EUnetHTA 21 JCAMD001 Optilume Assessment Report v1.1 2

JCAMD001 Assessment Report –
OPTILUME ® URETHRAL DRUG-COATED BALLOON
Version 1.1, 16/06/2023

Template Version 0.1, 03/03/2023
JCAMD001 Assessment Report
16 June 2023
Document history and contributors
Version Date Description

0.1 15-03-2023 First draft report
0.2 25-04-2023 Second draft report
0.3 22-05-2023 Final draft report validated by CSCQ
0.4 08-06-2022 Input from medical editor and factual accuracy check by the HTD
has been processed
0.5 08-06-2023 Final report endorsed by CEB
1.0 09-06-2023 Publication of report
1.1 16-06-2023 Minor editorial changes were made to the lay-out of the report. The
numbering of chapter 2 has been corrected. The titles of table 29 and
31 have been specified to indicate they address the main studies.
Disclaimers
This document was produced under the Third EU Health Programme through a service contract
with the European Health and Digital Executive Agency acting under mandate from the
European Commission. The information and views set out in this document are those of the
author(s) and do not necessarily reflect the official opinion of the Commission/Execut ive
Agency. The Commission/Executive Agency does not guarantee the accuracy of the data
included in this study. Neither the Commission/Executive Agency nor any person acting on the
Commission’s/Executive Agency’s behalf may be held responsible for the use which may be
made of the information contained herein.
This Joint Clinical Assessment (JCA) report is a pilot produced while the JCA report and
submission dossier templates were still in development, and it was used for further fine-tuning
of these templates.
Participants
Assessment team Haute Autorité de Santé (HAS), France
Austrian Institute for Health Technology Assessment (AIHTA), Austria
Project management Zorginstituut Nederland (ZIN), The Netherlands
CSCQ Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), Spain
CEB Austrian Institute for Health Technology Assessment (AIHTA), Austria
Belgian Health Care Knowledge Centre (KCE), Belgium
Gemeinsamer Bundesausschuss (G-BA), Germany
Haute Autorité de Santé (HAS), France
Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWIG), Germany
Italian Medicines Agency (AIFA), Italy
National Authority of Medicines and Health Products, I.P. (INFARMED), Portugal
National Centre for Pharmacoeconomics (NCPE), Ireland
National Institute of Pharmacy and Nutrition (NIPN), Hungary
Norwegian Medicines Agency (NOMA), Norway
The Dental and Pharmaceutical Benefits Agency (TLV), Sweden
Zorginstituut Nederland (ZIN), The Netherlands
The work in EUnetHTA 21 is a collaborative effort. While the agencies in the Assessment Team actively wrote
the joint clinical assessment (JCA) report, the entire EUnetHTA 21 consortium was involved in its production
throughout various stages. This means that the Committee for Scientific Consistency and Quality (CSCQ)
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reviewed and discussed several drafts of the deliverable. Afterwards the Consortium Executive Board (CEB)
endorsed the final deliverable before publication.
Conflict of Interest
All authors, co-authors, CSCQ members, CEB members and external experts involved in the
production of this JCA have declared they have no conflicts of interest in relation to the
technology and comparator(s) assessed according to the EUnetHTA 21 declaration of interest
form. Conflict of interest was evaluated following the EUnetHTA 21 Procedure Guidance for
handling declarations of interest form (https://eunethta.eu/doi).
Copyright
EUnetHTA 21 JCA reports are published under a “CC/BY/NC” Creative Commons License.
How to cite this assessment?

Please cite this assessment as follows:
EUnetHTA 21 JCAMD001. Authoring Team. Optilume urethral drug-coated balloon. Joint

Clinical Assessment. Diemen (The Netherlands). EUnetHTA 21; 2023. [date of citation]. 140
pages. Report No.: JCAMD001. Available from: https://www.eunethta.eu/
Please contact the EUnetHTA 21 Secretariat ([email protected]) if you have enquiries about
this JCA.
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List of abbreviations
Abbreviation Meaning
AE Adverse event
AIHTA Austrian Institute for Health Technology Assessment
atm Standard atmosphere (measure of pressure)
BPH Benign prostatic hyperplasia
CE Conformité Européenne
CEB Consortium Executive Board
CI Confidence interval
ClinROM Clinician-reported outcome measure
CSCQ Committee for Scientific Consistency and Quality
CSR Clinical study report
CTCAE Common Terminology Criteria for Adverse Events
DCB Drug-coated balloon
DVIU Direct vision internal urethrotomy
EAU European Association of Urology
EMDN European Medical Device Nomenclature
Fr French
HAS Haute Autorité de Santé
HCP Healthcare professional
HR Hazard ratio
HTD Health technology developer
IFU Instructions for use
IIEF International Index of Erectile Function
IPSS International Prostate Symptom Score
JCA Joint clinical assessment
LE Level of evidence
LUT Lower urinary tract
MD Mean difference
NA Not applicable
ND No data
NEC Not elsewhere classifiable
PerfO Performance outcome
PICO Population, Intervention, Comparator, Outcome
PROM Patient-reported outcome measure
PVR Postvoid residual volume
Qmax Maximum flow rate
QoL Quality of life
RCT Randomised controlled trial
RD Risk difference
RoB Risk of bias
SAP Statistical analysis plan
SD Standard deviation
SSCP Summary of Safety and Clinical Performance
UDI-DI Unique Device Identification-Device Identifier
UEMO European Union of General Practitioners
UTI Urinary tract infection
VAS Visual Analogue Scale
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Table of Contents
Document history and contributors .................................................................................. 2

