required notices and consents electronically from us or to sign electronically documents
from us.

All notices and disclosures will be sent to you electronically

Unless you tell us otherwise in accordance with the procedures described herein, we will provide
electronically to you through the DocuSign system all required notices, disclosures,
authorizations, acknowledgements, and other documents that are required to be provided or made
available to you during the course of our relationship with you. To reduce the chance of you
inadvertently not receiving any notice or disclosure, we prefer to provide all of the required
notices and disclosures to you by the same method and to the same address that you have given
us. Thus, you can receive all the disclosures and notices electronically or in paper format through
the paper mail delivery system. If you do not agree with this process, please let us know as
described below. Please also see the paragraph immediately above that describes the
consequences of your electing not to receive delivery of the notices and disclosures
electronically from us.

How to contact Comprehensive Clinical Trials Unit (CCTU) at UCL:

You may contact us to let us know of your changes as to how we may contact you electronically,
to request paper copies of certain information from us, and to withdraw your prior consent to
receive notices and disclosures electronically as follows:
To contact us by email send messages to: [email protected]

To advise Comprehensive Clinical Trials Unit (CCTU) at UCL of your new email address

To let us know of a change in your email address where we should send notices and disclosures
electronically to you, you must send an email message to us at [email protected] and in the
body of such request you must state: your previous email address, your new email address. We
do not require any other information from you to change your email address.

If you created a DocuSign account, you may update it with your new email address through your
account preferences.

To request paper copies from Comprehensive Clinical Trials Unit (CCTU) at UCL

To request delivery from us of paper copies of the notices and disclosures previously provided
by us to you electronically, you must send us an email to [email protected] and in the body of
such request you must state your email address, full name, mailing address, and telephone
number. We will bill you for any fees at that time, if any.

To withdraw your consent with Comprehensive Clinical Trials Unit (CCTU) at UCL

To inform us that you no longer wish to receive future notices and disclosures in electronic
format you may:
i. decline to sign a document from within your signing session, and on the subsequent page,
select the check-box indicating you wish to withdraw your consent, or you may;

ii. send us an email to [email protected] and in the body of such request you must state your
email, full name, mailing address, and telephone number. We do not need any other information
from you to withdraw consent.. The consequences of your withdrawing consent for online
documents will be that transactions may take a longer time to process..

Required hardware and software

The minimum system requirements for using the DocuSign system may change over time. The
current system requirements are found here: https://support.docusign.com/guides/signer-guide-
signing-system-requirements.

Acknowledging your access and consent to receive and sign documents electronically

To confirm to us that you can access this information electronically, which will be similar to
other electronic notices and disclosures that we will provide to you, please confirm that you have
read this ERSD, and (i) that you are able to print on paper or electronically save this ERSD for
your future reference and access; or (ii) that you are able to email this ERSD to an email address
where you will be able to print on paper or save it for your future reference and access. Further,
if you consent to receiving notices and disclosures exclusively in electronic format as described
herein, then select the check-box next to ‘I agree to use electronic records and signatures’ before
clicking ‘CONTINUE’ within the DocuSign system.

By selecting the check-box next to ‘I agree to use electronic records and signatures’, you confirm
that:

 You can access and read this Electronic Record and Signature Disclosure; and
 You can print on paper this Electronic Record and Signature Disclosure, or save or send
this Electronic Record and Disclosure to a location where you can print it, for future
reference and access; and
 Until or unless you notify Comprehensive Clinical Trials Unit (CCTU) at UCL as
described above, you consent to receive exclusively through electronic means all notices,
disclosures, authorizations, acknowledgements, and other documents that are required to
be provided or made available to you by Comprehensive Clinical Trials Unit (CCTU) at
UCL during the course of your relationship with Comprehensive Clinical Trials Unit
(CCTU) at UCL.
 A RANDOMISED CONTROLLED TRIAL

UCL CTU ID: CTU/2017/300

UCL SPONSOR ID: 132084
Protocol version: 5.0 dated 22 July 2021
Research Ethics Committee Number: 19/SC/0021 (all nations),
20/SS/0069 (Scotland)

STATISTICAL ANALYSIS PLAN (SAP)

VERSION 1.0, 1ST JULY 2024

Approved by: Signature Date

Professor David Werring
Chief Investigator

Professor Nick Freemantle

Director CCTU

Prepared by: Norin Ahmed

Trial Statistician
Email: [email protected]
Tel. +44 (0) 20 7679 9095
Professor Nick Freemantle
Oversight Statistician
Email: [email protected]
Tel: +44 (0)20 3549 5017
 CONTENTS
1 ABBREVIATIONS AND GLOSSARY ......................................................................... 3
2 INTRODUCTION ................................................................................................... 9
2.1 Background and rationale.................................................................................... 9
2.2 Objectives ........................................................................................................... 9
2.3 Estimand framework9 ........................................................................................ 10
3 STUDY METHODS .............................................................................................. 11
3.1 Trial design........................................................................................................ 11
3.2 Randomisation .................................................................................................. 11
3.3 Sample size ....................................................................................................... 11
3.4 Statistical interim analyses and stopping guidance ............................................ 12
3.5 Timing of final analysis ...................................................................................... 12
3.6 Timing of outcome assessments ........................................................................ 12
4 STATISTICAL PRINCIPLES .................................................................................... 12
4.1 Confidence intervals and p-values ..................................................................... 12
4.2 Analysis population ........................................................................................... 12
5 TRIAL POPULATION ........................................................................................... 13
5.1 Screening, recruitment, withdrawal/follow-up .................................................. 13
5.2 Eligibility ........................................................................................................... 13
5.3 Baseline patient characteristics ......................................................................... 13
6 ANALYSIS .......................................................................................................... 14
6.1 Outcome definitions .......................................................................................... 14
6.1.1 Primary outcome ......................................................................................................... 14
6.1.2 Secondary outcomes ................................................................................................... 14
6.1.3 Rationale and details for outcome measures.............................................................. 15
7 ANALYSIS METHODS.......................................................................................... 15
7.1 Adjustment factors ............................................................................................ 15
7.2 Primary outcome analysis.................................................................................. 16
7.3 Secondary outcome analysis (excluding Health Economic Outcomes) ................. 17
7.4 Subgroup analysis ............................................................................................. 18
7.5 Neuroimaging Substudy analysis ....................................................................... 19
7.6 Missing data...................................................................................................... 19
8 REFERENCES ...................................................................................................... 19
9 APPENDICES ...................................................................................................... 21
9.1 Dummy Tables .................................................................................................. 21
9.2 Neuroimaging Substudy Analysis Plan ............................................................... 28

OPTIMAS SAP V1.0, 1st July 2024 Page 2 of 37

 1 ABBREVIATIONS AND GLOSSARY

AE Adverse Event
AF Atrial fibrillation
AR Adverse Reaction
ASU Acute stroke unit
CA Competent Authority
CCTU Comprehensive Clinical Trials Unit
CI Chief Investigator
CRF Case Report Form
CSRI Client Service Receipt Inventory
CT Computed tomography
CTA Clinical Trial Authorisation
CTCAE Common Terminology Criteria for Adverse Events
CV Curriculum Vitae
CVT Cerebral venous thrombosis
DOAC Direct Oral Anticoagulant
DVT Deep vein thrombosis
EC Ethics Committee
EU European Union
EAC Event Adjudication Committee
ECASS European Cooperative Acute Stroke Study
EQ-5D-5L EuroQol EQ-5D 5 level
HSCIC Health & Social Care Information Centre
HEAP Health Economic Analysis Plan
HES Hospital Episode Statistics
ICH GCP International Conference on Harmonisation Good Clinical
Practice
GDPR General Data Protection Regulation
GP General Practitioner
HASU Hyperacute stroke unit
HDU High-dependency unit
HSCR Health and Social Care Resources questionnaire

ICF Informed consent form

ICH Intracerebral haemorrhage
IDMC Independent Data Monitoring Committee

INR International Normalized Ratio

IQCODE Informant Questionnaire on Cognitive Decline in the Elderly

ISF Investigator Site File

ISTH International Society on Thrombosis and Haemostasis

OPTIMAS SAP V1.0, 1st July 2024 Page 3 of 37

ITT/mITT Intention to Treat/Modified Intention to Treat
MDT Multidisciplinary team
mRS Modified Rankin Scale
MHRA Medicines and Healthcare products Regulatory Agency

MoCA Montreal Cognitive Assessment

MRI Magnetic resonance imaging
NAE Notifiable Adverse Event
NHS National Health Service
NHS IEP NHS Imaging Exchange Portal
NIHSS National Institute of Health Stroke Scale
NOAC Non-vitamin K antagonist oral anticoagulants; DOAC and NOAC
are interchangeable terms
Non-CTIMP Trials that do not involve an Investigational Medicinal Product
OAC Oral Anticoagulant
PE Pulmonary embolism
PI Principal Investigator
PIS Participant Information Sheet
PROMIS - 10 Patient-Reported Outcomes Measurement Information System
QA Quality Assurance
QC Quality Control
QMMP Quality Management and Monitoring Plan
R&D Research and Development
REC Research Ethics Committee
SAE Serious Adverse Event
SAP Statistical Analysis Plan
SAR Serious Adverse Reaction
sICH Symptomatic intracranial haemorrhage

SmPC Summary of Product Characteristics

SSA Site Specific Approval
TIA Transient ischaemic attack
TMF Trial Master File
TMG Trial Management Group
TMT Trial Management Team
ToR Terms of Reference
TSC Trial Steering Committee
UCL University College London
USM Urgent Safety Measure
VKA Vitamin K antagonist

OPTIMAS SAP V1.0, 1st July 2024 Page 4 of 37

 Acute ischaemic stroke An episode of neurological dysfunction caused by
focal cerebral, spinal, or retinal infarction due to
interruption of the relevant blood supply, typically
by a thrombus (blood clot)
Anticoagulants Blood-thinning medication
Apixaban A factor Xa inhibitor indicated for stroke prevention
in non-valvular atrial fibrillation, at a standard dose
of 5mg BD, reduced to 2.5mg BD in certain patients.
Atrial fibrillation (AF) An abnormal heart rhythm (tachyarrhythmia)
characterised by irregular atrial contraction, which
increases the risk of stroke and blood clots. On the
electrocardiogram (ECG), AF is described by the
absence of consistent P waves; instead there are
rapid oscillations or fibrillatory waves that vary in
size, shape and timing and are generally associated
with an irregular ventricular response when
atrioventricular (AV) conduction is intact.
Clinically relevant non-major Clinically relevant non-major bleeding was defined
bleeding as overt bleeding not meeting the criteria for major
bleeding but associated with medical intervention,
unscheduled contact (visit or telephone) with a
physician, interruption or discontinuation of study
treatment, or associated with any other discomfort
such as pain or impairment of activities of daily life.
Computed tomography (CT) A diagnostic imaging test using x-rays to create
detailed images of internal organs including the
brain.
Dabigatran A direct thrombin inhibitor indicated for stroke
prevention in non-valvular atrial fibrillation, at a
standard dose of 150mg BD, reduced to 110mg BD in
certain patients.

Deep vein thrombosis A blood clot that develops in the large veins, usually
(DVT) in the legs.
Direct Oral Anticoagulants Specific oral anticoagulant drugs acting directly on
(DOACs) components of the coagulation pathway, including
the factor Xa inhibitors rivaroxaban, apixaban, and
edoxaban, and the direct thrombin inhibitor
dabigatran.

OPTIMAS SAP V1.0, 1st July 2024 Page 5 of 37

 Edoxaban A factor Xa inhibitor indicated for stroke prevention
in non-valvular atrial fibrillation at a standard dose
of 60mg OD, reduced to 30mg OD in certain
patients.

Endarterectomy The surgical removal of plaque from a narrowed

artery (usually the carotid) to restore blood flow and
prevent strokes.
EQ-5D-5L A standardized instrument developed by the
EuroQol Group as a measure of health-related
quality of life that can be used in a wide range of
health conditions and treatments.
Estimand A systematic description of the treatment effect to
be quantified in order to answer the trial’s research
objective.
Haemorrhagic transformation Bleeding occurring within infarcted brain tissue
following ischaemic stroke. Severity classified
radiologically (ECASS-2 classification) as:
• HI1: scattered small petechiae, no mass effect
• HI2: confluent petechiae, no mass effect
• PH1: haematoma within infarcted tissue,
occupying <30% infarct zone, no significant mass
effect
• PH2: haematoma occupying 30% or more of the
infarcted tissue, with obvious mass effect

International Normalised Ratio A blood test measuring how quickly a person’s blood
(INR) clots
Intracranial haemorrhage Bleeding within the skull. This includes intracerebral
haemorrhage (within the brain matter) as well as
subarachnoid, subdural and extradural haemorrhage
(outside the brain substance). It also includes
haemorrhagic transformation of a brain infarct.
Infarct An area of cell death due to an inadequate blood
supply.
Informant Questionnaire on The Informant Questionnaire for Cognitive Decline in
Cognitive Decline in the Elderly the Elderly is a structured interview based on
(IQCODE) informant responses that is used to assess for
possible dementia. In OPTIMAS it will be used to
screen for pre-stroke dementia.

OPTIMAS SAP V1.0, 1st July 2024 Page 6 of 37

 Major bleeding Major bleeding is defined as clinically overt bleeding
associated with any of the following: fatal outcome,
involvement of a critical anatomic site (intracranial,
spinal, ocular, pericardial, articular, retroperitoneal,
or intramuscular with compartment syndrome), fall
in haemoglobin concentration of at least 20 g/L or
transfusion of 2 or more units of red blood cells.
Minor bleeding Bleeding events that do not meet the criteria of
major or clinically relevant non-major bleeding are
defined as minor.
Modified Rankin Scale (mRS) Modified Rankin Scale measures functional ability
(the degree of disability and dependence) following
a stroke.
Montreal Cognitive Assessment The Montreal Cognitive Assessment is a
(MoCA) questionnaire widely used as a screening assessment
for detecting cognitive impairment.
Magnetic resonance imaging Magnetic resonance imaging is a type of scan that
(MRI) uses strong magnetic fields and radio waves to
produce detailed images of the inside of the body.
National Institute of Health Stroke The NIHSS is a standardised clinical method for
Scale (NIHSS) assessing the severity of a stroke. The severity of
stroke is classified as: 0-4, 5-10, 11-15, 16-21, >21.
Nearest relative The Adults with Incapacity (Scotland) Act 2000 uses
the hierarchy of relationships defined in the Mental
Health (Scotland) Act 1984 as the definition of
nearest relative. In decreasing order of closeness,
these are Spouse; Child; Father or mother; Brother
or sister; Grandparent; Grandchild; Uncle or aunt;
Nephew or niece.
Patient-Reported Outcomes The PROMIS Global-10 is an assessment tool that
Measurement Information System allows measurements of symptoms, functioning, and
(PROMIS – 10) healthcare-related quality of life (HRQoL) for a wide
variety of chronic diseases and conditions.
Rivaroxaban A factor Xa inhibitor licensed for stroke prevention
in non-valvular atrial fibrillation at a standard dose
of 20mg OD, reduced to 15mg OD in certain
patients.
Symptomatic intracranial Bleeding within the cranial vault causing clinical
haemorrhage (sICH) symptoms or signs, typically a focal neurological
deficit, headache, seizure or change in level of
consciousness.
Transient ischaemic attack (TIA) Transient focal neurological symptoms due to
inadequate blood supply to part of the brain, lasting
less than 24hrs and typically less than an hour.

OPTIMAS SAP V1.0, 1st July 2024 Page 7 of 37

 Warfarin A vitamin K antagonist oral anticoagulant licensed
for stroke prevention in atrial fibrillation.
Welfare guardian A person appointed by court to take action and
make decisions on behalf of an adult with incapacity,
in relation to that adult’s personal welfare; under
the Adults with Incapacity (Scotland) Act.
Welfare attorney A power of attorney is an authority given by an
individual (known as the Granter) to another
person(s) (known as the Attorney/s) to deal with
aspects of the Granter’s affairs, under the Adult with
Incapacity (Scotland) Act. In the case of Welfare
Attorney, the Granter gives authority to deal with
their personal welfare.

OPTIMAS SAP V1.0, 1st July 2024 Page 8 of 37

 2 INTRODUCTION

2.1 Background and rationale

About 20-30% of all ischaemic strokes are associated with atrial fibrillation (AF)1. Although
the long-term net benefit of oral anticoagulation for stroke prevention in AF is well-
established2, when to start anticoagulation in the acute phase after ischaemic stroke –
balancing the risks of early recurrent ischaemic stroke and haemorrhagic transformation of
the acute infarct – is a frequent and important dilemma in stroke medicine3, 4 . Indeed, the
first large scale phase 3 DOAC AF trials excluded patients with recent ischaemic stroke due
to concerns about a potential increased risk of intracranial bleeding.

Although numerous observational studies5 and two randomised controlled trials6, 7 have
investigated this question, substantial clinical uncertainty remains due to biases and
confounding inherent in the observational data and limited statistical power in the
randomised trials3, 4, 8. Thus, uncertainty remains about the superiority of early
anticoagulation and the effects of DOAC timing in key subgroups such as infarct size or
stroke severity. In particular, the limited number of participants with moderate-to-severe
strokes limits generalisability to the full population of patients with acute ischaemic stroke
and atrial fibrillation. The ELAN trial7 also excluded the key high-risk group of patients taking
oral anticoagulation at the time of their stroke, and those with parenchymal haemorrhage
types 1 and 2 (but not those with haemorrhagic infarction type 1 and 2) 7.

2.2 Objectives

OPTIMAS will investigate whether early initiation of DOAC treatment, within 4 days (96hrs)
of onset, in patients with acute ischaemic stroke and AF is non-inferior to, or better than,
standard initiation of DOAC treatment, no sooner than day 7 (>144hrs) and no later than
day 14 (<336hrs) after onset, in preventing recurrent ischaemic stroke, systemic embolism
and symptomatic intracranial haemorrhage (sICH).