List of abbreviations ......................................................................................................... 4
List of tables...................................................................................................................... 7
List of figures .................................................................................................................... 8
1 GENERAL INFORMATION..................................................................................... 9
1.1 Assessment team .....................................................................................................9
1.2 Overview of procedural steps...................................................................................9
1.3 Stakeholder and external expert involvement.......................................................... 10
2 BACKGROUND....................................................................................................... 11
2.1 Overview of the health condition ........................................................................... 11
2.1.1 Epidemiology of the health condition ............................................................... 11
2.1.2 Characterisation of the health condition............................................................ 11
2.1.3 Management of the health condition................................................................. 12
2.2 Characterisation of the health technology ............................................................... 13
2.2.1 Characteristics of the health technology ........................................................... 13
2.2.2 Requirements/instructions for use .................................................................... 15
2.2.3 Regulatory status of the technology.................................................................. 16
3 RESEARCH QUESTION AND SCOPE .................................................................. 17
4 RESULTS ................................................................................................................. 18
4.1 Information retrieval.............................................................................................. 18
4.1.1 Resulting list of studies included, overall and by PICO question ....................... 18
4.2 Characteristics of the studies included .................................................................... 19
4.3 Study results on relative effectiveness and relative safety........................................ 19
4.3.1 Results for the patient population: men aged ≥18 years with bothersome
urinary symptoms associated with recurrent anterior urethral strictures ≤3 cm
in length.......................................................................................................... 19
4.3.1.1 Outcomes for PICO 1 ................................................................................ 19
4.4 Results from the main studies from the clinical development programme for the
intervention under assessment................................................................................ 20
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4.4.1 Relative effectiveness and safety results from the direct comparison:
Optilume DCB versus dilation or DVIU ........................................................... 28
4.4.1.1 Available outcomes in the ROBUST III study ............................................ 28
4.4.1.2 Risk of bias............................................................................................... 30
4.4.1.3 Health outcome results .............................................................................. 33
4.4.2 Safety results from noncomparative studies ...................................................... 40
4.4.2.1 Safety outcomes available from the ROBUST I and ROBUST II studies ..... 40
4.4.2.2 Risk of bias............................................................................................... 40
4.4.2.3 Health outcome results .............................................................................. 40
4.4.3 Summary table including the uncertainty of evidence ....................................... 42
5 REFERENCES ......................................................................................................... 45
6 SUMMARY REPORT.............................................................................................. 46
Appendix A Input from external experts ................................................................... 51
Appendix B Assessment of information retrieval ...................................................... 57
Appendix C Additional safety data from the ROBUST III CSR ............................... 59
Appendix D RoB 2.0 tables......................................................................................... 66
Appendix E Partial use of GRADE .......................................................................... 137
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List of tables
Table 1: Procedural steps for the joint clinical assessment of the Optilume urethral drug-coated balloon ....... 9
Table 2: Contributors to the joint clinical assessment ......................................................................................... 10
Table 3: European Association of Urology classification according to the degree of urethral narrowing for
male patients with a normal functioning bladder.......................................................................................... 12
Table 4: European Association of Urology guidelines on management of anterior urethral strictures in
males ................................................................................................................................................................ 12
Table 5: Characteristics of the health technology under assessment .................................................................. 13
Table 6: Characteristics of the use of the Optilume urethral drug-coated balloon ............................................ 15
Table 7: Regulatory information on the health technology under assessment................................................... 16
Table 8: Assessment scope including the consolidated PICO questions............................................................ 17
Table 9: Studies included: list of relevant studies used for the assessment ....................................................... 18
Table 10: List of studies excluded: studies included by the health technology developer but not used in the
joint clinical assessment report....................................................................................................................... 19
Table 11: List of relevant studies from the clinical development programme for the intervention under
assessment ....................................................................................................................................................... 20
Table 12: Characteristics of studies from the clinical development programme for the intervention under
assessment ....................................................................................................................................................... 22
Table 13: Characteristics of interventions in studies from the clinical development programme for the
intervention under assessment........................................................................................................................ 24
Table 14: Observation time points in studies from the clinical development programme for the intervention
under assessment (including planned duration of follow-up) ...................................................................... 24
Table 15: Characteristics of studies from the clinical development programme for the intervention under
assessment ....................................................................................................................................................... 25
Table 16: Patient baseline characteristics in the ROBUST III study.................................................................. 26
Table 17: Patient baseline characteristics in the ROBUST I and ROBUST II studies...................................... 27
Table 18: Matrix of outcomes in the ROBUST III study for direct comparison of the Optilume DCB versus
dilation or DVIU ............................................................................................................................................. 28
Table 19: Outcomes reported and their measurement instruments..................................................................... 28
Table 20: Risk of bias (randomised controlled trial at study outcome level; Cochrane RoB 2.0).................... 31
Table 21: Relative effectiveness results (dichotomous outcome) via direct comparison: Optilume DCB
versus dilation or DVIU.................................................................................................................................. 33
Table 22: Sensitivity analysis for the stricture-free rate...................................................................................... 34
Table 23: Relative effectiveness results (time-to-event outcomes) via direct comparison: Optilume DCB
Table 24: Relative effectiveness results (quantitative outcomes) via direct comparison: Optilume DCB
Table 25: Relative effectiveness outcomes (continuous) via direct comparison: Optilume DCB versus
dilation or DVIU ............................................................................................................................................. 37
Table 26: Relative safety outcomes: direct comparison of the Optilume DCB versus dilation or DVIU........ 39
Table 27: Matrix of outcomes in the ROBUST I and ROBUST II single-arm studies ..................................... 40
Table 28: Safety outcomes for the Optilume urethral drug-coated balloon from noncomparative evidence
(single-arm studies)......................................................................................................................................... 40
Table 29: Uncertainty of evidence from the clinical development programme................................................. 42
Table 30: Assessment scope including the consolidated PICO questions.......................................................... 46
Table 31: Uncertainty of evidence from the clinical development programme................................................. 48
Table 32: Adverse Events Categorised by Common Terminology Criteria for Adverse Events (CTCAE)
Severity for the Randomised Cohort (Adjudicated) - ROBUST III ............................................................ 59
Table 33: Reasons for Study Exit ROBUST III ................................................................................................... 65
Table 34: Uncertainties of the evidence categorised according to the partial use of GRADE ....................... 137
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List of figures
Figure 1. The Optilume urethral drug-coated balloon. ........................................................................................ 15
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1 GENERAL INFORMATION
The aim of this joint clinical assessment (JCA) is to assess the relative clinical effectiveness
and safety of the Optilume urethral drug-coated balloon (DCB) medical device in the target
patient population against relevant comparators. In accordance with the requirements of
EUnetHTA 21 members, the target patient population and relevant comparators were defined
before the start of the assessment in the assessment scope according to a Population,
Intervention, Comparator, Outcome (PICO) framework. The assessment scope is presented in
Section 3.
The assessment was based on the submission dossier submitted by the health technology
developer (HTD) of this medical device, Laborie Medical Technologies.
1.1 Assessment team

The assessment team consists of assessors from Haute Autorité de Santé (HAS) and co-assessor
from the Austrian Institute for Health Technology Assessment (AIHTA).
1.2 Overview of procedural steps

The procedural steps and corresponding dates for the JCA are listed in Table 1.
Table 1. Procedural steps for the joint clinical assessment of the Optilume urethral drug-coated balloon
Start date End date
Project duration 4 October 2022 6 June 2023
Receipt of the letter of intent from the HTD 4 October 2022
Scoping phase 4 October 2022 21 November 2022
PICO survey 13 October 2022 26 October 2022
PICO consolidation 27 October 2022 21 November 2022
Sharing of the consolidated PICO with the HTD 22 November 2022
Receipt of the submission dossier 9 January 2023
Check for formal completeness of the submission dossier 10 January 2023 20 January 2023
Final dossier (completed with the missing elements, CSR received) 1 March 2023
Assessment phase 30 January 2023 29 May 2023
First draft of the assessment 30 January 2023 15 March 2023
CSCQ review of the first draft 15 March 2023 24 March 2023
Second draft of the assessment 25 March 2023 25 April 2023
CSCQ validation review of the second draft 26 April 2023 5 May 2023
Medical editing and HTD fact checking 22 May 2023 26 May 2023
Final assessment 26 May 2023 30 May 2023
CEB review 19 May 23 30 May 2023
CEB endorsement 31 May 2023
Publication of the assessment report 1 June 2023 6 June 2023
Source: EUnetHTA 21 Secretariat.
Abbreviations: CEB=Consortium Executive Board; CSCQ=Committee for Scientific Consistency and Quality; CSR=clinical study report;
HTD=health technology developer; PICO=Population, Intervention, Comparator, Outcome.
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1.3 Stakeholder and external expert involvement

Stakeholders were consulted early in the JCA scoping process to support the development of
the PICO questions. Input from patients and clinical experts was subsequently used to support
the development of the PICO questions.
Table 2. Contributors to the joint clinical assessment

Contributor Patient or healthcare Organisation or individual Type and timing of
professional involvement
Stakeholders Patients and healthcare European Association of Urology, Participated in the open call
professionals the Netherlands for input during the scoping
process. Completed an
European Union of General online submission.
Practitioners, Belgium
Bundesverband Prostatakrebs
Selbsthilfe e.V., Germany
Expert Clinical expert Dr. Stefan Schleibner, independent Provided written input
medical advisor in the field of during the scoping process.
regulatory affairs, health
technology assessment,
reimbursement and pricing,
Germany
Source: EUnetHTA 21 Secretariat.
Stakeholder organisations were invited to provide input via an online questionnaire during the
scoping process. Three stakeholder organisations made submissions. Stakeholder organisations
represented healthcare professionals working in the therapeutic area of urology, general
practitioners and patients with prostate cancer. It must be noted that the disease for the
assessment scope was urethral stricture and not prostate cancer, and the latter is the focus of the
patient organisation that participated in the open call. However, there is no specific patient
organisation for urethral stricture. Two of the stakeholder organisations were Europe-wide and
one was a national organisation.
The aim of the public call for involvement was to identify patients and clinical experts. No
patient was identified for this JCA. One clinical expert was identified and was involved during
the scoping process. The clinical expert had clinical experience with the disease and/or clinical
experience with the technology under evaluation. The clinical expert had no conflict of interest.
Submissions from the stakeholder organisations, including details of their funding, are included
in Appendix A.
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2 BACKGROUND
2.1 Overview of the health condition