OPTIMAS SAP V1.0, 1st July 2024 Page 9 of 37

2.3 Estimand framework9

Characteristic of estimand (primary Definition and method of analysis

outcome)
Population Participants aged 18 years or over, clinical
diagnosis of acute ischaemic stroke, AF
(including paroxysmal, persistent or
permanent AF, or atrial flutter). Eligibility to
commence DOAC in accordance with
approved prescribing recommendations
and SmPC confirmed by treating physician
and uncertainty on the part of the treating
physician regarding early versus standard
initiation of DOAC.
Treatment conditions Early (within ≤4 days [96hrs]) versus
standard (between day 7 and day 14 after
stroke onset) initiation of anticoagulation
after stroke in patients with AF, using any
licensed dose of a DOAC.
Primary outcome Composite endpoint of all causes of stroke,
(i.e., recurrent ischaemic stroke,
symptomatic intracranial haemorrhage
(including haemorrhagic transformation of
the infarct, and strokes that cannot be
classified as ischaemic or haemorrhagic due
to insufficient data), unclassified stroke
syndromes) and systemic arterial embolism
at 90 days from randomisation.
Summary measure Difference between study arms in
proportion of patients with primary
outcome
Intercurrent events handling
i. DOAC not initiated (clinical Treatment policy
or patient decision not to
start DOAC)
ii. DOAC initiated outside of Treatment policy
allocated time
iii. Treatment allocation cross Treatment policy
over
iv. Death (patient died prior to While alive (Data collected up to point of
initiation of DOAC) death)
v. Patient withdrawing their Treatment policy
consent for further follow-up
vi. Patient lost-to-follow-up Treatment policy

OPTIMAS SAP V1.0, 1st July 2024 Page 10 of 37

 3 STUDY METHODS

3.1 Trial design

OPTIMAS is a large, prospective, partially blinded randomised controlled trial of early (within
≤4 days [96 hours]) or standard (between day 7 and day 14 after stroke onset) initiation of
anticoagulation after stroke in patients with AF, using any licensed dose of a DOAC.

3.2 Randomisation

An independent online randomisation service (www.sealedenvelope.com) will be used to

minimise allocation bias within the trial. Stratification by stroke severity (NIHSS score at
randomisation) comprising five strata will be carried out using random permuted blocks
with randomly varying block lengths to ensure that balance across randomisation groups
will be achieved. The strata cut-offs for NIHSS will be as follows: 0-4, 5-10, 11-15, 16-21,
>2110.

3.3 Sample size

Our original planned sample size of 3478 patients assumed a reduction in the primary
outcome event rate from 11.5% in the control group to 8% in the intervention group. We
judged this to be a clinically meaningful benefit likely to influence guidelines and practice.
The assumed composite event rate and hypothesized effect size were derived from the
Virtual International Stroke Trials Archive of trials in patients with ischemic stroke and AF 5.
The sample size calculation used 90% power for superiority, significance level 5%, and was
inflated by 10% for loss to follow-up.

We re-evaluated study power in November 2021 due to a lower-than-expected interim

adjudicated primary outcome rate of 4.3% averaged across both treatment arms. Data
published in 2022 from a comparable trial, TIMING6, showed a reduced rate of ischaemic
stroke from 4.57% to 3.11%. This corresponds to an odds ratio of 0.67 (95% CI: 0.33 to 1.35).
With this lower event rate, our planned sample size has 80% power to show non-inferiority
based on an absolute non-inferiority margin of 2% (i.e. 2 percentage points) assuming an
equal rate of 4.3% in both arms and one-sided alpha of 5%, and 80% power for superiority
assuming an odds ratio of 0.62 with an assumed event rate in the control arm of 5.3%.

The ELAN7 trial, published in 2023, also found a reduced rate of ischaemic stroke at 90 days
in the early compared to the later treatment arm (1.9% compared to 3.1%, odds ratio, 0.60;
95% CI, 0.33 to 1.06)7. There was no difference in the rate of intracranial haemorrhage at
90 days (0.2% in both arms). In ELAN, the rate of a similar composite outcome to that used
in OPTMAS was 24/968 (2.48%) in the early arm compared to 42/965 (4.35%) in the later
arm7.

OPTIMAS SAP V1.0, 1st July 2024 Page 11 of 37

3.4 Statistical interim analyses and stopping guidance

No formal interim analysis is planned within the RCT, but regular reports concerning
participant safety and key efficacy outcomes will be prepared for the IDMC as agreed in the
Terms of Reference (ToR).

Stopping guidelines for efficacy data are based on modified Haybittle-Peto boundaries of 4
Standard Deviations (SD) in the first half of the study (recruitment of 50% of planned sample
size) and 3 SD in the second half. This is equivalent to calculating a 99.99% confidence
interval (or 99.7% confidence interval in the second half of the study) for the difference in
the risk of an ischaemic event (systemic embolism, recurrent ischaemic stroke and/or
intracranial haemorrhage), between the treatment groups.

Full descriptions of stopping rules and guidelines, where applicable, are described in detail
in the OPTIMAS IDMC ToR.

3.5 Timing of final analysis

The final analysis will start when all data for the primary endpoint is entered into the
database and all corresponding queries are resolved, at this point the database will be
locked meaning no data can be entered and/or modified.

3.6 Timing of outcome assessments

Outcome data for the primary outcome is collected at 90 days from randomisation.

4 STATISTICAL PRINCIPLES

4.1 Confidence intervals and p-values

All applicable statistical tests will be 2-sided and will be performed using a 5% significance
level, unless otherwise specified. All confidence intervals presented will be 95% and two-
sided.

4.2 Analysis population

The primary analysis will be conducted following the modified intention-to-treat (mITT)
principle in accordance with the randomised intervention. The analysis will include all
participants randomised into the trial, except those subsequently found not to have AF
and/or not to have a confirmed acute ischemic stroke.
OPTIMAS SAP V1.0, 1st July 2024 Page 12 of 37
Participants who are lost to follow-up with respect to binary endpoints within the 90-day
timeframe (e.g. the primary endpoint and its components) will be included in the primary
mITT analysis, with the assumption that for these participants the event did not take place.
For patients who withdrew their consent for further follow-up, the analysis will include
them, with the assumption that the event did not take place. For patients who died during
the 90-day follow-up without experiencing the primary endpoint, these will be included in
the mITT analysis. The reasoning described in this paragraph also applies to binary
endpoints within the 30-day timeframe.

5 TRIAL POPULATION

5.1 Screening, recruitment, withdrawal/follow-up

Recruitment will be presented by year and centre. Participants will be followed up for 90
days from randomisation. The throughput of patients from those screened, those
randomised and those assessed at each visit and included in the analysis will be summarised
in a CONSORT flowchart. The number of patients who withdraw and are unwilling to provide
follow-up will be reported by treatment arm.

5.2 Eligibility

Eligibility and inclusion/exclusion criteria are provided in section 6.3 of the protocol11.

5.3 Baseline patient characteristics

The list of baseline characteristics to be summarised is provided in Table A1 of the Appendix

at the end of this document.

Baseline characteristics include demographics such as sex, age and ethnicity, as well as
details of presenting stroke, clinical presentation and medical history. Other baseline
assessments include estimated pre-stroke mRS (a measure of function and dependence for
mobility and self-care), IQCODE (a measure of pre-stroke cognitive function) and EQ-5D-5L
(a measure of health-related quality of life) scores. Baseline characteristics will be
summarised by treatment arm using appropriate descriptive statistics; means and standard
deviations for approximately normally distributed variables, medians and interquartile
ranges for non-normally distributed variables and counts (percentages) for categorical
variables.

OPTIMAS SAP V1.0, 1st July 2024 Page 13 of 37

 6 ANALYSIS

6.1 Outcome definitions

6.1.1 Primary outcome

The primary outcome is the composite endpoint of all causes of stroke (i.e. recurrent
ischaemic stroke, symptomatic intracranial haemorrhage (including haemorrhagic
transformation of the infarct), and strokes that cannot be classified as ischaemic or
haemorrhagic due to insufficient data), unclassified stroke syndromes and systemic arterial
embolism within 90 days from randomisation.

6.1.2 Secondary outcomes

All secondary outcomes are within 90 days of randomisation (unless stated otherwise).

Efficacy outcomes:
1. All-cause mortality
2. Vascular death
3. Recurrent ischaemic stroke
4. Systemic arterial embolism
5. Venous thromboembolism (deep vein thrombosis [DVT], pulmonary embolism [PE],
cerebral venous thrombosis [CVT])
6. Functional status (assessed by the mRS scale)
7. Cognitive ability (assessed by the MoCA questionnaire)
8. Quality of life at 90 days (assessed by EQ-5D 5 level [EQ-5D-5L])
9. Patient reported outcomes (assessed by the PROMIS-10)
10. Ongoing anticoagulation
11. Time to event for overall survival
12. Time to first incidence of composite primary outcome plus overall survival
13. Time to first incidence of composite primary outcome (recurrent ischaemic stroke,
systemic arterial embolism, sICH or unclassifiable stroke syndromes)
14. Time to first incidence composite of the ischaemic components of the primary
outcome (ischaemic stroke and systemic embolism)
15. Time to first incidence of symptomatic ICH
16. Time to first incidence of ischaemic stroke
17. Time to first incidence of systemic arterial embolism
18. Length of hospital stay for stroke-related care
19. Health and Social Care Resources (assessed by a study-specific questionnaire: HSCR).

Safety outcomes:
20. Incidence of sICH at 90 days, classified according to site: intracerebral haemorrhage
(within the brain parenchyma); subdural haemorrhage; extradural haemorrhage;
subarachnoid haemorrhage; and haemorrhagic transformation of a brain infarct
21. Incidence of major extracranial bleeding
22. Incidence of all major bleeding (intracranial and extracranial)

OPTIMAS SAP V1.0, 1st July 2024 Page 14 of 37

 23. Incidence of clinically relevant non-major bleeding

Exploratory outcomes
24. Individual cognitive domain sub-scores (measured using the MoCA questionnaire)

6.1.3 Rationale and details for outcome measures

In AF-associated acute ischaemic stroke, the risk of early recurrence (within 7-14 days) is
high, between 0.4% and 1.3% per day2, 3, 12. AF-associated ischaemic strokes are more often
disabling or fatal than other types of stroke, with longer hospital stays and higher costs 13, so
preventing early recurrence is a key clinical challenge. Anticoagulation is extremely effective
for long term AF stroke prevention14, but safety and benefit in acute stroke has not been
established. Early anticoagulation (i.e. in the first few days) might increase the risk of sICH,
including haemorrhagic transformation of the infarct (estimated at ~1% per day 15), leading
to clinical uncertainty about when to start anticoagulation. Observational studies reported
an 8-10% risk of recurrent ischaemic stroke and a 2-4% risk of symptomatic intracranial
haemorrhage within 90 days of AF-associated ischaemic stroke16.

DOACs - apixaban, dabigatran, edoxaban or rivaroxaban - have a 50% lower risk of

intracranial haemorrhage compared to VKA. DOACs might allow safe and earlier oral
anticoagulation after acute ischaemic stroke in patients with AF, providing net benefit by
reducing ischaemic stroke recurrence without increased ICH risk5.

We chose a composite primary outcome of all strokes (due to both ischaemia or intracranial
bleeding) and systemic embolism as these events are those most likely to be modified by
the timing of anticoagulation and to be most clinically relevant for patients and treating
clinicians.

7 ANALYSIS METHODS

The results of the analyses will be reported following the principle of the ICH E3 guidelines
on the Structure and Content of Clinical Study Reports. Dummy tables are presented in the
Appendix.

7.1 Adjustment factors

The primary outcome model will be adjusted by the stratifying variable for stroke severity at
randomisation (NIHSS).

OPTIMAS SAP V1.0, 1st July 2024 Page 15 of 37

7.2 Primary outcome analysis

The primary outcome is the difference in proportion of patients, according to treatment

arm, with the composite endpoint of all causes of stroke, i.e. recurrent ischaemic stroke,
symptomatic intracranial haemorrhage (including haemorrhagic transformation of the
infarct, and strokes that cannot be classified as ischaemic or haemorrhagic due to
insufficient data), unclassified stroke syndromes and systemic arterial embolism at 90 days
from randomisation.

Since we are using a gatekeeper approach, the first stage of the analysis of the primary
outcome will be to establish non-inferiority. The non-inferiority margin of 2 percentage
points was set based on a traditional power calculation with our original target sample size
of 3478. Here, the null hypothesis assumes no difference in risk between early vs standard
DOAC. The non-inferiority margin set in the TIMING6 trial was an absolute difference of 3
percentage points. In our judgement this is a large difference given contemporary data on
event rates (e.g., a total event rate for our primary outcome of 66/1933, 3.41% in ELAN7).
We therefore regard our original non-inferiority margin of 2 points to be reasonable
because an absolute risk increase in our primary outcome of 2% baseline event rate of 3-4%
is likely to be considered clinically important and discouraging for the use of early DOAC. If
the non-inferiority condition is met, such that early initiation of DOAC is found to be non-
inferior to standard initiation in preventing the primary outcome event, we will then test for
superiority of the intervention compared to control.

The primary outcome has a binary classification in which a participant has either
experienced at least 1 or more of the individual primary endpoints or has not experienced
any of them. Mixed effects logistic regression will be used to determine whether there is
any difference in the risk of a primary outcome event using treatment arm as a binary
covariate. The results will be adjusted for the stratifying variable, NIHSS score at
randomisation, which will be included as an additional covariate in the model. Sites will be
included as random effects.

Should there be any issues with fitting the adjusted model, standard logistic regression will
be used. In this case, it will not be possible to account for variability between sites. The
model coefficient due to treatment will give an estimate of the difference in log odds, or
equivalently an estimate of the odds ratio and 95% confidence interval, adjusted for stroke
severity.

OPTIMAS SAP V1.0, 1st July 2024 Page 16 of 37

7.3 Secondary outcome analysis (excluding Health Economic Outcomes)

Secondary and exploratory outcomes will be handled similarly with adjustment for the
stratifying variable (stroke severity) and with sites included as random effects. All secondary
outcomes are within 90 days of randomisation.

Binary Outcomes
Binary secondary outcomes will be analysed using mixed effects logistic regression models.

• All-cause mortality
• Incidence of vascular death
• Incidence of recurrent ischaemic stroke
• Incidence of systemic arterial embolism
• Incidence of venous thromboembolism (a composite of deep vein thrombosis [DVT],
pulmonary embolism [PE], and cerebral venous thrombosis [CVT])
• Ongoing anticoagulation
• Incidence of symptomatic intracranial haemorrhage (sICH), classified according to
site: intracerebral haemorrhage (within the brain parenchyma); subdural
haemorrhage; extradural haemorrhage; subarachnoid haemorrhage; and
haemorrhagic transformation of a brain infarct
• Incidence of major extracranial bleeding
• Incidence of all major bleeding (intracranial and extracranial)
• Incidence of clinically relevant non-major bleeding

Continuous Outcomes
Continuous outcome measures will be analysed using mixed effects linear regression
models.
• Patient reported outcomes (assessed by the PROMIS-10)
• Length of hospital stay for stroke-related care
• Individual cognitive domain sub-scores (measured using the MoCA questionnaire).
• Quality of life at 90 days (assessed by EQ-5D 5 level [EQ-5D-5L])

Time to Event Outcomes

Time-to-event outcomes will be analysed using Kaplan-Meier plots and Cox proportional
hazards models.
• Time to event for overall survival
• Time to first incidence of composite primary outcome plus overall survival
• Time to first incidence of composite primary outcome (recurrent ischaemic stroke,
systemic arterial embolism, sICH or unclassifiable stroke syndromes)

OPTIMAS SAP V1.0, 1st July 2024 Page 17 of 37

• Time to first incidence composite of the ischaemic components of the primary outcome
(ischaemic stroke and systemic embolism)
• Time to first incidence symptomatic ICH
• Time to first incidence ischaemic stroke
• Time to first incidence systemic arterial embolism

Categorical Outcomes
Ordered categorical outcomes will be analysed using a mixed effects ordinal logistic
regression model.
• Functional status (assessed by the mRS scale)
• Cognitive ability (assessed by the MoCA questionnaire)

Adverse Events
Adverse events will be summarised in terms of the number of (serious) adverse events and
the number of participants with any (serious) adverse events in each randomised group and
compared using Fisher’s exact test. The difference (in the number of serious adverse events
in each randomised group) and 95% CI will be presented.

7.4 Subgroup analysis

Results of the primary outcome will be presented by stratum, i.e. according to the levels of
stroke severity at randomisation, the only stratifying variable used in the randomisation
process. An interaction between the subgroup and treatment will be added to the primary
analysis model to investigate whether the treatment effect differs according to the levels of
stroke severity (NIHSS 0-4, 5-10, 11-15, 16-21, >21). As the trial has not been powered to
detect this, this should be considered a supportive analysis.

Further hypothesis generating, supportive subgroup analyses will be undertaken for the
following groups:

1. Age (<75 years vs ≥75 years)

2. Sex (Male/Female)
3. Use of anticoagulation at the time of qualifying acute ischaemic stroke (Yes/No)
4. Atrial fibrillation previously known before qualifying acute ischaemic stroke (Yes/No)
5. Diabetes mellitus (Yes/No)
6. Known chronic kidney disease (Yes/No)
7. Reperfusion therapy (none/intravenous thrombolysis alone/ intravenous
thrombolysis and mechanical thrombectomy/mechanical thrombectomy alone)

OPTIMAS SAP V1.0, 1st July 2024 Page 18 of 37

7.5 Neuroimaging Substudy analysis

We will undertake a pre-specified imaging substudy to determine whether any

neuroimaging features modify the primary results of the trial. We will undertake these
analyses on both CT scans (for all participants) and MRI scans where available.

Subgroups will include:

1. Infarct size (minor, moderate, severe)

2. Infarct location (anterior vs posterior circulation)
3. Haemorrhagic transformation (none, petechial (HI1, HI2), parenchymal (PH1, PH2),
or remote)
4. Presence of severe cerebral small vessel disease (leukoaraiosis) on CT (Yes/No)
5. Presence of severe cerebral small vessel disease (leukoaraiosis) on MRI (Yes/No)
6. Number of cerebral microbleeds on MRI, categorised as 0, 1, 2-4, and 5 or more.

A full description of the planned neuroimaging substudy is provided in the Appendix.

7.6 Missing data

Missing data on the primary outcome is expected to be less than 10% based on previous
studies in this area. The primary outcome is achieved (or not) at 90 days during which time
the participant population is expected to maintain close ties with health services during
their stroke rehabilitation period. Missing covariate data are not anticipated since covariates
must be recorded to allocate treatment. The primary analysis is likelihood based and
therefore robust to the assumption of missing-at-random, and missing observations in
primary and secondary outcomes will not be imputed, but should substantial missing data
be encountered, the reasons for missingness will be investigated using logistic regression of
covariates on an indicator of missingness to help inform the interpretation of the trial
results.

A sensitivity analysis for the primary endpoint and its components will be undertaken,
where patients lost-to-follow-up and patients who have withdrawn their consent for further
follow-up will be excluded.

8 REFERENCES

1. Meinel TR, Branca M, De Marchis GM, Nedeltchev K, Kahles T, Bonati L, et al. Prior
Anticoagulation in Patients with Ischemic Stroke and Atrial Fibrillation. Ann Neurol. 2021;89(1):42-53.
2. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation: a major contributor to stroke in the elderly.
The Framingham Study. Arch Intern Med. 1987;147(9):1561-4; Wolf PA, Abbott RD, Kannel WB. Atrial
fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22(8):983-8.