In males, a urethral stricture is a narrowing of the anterior urethra lumen due to chronic fibrosis
of the urethral mucosa and surrounding spongiosum tissue.
2.1.1 Epidemiology of the health condition

Urethral stricture is a relatively common disease among men, with an average annualised
incidence rate of 229 per 100,000 males over the period 1992–2000 in the USA.1 The rate of
urethral stricture disease increases sharply after the age of 55 years [1]. Corresponding
European epidemiological data could not be found. The anterior urethra is most frequently
affected (approx. 92%), in particular the bulbar urethra (approx. 47%) and the penile urethra
(approx. 31%) [2].
Urethral stricture disease has several aetiologies, including iatrogenic, idiopathic, inflammatory
and traumatic causes, which vary according to geographic location and socioeconomic
conditions. In well-resourced countries, the most frequent aetiologies are iatrogenic (resulting
from urethral manipulations related to catheterisation, hypospadias repair, transurethral
surgery, radiotherapy, prostate adenomectomy or prostatectomy) and idiopathic. Strictures can
also occur as a result of trauma associated with pelvic fractures or an infection (untreated
gonorrhoea and chlamydia, balanitis xerotica obliterans and lichen sclerosus) [2, 3].
2.1.2 Characterisation of the health condition

Urethral strictures may be characterised by their location, tightness and length.
The anterior urethra is made up of three segments (from proximal to distal):
 The bulbar urethra (segment fixed to the pelvic floor);

 The penile urethra (segment passing through the pendulous portion and glans penis);
 The segment including the fossa navicularis and the meatus.
These different segments may be involved in strictures at varying frequency, as mentioned

above.
The European Association of Urology (EAU) guidelines [4] on anterior strictures provide a
classification of urethral strictures according to location (meatal, penile, bulbar or penobulbar)
and tightness (Table 3).
1
On the basis of the number of “ physician office visits for males with urethral stricture listed as any diagnosis” out of a sample of 1,460,899
for 1992, 1994, 1996, 1998 and 2000 from the National Ambulatory Medical Care Survey [1].
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Table 3. European Association of Urology classification according to the degree of urethral narrowing for
male patients with a normal functioning bladder
Category Description Urethral lumen Degree
0 Normal urethra on imaging – –
1 Subclinical strictures Urethral narrowing but ≥16 Fr Low
2 Low-grade strictures 11–15 Fr
3 High-grade or flow significant 4–10 Fr High
strictures
4 Nearly obliterative strictures 1–3 Fr
5 Obliterative strictures No urethral lumen (0 Fr)
Source: European Association of Urology guidelines on urethral strictures [4].
Abbreviations: Fr=French (unit of measure of the outer diameter of a catheter; 1 Fr = 0.33 mm).
The EAU guidelines do not provide a formal classification of urethral strictures based on length
and report that the length of a “short” bulbar stricture is poorly defined. However, according to
these guidelines, bulbar strictures are considered short when measuring less than 2 cm and long
when measuring more than 2 cm. The guidelines also state that, in general, “short bulbar
strictures” are those amenable to stricture excision and subsequent tension-free anastomotic
repair. The limit is usually approximately 2–3 cm, but can be longer, depending on the patient’s
anatomy and the stricture location within the bulbar urethra [4].
2.1.3 Management of the health condition

From a functional perspective, urethral stricture has the effect of obstructing the lower urinary
tract (LUT). This condition adversely impacts physical health and quality of life (QoL). Left
untreated, strictures can lead to serious complications such as recurrent urinary tract infections ,
urinary retention and eventual renal impairment [4].
The management of anterior urethral strictures in males may differ between countries.
However, while not endorsed by EUnetHTA 21, the 2022 EAU guidelines2 present different
options for the management of this health condition, as detailed in Table 4.
Table 4. European Association of Urology guidelines on management of anterior urethral strictures in

males
Type of treatment Management of anterior urethral strictures in males
Conservative Observation in patients with asymptomatic incidental strictures >16 Fr
Long-term suprapubic catheter in patients with radioinduced bulbomembranous
strictures
Endoluminal treatment DVIU with “cold-knife” commonly performed as a first-line treatment under general
or spinal anaesthesia; the stricture is incised
DVIU with “hot-knife”: laser urethrotomy and plasmakinetic (bipolar) urethrotomy
are considered alternative techniques to cold-knife DVIU
Single dilation performed in the office under local anaesthesia: the urethral mucosa at
the stricture site is stretched and the scarring is disrupted
Open repair Urethroplasty: stricture excision and subsequent tension-free anastomotic repair is
generally performed for “short bulbar strictures” (2–3 cm)
Source: European Association of Urology guidelines on urethral strictures [4].
Abbreviations: DVIU=direct vision internal urethrotomy; Fr=French (unit of measure of the outer diameter of a catheter; 1 Fr = 0.33 mm.
2
The 2023 EAU guidelines update [5] has introduced the drug-coated balloon dilation as one of the several strategies for post-dilation/ direct
vision internal urethrotomy.
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The EAU guidelines on urethral strictures recommend the following strategies for management
of anterior urethral strictures [4] that are of interest in the context of this JCA.
Considering that “direct vision internal urethrotomy (DVIU) performs poorly in penile
strictures” and that it “might provoke venous leakage from the corpora cavernosa with a
subsequent risk of erectile dysfunction” (level of evidence (LE) 1b3), the EAU recommends
against using DVIU for penile strictures (strong recommendation4).
As “increased stricture length is associated with higher risk of failure of DVIU” (LE 1b3), the
EAU recommends against using “DVIU/dilation as solitary treatment for long (> 2 cm)
segment strictures” (strong recommendation4).
Considering that “in selected patients with a primary, single, short (<2 cm) and nonobliterat ive
bulbar stricture, a 5-year stricture-free rate of up to 77% can be expected” (LE 33), the EAU
recommends performing “DVIU/dilatation for a primary, single, short (<2 cm) and
nonobliterative stricture at the bulbar urethra” (weak recommendation4).
As “repetitive dilatations/DVIU have no long-term freedom of recurrence and increase stricture

complexity” (LE 1b), the EAU recommends against performing “repetitive (>2)
DVIU/dilatations if urethroplasty is a viable option” (strong recommendation4).
In addition, the EAU considers that “at present, there is a lack of evidence to support the claim
that dilatation is superior to DVIU (or vice versa) and therefore, the indications for single
dilatation are the same as for DVIU. Repetitive dilatation/DVIU with curative intent should be
avoided, as no long-term freedom of recurrence can be expected and because of the significant
risk of increasing stricture length and complexity and prolonging the time to urethroplasty
(which has better patency rates)” [4].
Stricture recurrence rates for endoscopic procedures vary considerably between 8% and 77%
for DVIU and between 36% and 92% for dilatation. Moreover, endoscopic procedures lead to
progressively worse outcomes over time, with a failure rate of almost 100% after three
treatments [6, 7].
2.2 Characterisation of the health technology