OPTIMAS SAP V1.0, 1st July 2024 Page 19 of 37

3. Saxena R, Lewis S, Berge E, Sandercock PA, Koudstaal PJ. Risk of early death and recurrent
stroke and effect of heparin in 3169 patients with acute ischemic stroke and atrial fibrillation in the
International Stroke Trial. Stroke. 2001;32(10):2333-7.
4. Seiffge DJ, Cancelloni V, Räber L, Paciaroni M, Metzner A, Kirchhof P, et al. Secondary stroke
prevention in people with atrial fibrillation: treatments and trials. Lancet Neurol. 2024;23(4):404-17.
5. Seiffge DJ, Traenka C, Polymeris A, Hert L, Peters N, Lyrer P, et al. Early start of DOAC after
ischemic stroke: Risk of intracranial hemorrhage and recurrent events. Neurology. 2016;87(18):1856-
62.
6. Oldgren J, Åsberg S, Hijazi Z, Wester P, Bertilsson M, Norrving B. Early Versus Delayed Non-
Vitamin K Antagonist Oral Anticoagulant Therapy After Acute Ischemic Stroke in Atrial Fibrillation
(TIMING): A Registry-Based Randomized Controlled Noninferiority Study. Circulation.
2022;146(14):1056-66.
7. Fischer U, Koga M, Strbian D, Branca M, Abend S, Trelle S, et al. Early versus Later
Anticoagulation for Stroke with Atrial Fibrillation. New England Journal of Medicine.
2023;388(26):2411-21.
8. Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, et al.
Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial
fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383(9921):955-62.
9. Kahan BC, Morris TP, White IR, Carpenter J, Cro S. Estimands in published protocols of
randomised trials: urgent improvement needed. Trials. 2021;22(1):686.
10. Whiteley WN, Emberson J, Lees KR, Blackwell L, Albers G, Bluhmki E, et al. Risk of intracerebral
haemorrhage with alteplase after acute ischaemic stroke: a secondary analysis of an individual patient
data meta-analysis. Lancet Neurol. 2016;15(9):925-33.
11. Best JG, Arram L, Ahmed N, Balogun M, Bennett K, Bordea E, et al. Optimal timing of
anticoagulation after acute ischemic stroke with atrial fibrillation (OPTIMAS): Protocol for a
randomized controlled trial. Int J Stroke. 2022;17(5):583-9.
12. Berge E, Abdelnoor M, Nakstad PH, Sandset PM. Low molecular-weight heparin versus aspirin
in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. HAEST
Study Group. Heparin in Acute Embolic Stroke Trial. Lancet. 2000;355(9211):1205-10; Hart RG, Coull
BM, Hart D. Early recurrent embolism associated with nonvalvular atrial fibrillation: a retrospective
study. Stroke. 1983;14(5):688-93; Paciaroni M, Agnelli G, Micheli S, Caso V. Efficacy and safety of
anticoagulant treatment in acute cardioembolic stroke: a meta-analysis of randomized controlled
trials. Stroke. 2007;38(2):423-30.
13. Lin HJ, Wolf PA, Kelly-Hayes M, Beiser AS, Kase CS, Benjamin EJ, D'Agostino RB. Stroke severity
in atrial fibrillation. The Framingham Study. Stroke. 1996;27(10):1760-4.
14. Freedman B, Potpara TS, Lip GY. Stroke prevention in atrial fibrillation. Lancet.
2016;388(10046):806-17.
15. Paciaroni M, Agnelli G, Corea F, Ageno W, Alberti A, Lanari A, et al. Early hemorrhagic
transformation of brain infarction: rate, predictive factors, and influence on clinical outcome: results
of a prospective multicenter study. Stroke. 2008;39(8):2249-56.
16. Abdul-Rahim AH, Fulton RL, Frank B, Tatlisumak T, Paciaroni M, Caso V, et al. Association of
improved outcome in acute ischaemic stroke patients with atrial fibrillation who receive early
antithrombotic therapy: analysis from VISTA. Eur J Neurol. 2015;22(7):1048-55; Paciaroni M, Agnelli
G, Falocci N, Caso V, Becattini C, Marcheselli S, et al. Early Recurrence and Cerebral Bleeding in Patients
With Acute Ischemic Stroke and Atrial Fibrillation: Effect of Anticoagulation and Its Timing: The RAF
Study. Stroke. 2015;46(8):2175-82.

OPTIMAS SAP V1.0, 1st July 2024 Page 20 of 37

 9 APPENDICES

9.1 Dummy Tables

Table A1: Baseline Characteristics

Baseline Characteristic Early n= Standard n= Total N=
Age (years); mean (sd)
Estimated pre-stroke mRS score; mean (sd)
Sex
Female; n (%)
Male; n (%)
Ethnicity
*Caucasian; n (%)
**All Other Ethnic Groups; n (%)
Not Stated; n (%)
Anticoagulant/Antiplatelet prior to admission
No; n (%)
Yes; n (%)
Was/is the participant on warfarin?
No; n (%)
Yes; n (%)
Was/is the participant taking a DOAC?
No; n (%)
Yes; n (%)
IV Thrombolysis
No; n (%)
Yes; n (%)
Endovascular treatment
No; n (%)
Yes; n (%)
Hypercholesterolemia
No; n (%)
Yes; n (%)
Not Known; n (%)
Diabetes type 1 or 2, known prior to stroke or
diagnosis
No; n (%)
Yes; n (%)
Not Known; n (%)

OPTIMAS SAP V1.0, 1st July 2024 Page 21 of 37

 Hypertension
No; n (%)
Yes; n (%)
Not Known; n (%)
Known chronic kidney disease
No; n (%)
Yes; n (%)
Not Known; n (%)
Known dementia/cognitive impairment
No; n (%)
Yes; n (%)
Not Known; n (%)
Smoker status
Current smoker; n (%)
Ex smoker; n (%)
Never smoked; n (%)
Not Known; n (%)
Current alcohol intake >14 units per week
No; n (%)
Yes; n (%)
Not Known; n (%)
Myocardial infarction
No; n (%)
Yes; n (%)
Not Known; n (%)
Coronary Revascularisation
No; n (%)
Yes; n (%)
Not Known; n (%)
Congestive heart failure
No; n (%)
Yes; n (%)
Not Known; n (%)
History of angina
No; n (%)
Yes; n (%)
Not Known; n (%)
Peripheral arterial disease
No; n (%)
Yes; n (%)

OPTIMAS SAP V1.0, 1st July 2024 Page 22 of 37

 Not Known; n (%)
Previous ischaemic stroke
No; n (%)
Yes; n (%)
Previous other intracranial bleeding
No; n (%)
Yes; n (%)
Type of Atrial fibrillation
Paroxysmal; n (%)
Persistent; n (%)
Previous hospitalisation for extracranial
bleeding?
No; n (%)
Yes; n (%)
Stroke severity (NIHSS) at Admission
0-4; n (%)
5-10; n (%)
11-15; n (%)
16-21; n (%)
>21; n (%)
Stroke severity (NIHSS) at Randomisation
0-4; n (%)
5-10; n (%)
11-15; n (%)
16-21; n (%)
>21; n (%)
*Caucasian include White British, White Other and White Irish
**All Other Ethnic Groups include Black, Asian and other ethnic minorities (BAME)

Table A2: Primary outcome

Early n= Standard n= Adjusted Risk
Difference (95% CI) p-value
*Composite
primary outcome
total; n (%)
*Composite primary outcome includes the number of participants experiencing at least 1 or
more of the composite endpoints, including stroke of any cause (recurrent symptomatic
ischaemic stroke, symptomatic intracranial haemorrhage, unclassified stroke syndromes)
and/or systemic arterial embolism, within the 90 days following randomisation.

OPTIMAS SAP V1.0, 1st July 2024 Page 23 of 37

Table A3: Secondary outcomes
Early n= Standard n= Adjusted Risk
Secondary Outcome Difference (95% CI) p-value
Recurrent ischaemic stroke; n
(%)
Symptomatic intracranial
haemorrhage (sICH); n (%)
Unclassifiable stroke syndromes;
n (%)
Systemic arterial embolism; n
(%)
All-cause mortality; n (%)
Vascular death; n (%)
Venous thromboembolism; n (%)
Functional status (assessed by
the mRS scale); n (%)
Ongoing anticoagulation at 90
days from randomisation; n (%)
Adjusted coefficient
(95% CI) p-value
Patient reported outcomes
(assessed by the PROMIS-10)
Physical health); mean (sd)
Mental health); mean (sd)

Length of hospital stay for

stroke-related care); mean (sd)
Individual cognitive domain
subscores (MoCA); mean (sd)
Overall MoCA; mean (sd)
Quality of life: EQ-5D-5L score;
mean (sd)
Adjusted Hazard
Ratio (95% CI) p-value
Time to event for overall
survival; med (IQR)
Time to first incidence of
composite primary outcome plus
overall survival; med (IQR)
Time to first incidence of
composite primary outcome;
med (IQR)
Time to first incidence
composite of the ischaemic
components of the primary

OPTIMAS SAP V1.0, 1st July 2024 Page 24 of 37

 outcome (ischaemic stroke and
systemic embolism); med (IQR)
Time to first incidence of
symptomatic ICH; med (IQR)
Time to first incidence ischaemic
stroke; med (IQR)
Time to first incidence systemic
arterial embolism; med (IQR)
med = median, IQR = interquartile range

Table A4: Safety Outcomes

Early n= Standard n= Adjusted
Risk
Difference
Safety Outcome (95% CI) p-value
Symptomatic intracranial haemorrhage
(sICH) according to site:
intracerebral haemorrhage (within the
brain parenchyma); n (%)

subdural haemorrhage; n (%)

extradural haemorrhage; n (%)

subarachnoid haemorrhage; n (%)

haemorrhagic transformation of a brain
infarct; n (%)
Major extracranial bleeding; n (%)
Major bleeding (intracranial and
extracranial); n (%)
Clinically relevant non-major bleeding; n
(%)

Table A5: Serious Adverse Events (SAE)

Number of Patients Adjusted
reporting at least one SAE Early n= Standard n= coefficient (95%
and by type CI) p-value
SAE (unrelated); n (%)
SAE (related); n (%)

OPTIMAS SAP V1.0, 1st July 2024 Page 25 of 37

Table A6: Subgroup analyses
Adjusted
Risk
Difference Interaction
Early n= Standard n= (95% CI) p-value test p-value
Stroke severity (NIHSS)
at randomisation 0-4; n (%)
5-10; n (%)
11-15; n (%)
16-21; n (%)
>21; n (%)
Age (years)
<75; n (%)
≥75; n (%)
Sex
Female; n (%)
Male; n (%)
Use of anticoagulation at
the time of qualifying acute
ischaemic stroke
No; n (%)
Yes; n (%)
Atrial fibrillation previously
known before qualifying
acute ischaemic stroke
No; n (%)
Yes; n (%)

OPTIMAS SAP V1.0, 1st July 2024 Page 26 of 37

 Diabetes type 1 or 2, known
prior to stroke or diagnosis
No; n (%)
Yes; n (%)
Known chronic kidney
disease No; n (%)
Yes; n (%)
Reperfusion therapy
none; n (%)
intravenous thrombolysis
alone; n (%)
intravenous thrombolysis
and mechanical
thrombectomy;
mechanical n (%)
thrombectomy
alone; n (%)

OPTIMAS SAP V1.0, 1st July 2024 Page 27 of 37

9.2 Neuroimaging Substudy Analysis Plan

Optimal Timing of Anticoagulation After Stroke: A

Randomised Controlled Trial: Neuroimaging-based
Secondary Analysis Plan

Introduction and rationale

Atrial fibrillation (AF) causes 20-25% of all ischaemic strokes, and around one-half of patients
presenting with an acute ischaemic stroke are already known to have atrial fibrillation, or will
be diagnosed with atrial fibrillation during their initial hospitalisation (1). Although the long-
term net benefit of oral anticoagulation for stroke prevention in AF is well-established (2,3),
when to start anticoagulation in the acute phase after ischaemic stroke – balancing the risks
of early recurrent ischaemic stroke and haemorrhagic transformation of the acute infarct – is
a frequent and important dilemma in stroke medicine (4). A large number of observational
studies (5) and a single randomised controlled trial (6) have investigated this question;
however, this uncertainty remains unresolved due to the inherent limitations of observational
data, most notably selection bias, and a lower-than-projected sample size and inclusion of
few patients with moderate or severe stroke in the TIMING trial.

Although ongoing larger randomised controlled trials in this area, including OPTIMAS and
ELAN (7,8), may provide more definitive data on the overall safety and efficacy of
anticoagulation with a direct oral anticoagulant (DOAC) within a few days of stroke onset
compared to more delayed initiation, determining the optimal timing of anticoagulation
initiation for an individual patient will continue to require an individualised assessment of
their risks of early recurrence and of intracranial haemorrhage (ICH). The volume of infarcted
tissue, on theoretical grounds and based on observational data (9), is an important
determinant of the risk of haemorrhagic transformation. Clinical decision rules using a clinical
assessment of stroke severity as a proxy for infarct size have been proposed (10,11), and
stroke severity has been shown to influence anticoagulation timing in clinical practice (12).
However, this approach is based only on observational data and expert opinion, and stroke
severity may underestimate infarct size (for example, in posterior cerebral artery occlusion)
or overestimate it (for example, in brainstem infarction). There are also very few data on
whether anticoagulation timing should be influenced by the presence of imaging markers of
cerebral small vessel disease, the major cause of spontaneous ICH and an important risk factor
for symptomatic ICH following intravenous thrombolysis (13).

There is therefore a need for imaging-based analyses of data from randomised controlled
trials. OPTIMAS is the largest ongoing trial in this area, having recruited 3,648 participants and
now in follow-up. Although OPTIMAS does not use imaging data to determine participant
eligibility or anticoagulation timing, or obtain study-specific imaging, brain imaging performed
for clinical reasons is collected for all participants, providing the opportunity for imaging-
based secondary analyses. Here, we present the protocol for CT and MRI-based sub-studies

OPTIMAS SAP V1.0, 1st July 2024 Page 28 of 37

in OPTIMAS, investigating the influence of infarct size and cerebral small vessel disease on the
net benefit of early versus delayed anticoagulation with a direct oral anticoagulation (DOAC)
after AF-associated acute ischaemic stroke.

Methods and design

Study setting
The present study is a neuroimaging-based secondary analysis of OPTIMAS, a phase IV
multicentre randomised controlled trial with an open-label intervention, blinded end-point
adjudication, and hierarchical non-inferiority/superiority gatekeeper design, comparing a
policy of early DOAC initiation, within 4 days of stroke onset, to delayed initiation, 7 to 14
days from onset, in patients with AF and acute ischaemic stroke. The primary outcome of
OPTIMAS is a composite of recurrent ischaemic stroke, symptomatic ICH (including
haemorrhagic transformation), unclassifiable stroke syndromes, and systemic arterial
embolism incidence at 90 days post-randomisation. The target study sample size is 3,478
participants. OPTIMAS opened to recruitment in June 2019 and closed at the end of January
2024. It has recruited 3,648 participants from 100 stroke units in the United Kingdom.

Patient population
For each imaging exposure of interest, we will include all participants in OPTIMAS for whom
the relevant imaging exposure can be assessed on imaging acquired within 96 hours of stroke
onset and prior to DOAC administration. We will exclude participants for whom the imaging
exposure of interest cannot be measured due to absence of the relevant imaging modality or
the failure to acquire images of diagnostic quality (as assessed by the OPTIMAS imaging rating
team). For measurement of infarct size when participants have both MR and CT available to
assess, we will segment the infarct in MRI owing its higher diagnostic accuracy, and when
more than one CT is available we will choose the latest one prior to 96 hours.

When stroke onset is unknown and cannot be estimated clinically with reasonable
confidence, it should be determined in accordance with the main study protocol i.e. taken as
the time the patient was last known to be well.

Imaging data collection

Any brain imaging performed for clinical reasons while a participant is enrolled in OPTIMAS is
collected by the central study team, as well as imaging related to the qualifying stroke
performed prior to randomisation. Sites send imaging via a secure online file transfer portal
hosted at upload.optimas.org.uk, or exceptionally via posted CD if unable to use the online
portal due to local technical or information governance requirements. Sites are required to
pseudonymise imaging with the participant’s study ID prior to transfer. Files are sent in
DICOM format. Once received, imaging is checked, backed up to the study imaging repository
hosted by the UCL Research Data Storage service, and added to the study DICOM database
(accessed via RadiAnt). Before infarct segmentation we will convert all the data to nifti format
using the niftiReg software.

OPTIMAS SAP V1.0, 1st July 2024 Page 29 of 37

Imaging data quality assurance
The completeness of imaging data is monitored by the central study team. Sites report
imaging performed to the central study team at discharge from the recruiting hospital site,
and at the 90-day follow-up visit. These reports are regularly cross-checked against the
imaging received, and sites contacted with prompts as needed.
On receipt, scans are checked for completeness by trained research fellows, and sites
requested to resend incomplete imaging if needed. Scan quality will be assessed prior to
analysis, and scans which are not of diagnostic quality excluded. When multiple eligible scans
of the same modality and adequate technical quality are available, the last scan prior to DOAC
administration will be preferred.

Imaging rating procedures

Imaging variables of interest will be rated by trained research fellows, using validated rating
scales and consensus definitions when available (e.g. STRIVE, MARS) (14,15). To minimise
inter-rater variability, before analysing study images, all raters will be required to rate a
training set of thirty images of each modality for the primary exposures of interest and obtain
an inter-rater reliability of >0.8 with the reference labels. The training set will be labelled by
consultant neuroradiologists. To allow assessment of inter-rater reliability in the main study
dataset, a random 10% of study images will be rated by at least two raters. Inter-rater
reliability will be assessed using Krippendorff’s alpha for nominal or ordinal data, and the
intraclass correlation coefficient for continuous variables. When manually segmenting CT
infarcts, raters will use standard stroke windows (window 40, width 40) to identify the lesion,
and these can be adjusted manually to optimally delineate the margins. If available we will
segment the infarct on the thick axial slices, but we will use the thin slices if necessary for
difficult cases. We will use ITKSnap version 3.6.0 to segment the infarcts.

Automated segmentation of MR infarcts

For the quantitative assessment of infarcts on MRI, we will utilise a deep learning
segmentation model developed, validated out of sample, and described in detail elsewhere
(16). In brief, this model uses the Swin UNet TRansformer (SwinUNETR) architecture with a
custom loss function that optimises quantifying the volume and number of infarcts. This
provides fidelity in delineating not only single infarcts but multifocal embolic ischaemia. It was
trained on neuroimaging data from 10,463 patients, which includes 3563 infarct-positive
diffusion-weighted imaging (B1000) cases acquired as part of routine clinical care at a tertiary
neuroscience centre, and 6900 healthy controls. The model yields state-of-the-art
performance evaluated on a large clinical held-out test set, with equitable performance (17)
across patient demographics and all vascular territories. All model-derived lesion masks shall
be reviewed and – if required – corrected by a trained reader under the supervision of an
experienced neuroradiologist specialising in stroke imaging with more than 15 years of
experience.