The Optilume urethral drug-coated balloon (DCB) is a urethral balloon that is precoated with
an antiproliferative medicinal product (paclitaxel).
2.2.1 Characteristics of the health technology

The characteristics of the medical device under assessment are presented in Table 5.
3
Level of evidence graded by the EAU according to a classification system modified from the Oxford Centre for Evidence-Based Medicine:
Levels of Evidence (March 2009). LE 1b: based on an individual RCT with a narrow confidence interval; LE 3: based on case series.
4
The EAU rate the strength of their recommendations as “ strong” or “ weak” on the basis of six key elements: 1) the overall quality of evidence
graded according to levels of evidence (see note above); 2) the magnitude of the effect (individual or combined effects); 3) the certainty of
the results (precision, consistency, heterogeneity and other statistical or study-related factors); 4) the balance between desirable and
undesirable outcomes; 5) the impact of patient values and preferences on the intervention; and 6) the certainty of those patient values and
preferences.
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Table 5. Characteristics of the health technology under assessment

Device trade name Optilume
Name of manufacturer Laborie Medical Technologies
Device description according to U0399: Devices for urinary tract dilation – other
the EMDN
Risk class of the device Class III
Function of the device Therapeutic
Models of the device/reference The device is CE marked for three different diameters and two different lengths.
numbers Product number Description Diameter Length Rated burst Paclitaxel
(Fr) (cm) pressure (atm) dose (mg)
OPTBDL7000C 18 3 12 1.979
OPTBDL7001C 18 5 12 3.299
OPTBDL7002C 24 3 12 2.639
Optilume DCB and
OPTBDL7003C inflation device 24 5 12 4.398
OPTBDL7004C 30 3 10 3.299
OPTBDL7005C 30 5 10 5.498
The Optilume DCB catheter and the inflation device are supplied sterile
(ethylene oxide sterilisation) for single use only in a double-pouch packaging
system contained with a single unit box. It should be stored at room temperature
in a dry location.
Intended purpose of the device The Optilume urethral DCB catheter is intended for the treatment of strictures
in the anterior urethra in adult males.
Indication and target population The Optilume urethral DCB catheter is used to treat men aged ≥18 years with
bothersome urinary symptoms associated with recurrent anterior urethral
stricture. It is designed to be used as a dilation balloon for a single, tandem, or
diffuse anterior urethral stricture of ≤3 cm in length or used as an adjunctive
therapy with other dilation devices and/or procedures.
Contraindications and/or The Optilume urethral DCB catheter is contraindicated for use in:
restrictions for use and/or – Patients with known hypersensitivity to paclitaxel or structurally related
limitations of the device compounds;
– Patients with lesions that cannot be crossed with a 0.038-inch guidewire.
Description of the device The Optilume urethral DCB is a coaxial catheter, compatible with a 0.038-inch
including its constituents (0.97 mm) guide and a flexible cystoscope, with two lumens and an atraumatic
bevelled tip. The distal end of the catheter is equipped with a semicompliant
inflatable balloon that is coated with paclitaxel and excipients. The device has
two radiopaque marks that indicate the useful length of the balloon (Figure 1).
Mode of action The Optilume urethral DCB exerts radial force to dilate narrow urethral
segments when introduced and inflated in the stricture area and
circumferentially delivers an antiproliferative medicinal product (paclitaxel) to
the inner urethral wall during the procedure. It has been reported that paclitaxel
inhibits the proliferation and migration of smooth muscle cells and fibroblasts,
and the secretion of extracellular matrix. The combination of these effects may
result in inhibition of urothelium hyperplasia and therefore stricture recurrence.
Source: Submission dossier.
Abbreviations: atm=atmosphere; CE=Conformité Européenne; DCB=drug-coated balloon; EMDN=European Medical Device Nomenclature;
Fr=French.
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Figure 1. The Optilume urethral drug-coated balloon.

2.2.2 Requirements/instructions for use

The characteristics of use of the Optilume urethral DCB are described in Table 6.
Table 6. Characteristics of the use of the Optilume urethral drug-coated balloon

Specific feature of the device To administer a medicinal product (paclitaxel)
Description of (surgical) The Optilume urethral DCB procedure can be performed via rigid or
procedures, services and flexible cystoscopy. Fluoroscopy may be used at the time of the
organisational aspects associated procedure to assess or confirm the stricture length and location.
with use of the device The Optilume urethral DCB is passed over a guidewire under direct
vision and positioned along the length of the urethral stricture. It is then
inflated using normal saline or sterile water with a pressure inflation
device. The Optilume urethral DCB is left in situ across the urethral
stricture for a minimum of 5 minutes to facilitate drug uptake.
The Optilume urethral DCB is then deflated and removed.
A catheter may be inserted and left in place for a few days at the
discretion of the clinician.
Suggested profile and training for According to the IFU, Optilume urethral DCB balloon catheters are
users as outlined in the SSCP or intended for use by physicians trained and experienced in techniques for
IFU balloon catheter dilation.
The procedure follows the established urological practice for urethral
dilation. It can be performed under direct visualisation in a hospital
setting or in an outpatient setting under local anaesthesia or conscious
sedation.
Abbreviations: DCB=drug-coated balloon; IFU=instructions for use; SSCP=summary of safety and clinical performance.
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2.2.3 Regulatory status of the technology

Regulatory information on the medical device under assessment is provided in Table 7.
Table 7. Regulatory information on the health technology under assessment

UDI-DI 08530950081110L6
Name, identification number and country of notified Polskie Centrum Badad I Certyfikacji S.A., 1434,
body Poland
Date of initial CE marking 14/01/2021
Expiry date of current certificate 27/05/2024
Date and reference of the expert panel opinion Not applicable
Abbreviations: CE=Conformité Européenne; UDI-DI=Unique Device Identification-Device Identifier
Further regulatory information is included in the submission dossier.5
5
https://www.eunethta.eu/d5-4/
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3 RESEARCH QUESTION AND SCOPE
The JCA is performed against the parameters chosen after identification of the assessment scope
via a survey of member states, a consolidation process and subsequent endorsement by the
CSCQ. The consolidated assessment scope including the PICO questions is presented in Table
8.
Table 8: Assessment scope including the consolidated PICO questions

Description PICO 1 PICO 2 PICO 3
of PICO
elements
Population According to the intended use: The same as for PICO 1 The same as for
Men aged ≥18 yr with bothersome urinary PICO 1
symptoms associated with recurrent anterior
urethral strictures ≤3 cm in length.
Intervention According to the intended use: * The same as for PICO 1 The same as for
The Optilume urethral drug-coated balloon PICO 1
catheter is used as a dilation balloon for a
single, tandem or diffuse anterior urethral
stricture ≤3 cm in length or used as an
adjunctive therapy with other dilation
devices and/or procedures.
Comparator Urethrotomy a Dilation Urethroplasty
Outcomes The following outcomes are assessed across all PICO questions:
– All-cause mortality
– Urinary function (lower urinary tract symptoms related to stricture) measured using:
International Prostate Symptom Score, postvoid residual urine volume, maximum flow rate
– Erectile function measured using: International Index of Erectile Function
– Pain
– Treatment success preferably measured as: stricture-free rate, recurrence rate, reintervention
or time to treatment failure (preferably at a minimum of 6 months, 1 year, 2 years and in the
long term)
– Anatomical success, preferably measured in terms of stricture tightness
– Health-related quality of life (generic and disease- or population-specific measures), any
other patient-centred outcome and health status measured using PROMs
– Safety, including a description of each AE included in the following categories:
 Any AEs and device-related AEs including but not limited to: perioperative and
postoperative complications, urinary tract infection, urinary retention, incontinence,
erectile dysfunction
 Drug-related AEs
 Serious adverse events
* The other dilation devices and/or procedures used with the Optilume DCB will have to be specified in the
description of the procedure used in the clinical study/studies in the “Characteristics of the studies included”
section of the health technology developer’s submission dossier, if relevant.
a
Urethrotomy and direct vision internal urethrotomy (DVIU) are used indistinctly in the report.
Source: EUnetHTA 21 Committee for Scientific Consistency and Quality.
Abbreviations: AE=adverse event; DCB=drug-coated balloon; PICO=Population, Intervention, Comparator, Outcome; PROM=patient-
reported outcome measure.
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4 RESULTS
This section describes findings from the systematic information retrieval, characterises the
studies included and presents results on the relative effectiveness and relative safety of the
health technology under assessment versus the comparators defined in the PICO questions .
Factors that may affect the degree of certainty of the relative effects are identified, taking into
account the strengths and limitations of the available evidence.
4.1 Information retrieval

An assessment of the appropriateness of the sources and the search strategies is provided in
Appendix B. The studies included in the assessment were compiled using the following
information.
Sources provided by the HTD in the dossier were as follows:
 List of HTD-sponsored studies on the Optilume DCB (as of 1 March 2023).

 Bibliographic search for the Optilume DCB (last search on 12 January 2023).
 Searches in study registers and study result databases for the Optilume DCB (last
search on 12 January 2023).
The assessment team verified the completeness of the studies included by searching study
registries and bibliographic databases on Optilume DCB (last search on 14 December 2022);
Appendix B lists the search strategies used.
No additional relevant study was identified via the supplementary searches conducted by the
assessment team.
4.1.1 Resulting list of studies included, overall and by PICO question

The HTD did not provide any study individually addressing the PICO 1, PICO 2 or PICO 3
question (Table 9).
Table 9. Studies included: list of relevant studies used for the assessment
Study Study for marketing Sponsored or third-party Documentation
reference/ID authorisation/CE marking study of the technology available from the
Study information of the technology under under assessment submission dossier
assessment
PICO 1
No evidence provided by the health technology developer.
PICO 2
PICO 3
Abbreviations: CE=Conformité Européenne.
However, three studies from the clinical development programme for the intervention under
assessment were provided by the HTD and are presented in Section 4.4. The first study is an
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RCT (ROBUST III) comparing the Optilume DCB to urethrotomy or dilation (without any
separate analysis for the comparators). The other two are single-arm studies considered for
safety outcomes only. The ROBUST I study has 4-year follow-up data; the ROBUST II study
has 3-year follow-up data.
Table 10 lists studies that were included by the HTD in the submission dossier but that were
not considered relevant for the assessment.
Table 10. List of studies excluded: studies included by the health technology developer but not used in the
joint clinical assessment report
Study reference/ID Reason for exclusion
The OPEN RCT Study did not include use of the Optilume DCB. RCT comparing DVIU and
urethroplasty.
Steenkamp, 1997 Study did not include use of the Optilume DCB. RCT comparing DVIU and dilation.
Heyns, 1998 Study did not include use of the Optilume DCB. RCT comparing DVIU and dilation.
Jordan, 2013 Study did not include use of the Optilume DCB. RCT comparing a Memokath TW44
stent and DVIU.
Hoy, 2013 Study did not include use of the Optilume DCB. Single-arm study on urethroplasty.
Cecen, 2014 Study did not include use of the Optilume DCB. RCT comparing DVIU and laser
urethrotomy.
Azab, 2020 Study did not include use of the Optilume DCB. RCT comparing DVIU and an Amplatz
renal dilator.
Elkady, 2019 Study did not include use of the Optilume DCB. RCT comparing two types of
urethroplasty.
Isen, 2015 Study did not include use of the Optilume DCB. Single-arm study on DVIU.
Guo, 2010 Study did not include use of the Optilume DCB. Single-arm study on laser urethrotomy.
Pansadoro, 1996 Study did not include use of the Optilume DCB. Single-arm study on DVIU.
Santucci, 2010 Study did not include use of the Optilume DCB. Single-arm study on DVIU.
Algadagossi, 2014 Study did not include use of the Optilume DCB. RCT comparing two types of
urethroplasty.
Erickson, 2014 Study did not include use of the Optilume DCB. Single-arm study on urethroplasty.
Abbreviations: DCB=drug-coated balloon; DVIU=direct vision internal urethrotomy; HTD=health technology developer;
RCT=randomised controlled trial.
4.2 Characteristics of the studies included

No study individually addressed the PICO 1, PICO 2 or PICO 3 question.
4.3 Study results on relative effectiveness and relative safety

4.3.1 Results for the patient population: men aged ≥18 years with bothersome urinary
symptoms associated with recurrent anterior urethral strictures ≤3 cm in length
4.3.1.1 Outcomes for PICO 1
The HTD did not provide any study addressing the PICO 1 question, and in particular for
urethrotomy as the comparator. No study could be identified to address this PICO question in
the search conducted by the assessment team.
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The HTD did not provide any study addressing the PICO 2 question, and in particular for
dilation as the comparator. No study could be identified to address this PICO question in the
search conducted by the assessment team.

The HTD did not provide any study to address the PICO 3 question, and in particular for
urethroplasty as the comparator. No study could be identified to address this PICO question in
the search conducted by the assessment team.
4.4 Results from the main studies from the clinical development programme for the
intervention under assessment
Table 11 lists relevant studies provided by the HTD from the clinical development programme
for the intervention under assessment that were considered to be outside the assessment scope.
Table 11. List of relevant studies from the clinical development programme for the intervention under
assessment
Study Study for marketing Sponsored a or Documentation available
reference/ID authorisation/CE third-party study
Study marking of the technology of the technology
information under assessment under assessment
Direct comparison: Optilume DCB versus dilation or DVIU
ROBUST III b Yes c Sponsored  CSR for the 2-year results (RP1076-001
RCT Rev C, 27 October 2022)
 Protocol PR1076-001 version J (13 May
2020) d
 Registry entry: NCT03499964 [8]
 Publication: [9] e,f
Uncontrolled interventional studies
ROBUST I b No information Sponsored  CSR for the 4-year results (DSC016-004
Single-arm Rev H, 19 October 2021)
study  Registry entry: NCT03014726 [10]
 Publications: 3-year results [11], 2-year
results [12] and 1-year results [13]
ROBUST II b No information Sponsored  CSR for 3-year results (RP1032-004 Rev
Single-arm D, 15 June 2022)
study  Registry entry: NCT03270384 [14]
 Publication: 1-year results [15]
a
Study sponsored by the HTD.
b
In the following tables, the study is referred to using this abbreviated form.
c
This study was designed for US market approval.
d
From ClinicalTrials.gov.
e
A Letter to the Editor requesting separate analyses for the comparators used in the Elliott study and a reply to this
letter from the HTD were found in the literature search [16, 17].
f
Additional information was submitted by the HTD as part of a German health technology assessment process
(national report from 3 May 2023 [18]).
Abbreviations: CSR=clinical study report; DVIU=direct vision internal urethrotomy; HTD=health technology developer; RCT =randomised
controlled trial.
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Study design and study populations