OPTIMAS SAP V1.0, 1st July 2024 Page 30 of 37

Imaging variables of interest

Our primary exposures of interest are:

• Infarct volume, measured manually through computer-assisted planimetry. Infarct

volume will be measured on diffusion-weighted MRI sequences if available. If not, the
last CT scan acquired prior to DOAC administration and within 96 hours of stroke onset
will be used.

• Number of cerebral microbleeds on MRI, categorised as 0, 1, 2-4, and 5 or more.

Our secondary exposures of interest are:

• A semiquantitative classification of infarct size used previously in observational

studies and in the ELAN trial (8,9,16), estimated using diffusion-weighted MRI if
available, or the last eligible CT scan if not. Infarct size is classified as below:
 Minor: lesion <1.5cm maximum diameter in anterior or posterior circulation, or
multiple tiny spots (“embolic shower”)
 Moderate: lesion in cortical superficial branch of anterior, middle or posterior
cerebral arteries; in deep branch of middle cerebral artery; in internal borderzone
territories; or two minor lesions
 Major: lesion involving complete territory of anterior, middle or posterior cerebral
artery; lesion ≥ 1.5cm maximum diameter in brainstem or cerebellum; or two
moderate lesions

• CT markers of cerebral small vessel disease:

 Leukoaraiosis measured through total simplified Fazekas scale (17)
 Presence of one or more lacunes according to STRIVE definition (14)
 Overall CT Small Vessel Disease score, comprising leukoaraiosis, lacunes, and
atrophy (18)

• MRI markers of cerebral small vessel disease:

 Presence of multiple cerebral microbleeds in strictly lobar distribution (suggestive
of cerebral amyloid angiopathy)
 Presence of cortical superficial siderosis (focal or disseminated)
 White matter hyperintensity burden measured through total Fazekas score (19)
 Presence of one or more lacunes according to STRIVE definition
 Burden of MR-visible perivascular spaces in basal ganglia region, rated using an
established five-level ordinal scale (20)
 Overall MRI Total Small Vessel Disease score, comprising leukoaraiosis, white
matter hyperintensities, basal ganglia perivascular spaces and cerebral
microbleeds (21)

OPTIMAS SAP V1.0, 1st July 2024 Page 31 of 37

 • Presence of haemorrhagic transformation of the qualifying infarct classified by
Heidelberg criteria as petechial (1a/HI1 or 1b/HI2), parenchymal (1c/PH1 or 2/PH2),
or remote (3) (22).

Sample size estimates

The target sample size for OPTIMAS is 3,478 participants. In an interim analysis of the first
2,965 participants, all participants had a CT within 96 hours of onset, 33% had a CT between
12 and 96 hours of onset, 24% had an MRI within 96 hours of onset, and 57% had either a CT
acquired between 12 and 96 hours of onset or an MRI. Interim data suggests a primary
outcome rate of 4.3% (7). Allowing a conservative 5% margin for missing or poor-quality
imaging, we estimate a sample size of 1,883 participants (81 events) for analyses of infarct
volume, infarct size and haemorrhagic transformation, 790 participants (34 events) for
analyses of MRI markers of cerebral small vessel disease, and 3,304 participants (142 events)
for analyses of CT markers of cerebral small vessel disease.

Statistical analysis
For each imaging variable of interest, we will test for modification of the effect of treatment
allocation (early or delayed DOAC initiation) by including the imaging variable as an
interaction term with the independent variable representing treatment allocation (based on
the intention-to-treat principle) in a mixed-effects logistic regression model with the
occurrence of the primary study outcome as the dependent variable. If there is a significant
difference in NIHSS between the main trial groups, we will consider adjusting for stroke
severity (NIHSS) at randomisation. We will adjust for clustering by including sites as random
intercept terms. An interaction with p-value <0.05 will be accepted as statistically significant.
We will not adjust for multiple comparisons, but significant interactions for our secondary
exposures of interest will be treated as hypothesis-generating (23). We will not impute
missing exposures of interest but will include in each analysis all participants for whom the
relevant exposure of interest is available.

Additional secondary analyses may include:

• A sensitivity analysis excluding participants with CT imaging acquired between before
24 hours of stroke onset
• Sensitivity analyses around infarct size and volume assessed using CT only or MRI only
• Analysis of exposures of interest with respect to individual components of the primary
study outcome (e.g. ischaemic stroke, ICH)
• The feasibility and reliability of automated approaches to the measurement of infarct
volume

Discussion
Based on methodological recommendations for secondary analyses of clinical trials, our
imaging variables of interest are divided into primary and secondary exposures (23). Primary
exposures are those for which a subgroup analysis is well-motivated by external evidence,
and the results of which are intended to influence clinical practice; whereas analyses of
secondary exposures are less strongly supported by external evidence and are intended to be
hypothesis-generating.

OPTIMAS SAP V1.0, 1st July 2024 Page 32 of 37

We chose infarct volume measured by computer-assisted planimetry as our primary exposure
of interest for CT and MRI sub-studies as the volume of infarcted tissue is thought on
theoretical grounds to be a key determinant of the risk of haemorrhagic transformation, and
infarct size has been associated with risk of intracranial haemorrhage and recurrent ischaemic
stroke in a number of observational studies of patients initiating anticoagulation after AF-
associated stroke (4). Although time-consuming, planimetry is the current gold standard for
the measurement of infarct volume (24), with excellent inter-rater reliability between trained
raters (25). Assessing infarct size as volume, a continuous variable, gives the greatest
statistical power to detect an interaction and determine whether infarct size should influence
anticoagulation timing (26). Recognising the difficulty in manually measuring infarct volume
in clinical practice, we include a semiquantitative classification of infarct size as a secondary
outcome for both sub-studies, and a pooled analysis with the ELAN trial, which uses this
classification, is planned. In the future, improved image segmentation techniques may allow
the automated measurement of infarct volume in clinical practice.

To our knowledge, whether neuroimaging markers of cerebral small vessel disease should
influence the timing of anticoagulation initiation after ischaemic stroke is largely unstudied.
It is clear that cerebral small vessel disease is the main cause of intracerebral haemorrhage
overall, and likely also accounts for the majority of intracerebral haemorrhage in patients
taking oral anticoagulants (27). Although haemorrhagic transformation generally occurs
within infarcted brain tissue, it might be hypothesised that the risk of haemorrhagic
transformation would be higher in the presence of pre-existing vascular fragility. Of the
various CT and MRI markers of cerebral small vessel disease, we selected the burden of
cerebral microbleeds on MRI as a primary exposure of interest as it is the most prognostically
significant marker of long-term ICH risk in patients taking antithrombotics (28), and also
influences the risk of ICH after intravenous thrombolysis (29).
Haemorrhagic transformation is relatively common after cardioembolic stroke and often
delays anticoagulation (30,31). Participants with severe parenchymal or remote
haemorrhagic transformation (grade 2 or 3 by Heidelberg classification) are excluded from
OPTIMAS on safety grounds. However, minor haemorrhagic transformation (Heidelberg
grade 1) is not clearly associated with worse clinical outcome (32), and has not yet been
shown to affect the risk-benefit balance of early anticoagulation. As haemorrhagic
transformation is anticipated to be a rare baseline characteristic in the study sample, we will
investigate this question by combining CT and MRI data - the Heidelberg classification has
been proposed to apply to both (22). We will perform sensitivity analyses to address the
possibility that the prevalence and significance of haemorrhagic transformation may vary
according to imaging modality, given the very high sensitivity of blood-sensitive MRI
sequences.

To reflect how imaging might be used in clinical practice to decide between early and more
delayed anticoagulation, we include only participants with imaging acquired within 96 hours
of stroke onset. We exclude imaging acquired after DOAC initiation, as DOAC initiation could
affect some imaging features, notably the presence of haemorrhagic transformation and
cerebral microbleeds. We also exclude CT scans acquired fewer than 12 hours from stroke
onset, as the growth of the ischaemic core and the associated development of cytotoxic

OPTIMAS SAP V1.0, 1st July 2024 Page 33 of 37

oedema and CT hypodensity occurs over hours (33). We do not have an early limit on the
timing of MRI, as changes on diffusion-weighted MRI appear within minutes of stroke
symptom onset (34,35), although a relatively limited increase in lesion size may occur over
the first 72 hours (36). Excluding imaging acquired after 96 hours avoids the underestimation
of infarct size, as DWI changes may begin to normalise after this (36), and CT changes become
less conspicuous due to fogging (37).

References

1. Sposato LA, Cipriano LE, Saposnik G, Ruíz Vargas E, Riccio PM, Hachinski V. Diagnosis of
atrial fibrillation after stroke and transient ischaemic attack: a systematic review and
meta-analysis. Lancet Neurol. 2015 Apr;14(4):377–87.

2. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke
in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007 Jun
19;146(12):857–67.

3. Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, et al.
Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients
with atrial fibrillation: a meta-analysis of randomised trials. Lancet Lond Engl. 2014 Mar
15;383(9921):955–62.

4. Best JG, Cardus B, Klijn CJM, Lip G, Seiffge DJ, Smith EE, et al. Antithrombotic dilemmas in
stroke medicine: new data, unsolved challenges. J Neurol Neurosurg Psychiatry. 2022 Sep
1;93(9):939–51.

5. Seiffge DJ, Werring DJ, Paciaroni M, Dawson J, Warach S, Milling TJ, et al. Timing of
anticoagulation after recent ischaemic stroke in patients with atrial fibrillation. Lancet
Neurol. 2019 Jan 1;18(1):117–26.