Table 12 lists characteristics of studies from the clinical development programme for the
intervention under assessment.
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Table 12. Characteristics of studies from the clinical development programme for the intervention under assessment
Study Study type Study population Study arms Study duration, data Study endpoints
reference/ID (number of patients cutoffs and locations
randomised/included)
ROBUST I Prospective, Males aged ≥18 years N = 53  Study duration: 5 years Primary: rate of treatment-
interventional Visual confirmation of stricture via  Start date: November related serious complication at
uncontrolled cystoscopy or urethrogram 2016 90 days after the procedure
study (single-arm Single-lesion anterior urethral  Primary completion
study) stricture or bladder neck contracture date: October 2018 Other a : stricture recurrence rate
<2 cm  Estimated study at 90 days after the procedure,
At least 1 and <4 prior diagnoses and completion date: April improvement in IPSS, Qmax,
treatments of the same urethral 2023 PVR, freedom from repeat
stricture (including self-  Location: Latin intervention, functional success
catheterisation, dilation and/or DVIU America, 4 study sites (reported as the percentage of
but no prior urethroplasty) subjects with IPSS improvement
Significant LUT symptoms, IPSS >13 ≥50% without need for
Urethral lumen diameter <12 Fr by retreatment), IIEF
urethrogram
Able to complete validated
questionnaire independently
Qmax <10 ml/s
ROBUST II Prospective, Males aged ≥18 years N = 16  Study duration: 5 years Primary: rate of device-related
interventional Visual confirmation of stricture via  Start date: October 25, serious complications at 90 days
uncontrolled cystoscopy or urethrogram 2017
study (single-arm Single-lesion anterior urethral  Primary completion Other a : change in IIEF at
study) stricture <3 cm date: November 1, 90 days, stricture recurrence at
>2 prior diagnoses and treatments of 2019 6 months, IPSS, anatomic
urethral stricture (including self-  Estimated study success at 6 months, urethral
catheterisation, dilation and/or DVIU completion date: June stricture-specific PROM, Qmax,
but no prior urethroplasty) 2024 freedom from repeat
Significant LUT symptoms  Location: USA, 5 study intervention, IPSS responder
IPSS >13 sites rate (defined as the proportion
Urethral lumen diameter <12 Fr on of subjects with ≥50%
urethrogram improvement in IPSS without
Able to complete validated repeat treatment), anatomic
questionnaire independently success (ability to pass a 16 Fr
Qmax <15 ml/s, guidewire must be flexible cystoscope through the
able to cross the lesion treatment site), pain
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ROBUST III Prospective, Adult males with anterior strictures Optilume DCB  Study duration: 5 years Primary: stricture-free rate at
interventional ≤12 Fr and ≤3 cm, (N = 79)  Start date: October 6 months f
RCT b, patient- ≥2 prior endoscopic treatments, IPSS 2018
blinded, parallel, ≥11 and Qmax <15 ml/s c Standard-of-care  Estimated completion
endoscopic date: December 2025 Other a : all-cause mortality;
with superiority composite of specific device- or
objective management as  Data cutoff: December
determined by the procedure-related serious
2020 (planned interim
treating physician, complications at 3 months g;
analysis)
+ adaptive including rigid rod freedom from repeat
 22 centres in North intervention at 1 year; Qmax,
sample size with dilation, DVIU, America
a nonrandomised balloon dilation or a IPSS, PVR, IPSS-QoL and IIEF
pharmacokinetics combination d (N = over time; periprocedural pain
study arm. 48): and adverse events
– Dilation (N = 36)
– DVIU (N=12)
Pharmacokinetics
study arm (N = 15) e
a
Only if included in the PICO.
b
Randomisation was planned as 2:1 allocation to treatment versus control, stratified by investigational centre and by prior rad iation treatment and number of prior
dilation treatments using randomly permuted blocks.
c
Participants with previous urethroplasty, hypospadias repair, lichen sclerosis or unresolved confounding aetiologies were excluded.
d
The control arm as defined in the CSR. According to the CSR, “all three methods of dilation have been shown to be equivalent in terms of outcome and safety
profile and therefore were considered interchangeable in this study. Physicians were able to use one or more of these methods to dilate the stricture as is his/her best
practice to dilate the lesion”. The “standard-of-care endoscopic management” group is referred to as the “dilation or DVIU” group in most of the text and tables
hereafter.
e
The pharmacokinetics arm is not relevant for the joint clinical assessment and is not presented in any further tables.
f
Proportion of participants in whom a 16 Fr flexible cystoscope or a 14 Fr catheter could be atraumatically passed through the treated area.
g
Composite of specific device- or procedure-related serious complications including urethral fistula, unresolved de novo stress urinary incontinence and urethral
rupture.
Source: Refer to Table 11.
Abbreviations: DCB=drug-coated balloon; DVIU=direct vision internal urethrotomy; Fr=French; IIEF=International Index of Erectile Function; IPSS=International Prostate Symptom Score; LUT =lower
urinary tract; N: number of included patients; PROM=patient-reported outcome measure; PVR=postvoid residual volume; Qmax=maximum urinary flow rate; QoL=quality of life; RCT =randomised
controlled trial.
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Table 13 describes the interventions in studies from the clinical development programme for
the intervention under assessment.
Table 13. Characteristics of interventions in studies from the clinical development programme for the
intervention under assessment.
Study Study intervention Study comparator
reference/ID
ROBUST I Predilation with an uncoated balloon Not applicable
and/or DVIU + Optilume DCB
ROBUST II Predilation with an uncoated balloon, Not applicable
rigid rods or DVIU + Optilume DCB or
Optilume DCB without predilation
ROBUST III Predilation with an uncoated balloon Standard-of-care endoscopic management as
and/or DVIU to ≥20 Fr + Optilume determined by the treating physician,
DCB (24 Fr, 30 Fr or 36 Fr) including rigid rod dilation, DVIU, uncoated
balloon dilation or a combination of rigid rod
+ uncoated balloon dilation
Source: Clinical study reports.
Abbreviations: DCB=drug-coated balloon; DVIU=direct vision internal urethrotomy.
Table 14 provides information on observation time points in the studies from the clinical
development programme for the intervention under assessment.
Table 14. Observation time points in studies from the clinical development programme for the
intervention under assessment (including planned follow-up duration)
Study reference/ID Planned follow-up
Outcome category
ROBUST I
(3-year results)
Composite of specific device- or procedure-related serious complications 3 months
Safety events 5 years
ROBUST II
(1-year results)
Safety: rate of device-related serious complications 3 months
Safety: change in IIEF 3 months
Safety events 5 years
ROBUST III
(1-year results)
Stricture-free rate 6 months
Composite of specific device- or procedure-related serious complications 3 months
Freedom from repeat intervention 12 months
Qmax and PVR 1, 3, 6, 12 months
IPSS and IPSS-QoL 1, 3, 6, 12 months
IIEF 1, 3, 6, 12 months
Abbreviations: IIEF=International Index of Erectile Function; IPSS=International Prostate Symptom Score; PVR=postvoid residual
volume; Qmax=maximum urinary flow rate; QoL=quality of life.
No mean or median observation period was reported for any outcome in any of the studies.
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Table 15 describes studies from the clinical development programme for the intervention under
assessment.
Table 15. Population characteristics of studies from the clinical development programme for the
intervention under assessment
Study reference/ID Population analysed
Relevant study arms
(number of patients randomised/included)
Direct comparison: Optilume DCB versus dilation or DVIU
ROBUST III Men aged ≥18 years with bothersome urinary symptoms
Optilume DCB (N = 79) associated with recurrent anterior urethral strictures ≤3 cm
Dilation or DVIU (N = 48) in length
Uncontrolled interventional studies
ROBUST I Men aged ≥18 years with bothersome urinary symptoms
in length
ROBUST II Men aged ≥18 years with bothersome urinary symptoms
in length
Abbreviations: DCB=drug-coated balloon; DVIU=direct vision internal urethrotomy; N: number of randomised patients.
The patient population for the ROBUST III study corresponds to the unique patient population
defined in the assessment scope (PICO 1, PICO 2, and PICO 3). Table 16 lists the
characteristics of patients in the ROBUST III study.
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Table 16. Baseline patient characteristics in the ROBUST III study

Study reference/ID Study intervention Study comparator
Characteristics and category
ROBUST III (1-year results) Optilume DCB (N = 79) Dilation or DVIU (N = 48)
Age (years)
Mean ± SD 59 ± 16 61 ± 16
Median (range) 61 (25–87) 63 (23–86)
Ethnicity, n/N (%)
Black or African American 9/78 (12) 6/48 (13)
White 65/78 (83) 39/48 (81)
Other a 4/78 (5) 3/48 (6)
Hispanic or Latino 3/78 (4) 3/48 (6)
Not Hispanic or Latino 75/78 (96) 45/48 (94)
2
Body mass index (kg/m )
Mean ± SD 31 ± 7 b 29 ± 7
Median (range) 30 (20–58) 27 (15–48)
Baseline stricture characteristics
Stricture aetiology, n/N (%)
Iatrogenic 21/78 (27) 16/47 (34)
Idiopathic 42/78 (54) 22/47 (47)
Inflammatory 1/78 (1) 2/47 (4)
Traumatic 14/78 (18) 7/47 (15)
Prior pelvic radiation 9/79 (11) 6/48 (13)
Anatomic location, n/N (%)
Bulbar 71/79 (90) 45/47 (96)
Penile 8/79 (10) 2/47 (4)
Stricture measurements, mean ± SD
Length (cm) 1.63 ± 0.76 1.72 ± 0.73
Diameter (mm) 2.46 ± 0.96 2.33 ± 0.88
Prior dilations
Mean ± SD 3.2 ± 1.7 4.3 ± 7.5 c
Median 3 3
Number ≥5 overall (%) 13/79 (17) 10/48 (21)
d
Study discontinuation, n/N (%) 11/79 (14) 27/48 (56) e
a
Pacific Islander, Asian or Native American.
b
Body mass index was only reported for 77 patients in this group.
c
One individual in the dilation or DVIU group had 53 prior dilations; the mean number is 3.3 when excluding
this patient.
d
Reasons for study discontinuation: 1 death, 6 treatment failures, 2 withdrawal of consent, 1 adverse event
and 1 lost to follow-up.
e
Reasons for study discontinuation: 24 crossed over to the other arm, 2 treatment failures and 1 withdrawal of
consent.
Source: Clinical study report.
Abbreviations: DCB=drug-coated balloon; DVIU=direct vision internal urethrotomy; N=number of randomised patients; n=number of
patients; SD=standard deviation.
There were no major differences in patient characteristics between the treatment groups in the
ROBUST III study.
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Table 17 lists the characteristics of patients in the noncomparative studies presented for the
safety outcomes (ROBUST I and ROBUST II).
Table 17. Patient baseline characteristics in the ROBUST I and ROBUST II studies
Study reference/ID ROBUST I ROBUST II
Characteristic and category (4-year results) (3-year results)
Age (years), mean ± SD 51 ± 15 64 ± 16
Ethnicity, n/N (%)
Black or African American 8 /53 (15) ND
Hispanic or Latino 44/53 (83) ND
Other 1/ 53 (2) ND
Baseline stricture characteristics
Stricture aetiology, n/N (%)
Iatrogenic 24/53 (45) 2/16 (13)
Idiopathic 2/53 (4) 11/16 (69)
Traumatic 27/53 (51) 3/16 (19)
Anatomic location, n/N (%)
Bulbar ND ND
Penile ND ND
Stricture measurements, mean ± SD
Length (cm) 0.9 ± 0.5 2.1 ± 0.7
Diameter (mm) 2.47 ± 1.97 2.3 ± 0.9
Pretreatments a , n (%)
Uncoated balloon 31 (59) ND
DVIU 8 (15) ND
DVIU + uncoated balloon 14 (26) ND
Direct DCB dilation ND 10 (63)
Predilation with uncoated balloon or DVIU ND 6 (37)
Direct DCB dilation with postdilation ND 0 (0)
Number of previous endoscopic treatments, mean ± SD ND 4.1 ± 4.9

Number of previous endoscopic treatments, n (%)
1 30 (57) ND
2 13 (25) ND
3 8 (15) ND
4 2 (4) ND
Study discontinuation, n (%) ND ND
a
Pretreatments were reported in a different way. ROBUST I considered uncoated balloon, DVIU and the
combination of these two, while ROBUST II considered DCB dilation, uncoated balloon or DVIU and DCB
with postdilation.
Abbreviations: DCB=drug-coated balloon; DVIU=direct vision internal urethrotomy; N=number of patients included; n=number of
patients; ND=no data; SD=standard deviation.
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4.4.1 Relative effectiveness and safety results from the direct comparison: Optilume DCB
versus dilation or DVIU
4.4.1.1 Available outcomes in the ROBUST III study
Table 18 provides an overview of the endpoints available in the ROBUST III study of the direct
comparison: Optilume DCB vs. dilation or DVIU.
Table 18. Matrix of outcomes in the ROBUST III study for direct comparison of the Optilume DCB versus
dilation or DVIU
Outcomes defined in the PICO questions Study reference/ID
ROBUST III
All-cause mortality Yes a
Urinary function (LUT symptoms related to stricture) (IPSS) Yes
Urinary function (LUT symptoms related to stricture) (PVR) Yes
Urinary function (LUT symptoms related to stricture) (Qmax) Yes
Erectile function (IIEF) Yes
Pain Yes b
Treatment success (stricture-free rate at 6 months) c Yes
Treatment success (freedom from repeat intervention at 1 year) Yes
Anatomical success (stricture-free rate at 6 months) c Yes
Health-related QoL (generic and disease- or population specific measures), any other Yes
patient centred outcome and health status measured via patient-reported outcome
measures (IPSS-QoL)
Any AEs and device-related AEs including but not limited to: perioperative and Yes
postoperative complications, urinary tract infection, urinary retention, incontinence and
Drug-related AEs d No
Serious AEs Yes
a
From the clinical study report only.
b
Periprocedural pain (reported in the clinical study report only).
c
Proportion of participants in whom a 16 Fr flexible cystoscope or a 14 Fr catheter could be atraumatically
passed through the treated area.
d
Refers to AEs related to the drug only (and not to the device).
Source: Refer to Table 11.
Abbreviations: AE=adverse event; DCB=drug-coated balloon; DVIU=direct vision internal urethrotomy; IIEF=International Index of
Erectile Function; IPSS=International Prostate Symptom Score; LUT =lower urinary tract; PICO=Population, Intervention, Comparator,
Outcome; PVR=postvoid residual volume; Qmax: maximum flow rate; QoL=quality of life.
The outcomes reported are presented in brief in Table 19.
Table 19. Outcomes reported and their measurement instruments

Outcome Outcome Outcome measurement instrument definition/ Interpretation
(concept) measurement
instrument/ Type of
outcome
measurement
instrument
Urinary International Prostate A 7-item self-administered questionnaire to screen for, rapidly
function Symptom Score/ diagnose, track the symptoms of and suggest management for lower
PROM urinary tract symptoms of BPH. Scores range from 0 to 35,
interpreted as follows:
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Outcome Outcome Outcome measurement instrument definition/ Interpretation