6. Oldgren J, Åsberg S, Hijazi Z, Wester P, Bertilsson M, Norrving B, et al. Early Versus Delayed
Non–Vitamin K Antagonist Oral Anticoagulant Therapy After Acute Ischemic Stroke in
Atrial Fibrillation (TIMING): A Registry-Based Randomized Controlled Noninferiority
Study. Circulation. 2022 Oct 4;146(14):1056–66.

7. Best JG, Arram L, Ahmed N, Balogun M, Bennett K, Bordea E, et al. Optimal timing of
anticoagulation after acute ischemic stroke with atrial fibrillation (OPTIMAS): Protocol for
a randomized controlled trial. Int J Stroke Off J Int Stroke Soc. 2022 Jun;17(5):583–9.

8. Fischer U, Trelle S, Branca M, Salanti G, Paciaroni M, Ferrari C, et al. Early versus Late
initiation of direct oral Anticoagulants in post-ischaemic stroke patients with atrial
fibrillatioN (ELAN): Protocol for an international, multicentre, randomised-controlled,
two-arm, open, assessor-blinded trial. Eur Stroke J. 2022 Jun 15;23969873221106044.

OPTIMAS SAP V1.0, 1st July 2024 Page 34 of 37

9. Paciaroni M, Agnelli G, Falocci N, Caso V, Becattini C, Marcheselli S, et al. Early Recurrence
and Cerebral Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation: Effect
of Anticoagulation and Its Timing: The RAF Study. Stroke. 2015 Aug;46(8):2175–82.

10. Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, et al. 2016 ESC Guidelines
for the management of atrial fibrillation developed in collaboration with EACTS. Eur Eur
Pacing Arrhythm Card Electrophysiol J Work Groups Card Pacing Arrhythm Card Cell
Electrophysiol Eur Soc Cardiol. 2016 Nov;18(11):1609–78.

11. Kimura S, Toyoda K, Yoshimura S, Minematsu K, Yasaka M, Paciaroni M, et al. Practical “1-
2-3-4-Day” Rule for Starting Direct Oral Anticoagulants After Ischemic Stroke With Atrial
Fibrillation: Combined Hospital-Based Cohort Study. Stroke. 2022 May;53(5):1540–9.

12. Munn D, Abdul-Rahim AH, Fischer U, Werring DJ, Robinson TG, Dawson J. A survey of
opinion: When to start oral anticoagulants in patients with acute ischaemic stroke and
atrial fibrillation? Eur Stroke J. 2018 Dec;3(4):355–60.

13. Best JG, Jesuthasan A, Werring DJ. Cerebral small vessel disease and intracranial bleeding
risk: Prognostic and practical significance. Int J Stroke. 2023 Jan 1;18(1):44–52.

14. Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, et al. Neuroimaging
standards for research into small vessel disease and its contribution to ageing and
neurodegeneration. Lancet Neurol. 2013 Aug;12(8):822–38.

15. Gregoire SM, Chaudhary UJ, Brown MM, Yousry TA, Kallis C, Jäger HR, et al. The
Microbleed Anatomical Rating Scale (MARS): reliability of a tool to map brain
microbleeds. Neurology. 2009 Nov 24;73(21):1759–66.

16. Hatamizadeh A, Nath V, Tang Y, Yang D, Roth H, Xu D. Swin UNETR: Swin Transformers for
Semantic Segmentation of Brain Tumors in MRI Images. 2022;arXiv:2201.01266. Available
at: https://ui.adsabs.harvard.edu/abs/2022arXiv220101266H. Accessed January 01,
2022.

17. Carruthers R, Straw I, Ruffle JK, et al. Representational ethical model calibration. NPJ Digit
Med 2022;5:170.

18. Paciaroni M, Agnelli G, Falocci N, Tsivgoulis G, Vadikolias K, Liantinioti C, et al. Early

Recurrence and Major Bleeding in Patients With Acute Ischemic Stroke and Atrial
Fibrillation Treated With Non-Vitamin-K Oral Anticoagulants (RAF-NOACs) Study. J Am
Heart Assoc. 2017 Nov 29;6(12).

19. Swieten JC van, Hijdra A, Koudstaal PJ, Gijn J van. Grading white matter lesions on CT and
MRI: a simple scale. J Neurol Neurosurg Psychiatry. 1990 Dec 1;53(12):1080–3.

20. Appleton JP, Woodhouse LJ, Adami A, Becker JL, Berge E, Cala LA, et al. Imaging markers
of small vessel disease and brain frailty, and outcomes in acute stroke. Neurology. 2020
Feb 4;94(5):e439–52.

OPTIMAS SAP V1.0, 1st July 2024 Page 35 of 37

21. Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal abnormalities at 1.5
T in Alzheimer’s dementia and normal aging. AJR Am J Roentgenol. 1987 Aug;149(2):351–
6.

22. Potter GM, Chappell FM, Morris Z, Wardlaw JM. Cerebral perivascular spaces visible on
magnetic resonance imaging: development of a qualitative rating scale and its observer
reliability. Cerebrovasc Dis Basel Switz. 2015;39(3–4):224–31.

23. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. Stroke subtype, vascular risk
factors, and total MRI brain small-vessel disease burden. Neurology. 2014 Sep
30;83(14):1228–34.

24. von Kummer R, Broderick JP, Campbell BCV, Demchuk A, Goyal M, Hill MD, et al. The
Heidelberg Bleeding Classification. Stroke. 2015 Oct;46(10):2981–6.

25. Kent DM, Rothwell PM, Ioannidis JPA, Altman DG, Hayward RA. Assessing and reporting
heterogeneity in treatment effects in clinical trials: a proposal. Trials. 2010 Aug 12;11:85.

26. van der Worp HB, Claus SP, Bär PR, Ramos LM, Algra A, van Gijn J, et al. Reproducibility of
measurements of cerebral infarct volume on CT scans. Stroke. 2001 Feb;32(2):424–30.

27. Braun T, Pukropski J, Yeniguen M, El-Shazly J, Schoenburg M, Gerriets T, et al. Inter- and
intra-rater reliability of computer-assisted planimetry in experimental stroke research. J
Neurosci Methods. 2019 Jan 15;312:12–5.

28. Altman DG, Royston P. The cost of dichotomising continuous variables. BMJ. 2006 May
6;332(7549):1080.

29. Seiffge DJ, Wilson D, Ambler G, Banerjee G, Hostettler IC, Houlden H, et al. Small vessel
disease burden and intracerebral haemorrhage in patients taking oral anticoagulants. J
Neurol Neurosurg Psychiatry [Internet]. 2021 Mar 19 [cited 2021 Jul 12]; Available from:
https://jnnp.bmj.com/content/early/2021/03/18/jnnp-2020-325299

30. Best JG, Ambler G, Wilson D, Lee KJ, Lim JS, Shiozawa M, et al. Development of imaging-
based risk scores for prediction of intracranial haemorrhage and ischaemic stroke in
patients taking antithrombotic therapy after ischaemic stroke or transient ischaemic
attack: a pooled analysis of individual patient data from cohort studies. Lancet Neurol.
2021 Apr;20(4):294–303.

31. Charidimou A, Shoamanesh A, Wilson D, Gang Q, Fox Z, Jäger HR, et al. Cerebral
microbleeds and postthrombolysis intracerebral hemorrhage risk Updated meta-
analysis. Neurology. 2015 Sep 15;85(11):927–924.

32. Arboix A, Oliveres M, Massons J, Pujades R, García-Eroles L. Early differentiation of

cardioembolic from atherothrombotic cerebral infarction: a multivariate analysis. Eur J
Neurol. 1999;6(6):677–83.

OPTIMAS SAP V1.0, 1st July 2024 Page 36 of 37

33. Paciaroni M, Bandini F, Agnelli G, Tsivgoulis G, Yaghi S, Furie KL, et al. Hemorrhagic
Transformation in Patients With Acute Ischemic Stroke and Atrial Fibrillation: Time to
Initiation of Oral Anticoagulant Therapy and Outcomes. J Am Heart Assoc. 2018 Nov
20;7(22):e010133.

34. Berger C, Fiorelli M, Steiner T, Schäbitz WR, Bozzao L, Bluhmki E, et al. Hemorrhagic
transformation of ischemic brain tissue: asymptomatic or symptomatic? Stroke. 2001
Jun;32(6):1330–5.

35. Saver JL. Time Is Brain—Quantified. Stroke. 2006 Jan;37(1):263–6.

36. Yoneda Y, Tokui K, Hanihara T, Kitagaki H, Tabuchi M, Mori E. Diffusion-weighted magnetic

resonance imaging: Detection of ischemic injury 39 minutes after onset in a stroke
patient. Ann Neurol. 1999;45(6):794–7.

37. Hjort N, Christensen S, Sølling C, Ashkanian M, Wu O, Røhl L, et al. Ischemic injury

detected by diffusion imaging 11 minutes after stroke. Ann Neurol. 2005;58(3):462–5.

38. Lansberg MG, O’Brien MW, Tong DC, Moseley ME, Albers GW. Evolution of Cerebral
Infarct Volume Assessed by Diffusion-Weighted Magnetic Resonance Imaging. Arch
Neurol. 2001 Apr 1;58(4):613–7.

39. Wardlaw JM. RADIOLOGY OF STROKE. J Neurol Neurosurg Psychiatry. 2001 Apr
1;70(90001):7i–11.

OPTIMAS SAP V1.0, 1st July 2024 Page 37 of 37