(concept) measurement
instrument/ Type of
outcome
measurement
instrument
 0–7: mildly symptomatic
 8–19: moderately symptomatic
 20–35: severely symptomatic
PVR/ ClinROM Quantity of urine (in ml) that remains in the bladder after urination.
PVR is evaluated using ultrasound, a bladder scanner or a urinary
catheter.
Qmax/ PerfO Maximum urinary flow rate measured in ml/s to assess the degree of
obstruction in a patient with lower urinary tract symptoms.
In men, Qmax >15 ml/s is considered normal and <10 ml/s
abnormal.
Erectile International Index of A 15-item self-administered questionnaire for evaluation of male
function Erectile Function/ sexual function that includes 5 dimensions:
PROM  Erectile function (score 1–30 score)
 Orgasmic function (score 1–10)
 Sexual desire (score 2–10)
 Intercourse satisfaction (score 0–15 score)
 Overall satisfaction (score 2–10 score)
For all domains, a higher score indicates less dysfunction.
Treatment Anatomical success, The stricture-free rate was evaluated in ROBUST III as the
success defined as the proportion of patients in whom a flexible cystoscope (≥16 Fr) or
stricture-free rate/ 14 Fr rubber catheter could be atraumatically passed through the
ClinROM treated area.
If at least one of the stated instruments is able to pass: subject is
considered a success. If neither instrument can pass, the subject is
considered a failure.
Any subjects who have a second dilation procedure, pursue surgical
intervention or otherwise seek alternative treatment for the target
stricture before the visit window are considered treatment failures.
Freedom from repeat Repeat intervention in ROBUST III study included repeated dilation
intervention a / of the study stricture with sounds, balloon dilation (including
ClinROM crossover treatment with Optilume DCB), DVIU and urethroplasty.
Health-related IPSS-QoL/ PROM IPSS-QoL is an additional item on QoL in relation to urinary
QoL symptoms on the self-administered IPSS questionnaire.
The score ranges from 0 (patient “delighted” with their QoL) to 6
(patient perceives their QoL as “terrible”).
Periprocedural Visual Analogue A standardised VAS pain questionnaire was completed by the
pain Scale (VAS) for pain/ patients before the procedure and at the 30-day visit.
PROM The scale ranges from 0 (no pain) to 10 (worst possible pain).
a
Also referred to as “time to treatment failure” in the ROBUST III study protocol.
Abbreviations: BPH=benign prostatic hyperplasia; ClinROM=clinician-reported outcome measure; DCB=drug-coated balloon;
DVIU=direct vision internal urethrotomy; Fr=French; PerfO=performance outcome; PROM=patient-reported outcome measure;
Qmax=maximum flow rate; QoL=quality of life; VAS=Visual Analogue Scale.
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4.4.1.2 Risk of bias

Table 20 summarises the risk-of-bias (RoB) assessment for the ROBUST III study conducted
by the assessment team at the outcome level using the Cochrane RoB 2.0 method. These
assessments were based on the ROBUST III publication [9], on publicly available evidence
from ClinicalTrials.gov, in particular study protocol #PR1076-001 version J of 13 May 2020,
and on the clinical study report (CSR) RP1076-001 Rev C of 27 October 2022.
Seven different outcomes or groups of outcomes were assessed. Six outcomes were assessed as
single outcomes:
 The stricture-free rate at 6 months;
 The rate of freedom from repeat intervention at 12 months;
 The change in Qmax at 6 months;
 Qmax measured over time (at 30 days and 3, 6 and 12 months);
 PVR measured over time (at 30 days and 3, 6 and 12 months); and
 Freedom from a composite of serious device- or procedure-related events including
urethral fistula, unresolved de novo stress urinary incontinence and urethral rupture up
to 3 months.
The other outcomes assumed to have similar RoB were grouped according to the way they were
collected and analysed:
 IPSS, IPSS-QoL, IIEF (at 30 days and 3 and 6 months) and periprocedural pain were
grouped, as they are all self-reported PROMs assessed using administered
questionnaires with prespecified response formats.
Detailed reports on the seven assessments are provided in Appendix D.
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Table 20. Risk of bias (randomised controlled trial at study outcome level; Cochrane RoB 2.0)
Bias due to Bias due Bias in
Bias arising Bias in
deviations to selection Overall
from measurement
Domain from missing of the risk of Comments
randomisation of the
intended outcome reported bias
process outcome
interventions data result
ROBUST III: stricture-free rate at 6 months Low a Low b,c Low d High e Low f High
a
ROBUST III: Freedom from repeat Low Low b,g Low h High e
High i High
intervention rate at 12 months
ROBUST III: change in Qmax at 6 months Low a Low b,c High j,k Low l Low f High
a b,m j l n
ROBUST III: Qmax at 30 days and 3, 6 and Low High High Low High High
12 months
ROBUST III: PVR at 30 days and 3, 6 and Low a High b,m High j Some High n High
o
12 months concerns
ROBUST III: patient-reported outcomes at Low a High b,p High k,q High r High n High Patients were blinded to the
30 days and 3 and 6 months: treatment until 6 months.
– IPSS After this 6-month time
– IPSS-QoL point we assume that the risk
– IIEF (overall satisfaction) of bias for these outcomes
– Periprocedural pain will be higher.
a b s t u
ROBUST III: freedom from a composite of Low High Low High Low High
serious device- or procedure-related events
(including urethral fistula, unresolved de
novo stress urinary incontinence and
urethral rupture) up to 3 months
a
According to the protocol, randomisation was planned at 2:1 allocation to treatment versus control, stratified by investigational centre and by prior radiation treatment
and number of prior dilation treatments using randomly permuted blocks. There is no s pecific information on the concealment of the allocation sequence.
b
Some participants who experienced stricture recurrence requiring intervention were unblinded before 6 months: 12/48 (25%) pat ients in the control group crossed over.
Surgeons and investigators were not blinded to the intervention over the entire study period.
c
Intention-to-treat analysis with multiple imputation of missing data was prespecified and conducted.
d
Data were missing for this outcome for 12/79 patients in the Optilume group and 7/48 in the control group (15% in each group). A sensitivity analysis comprising 5
subanalyses yielded results with the same directionality as for the primary analysis.
e
The surgeons and investigators were not blinded to the intervention over the entire study period and the study authors note t hat this might have biased their interpretation
of cystoscopic findings or the decision to proceed with repeat treatment. Therefore, assessment of this clinician-reported outcome may have been subject to measurement
bias.
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16 June 2023
Bias due to Bias due Bias in

Bias arising Bias in
deviations to selection Overall
from measurement
Domain from missing of the risk of Comments
randomisation of the
intended outcome reported bias
process outcome
interventions data result
f
Only one outcome measure was defined for the outcome and there is only one way in which the outcome measure can be analysed. Analysis reported in the CSR is
consistent with what was planned in the protocol.
g
While a Kaplan-Meier curve and a p value for a log-rank test are available, neither a difference in medians (point estimate and CI), nor a hazard ratio (point estimate
and CI) is provided.
h
According to the Kaplan-Meier curve, there was a low rate of loss to follow up in both groups for most of the follow-up period. However, during the last 20 days of
follow-up, more patients are censored in the Optilume group than in the control group.
i
A nominal p value is reported for this outcome at 12 months. Its analysis at 6 months was prespecified in the protocol, but group Kaplan-Meier estimates are only
reported for 12 months in the publication. Several analyses are reported in the CSR (2 for 6 months) and in the publication (1 at 12 months).
j
Data are missing data 12/79 (15%) patients in the intervention group and 4/48 (8%) in the control group.
k
No sensitivity analysis was conducted for this outcome.
l
Even though the measurement tool for this performance outcome is not detailed in the study, it can be assumed that, as in most routine care situations, uroflowmetry is
carried out in a fully automatic way without any need for medical staff to read the results.
m
The results for this outcome are only descriptive. There is no clear explanation for the handling of missing data (it was only stated in the CSR that failure -carried-forward
analysis was performed).
n
Analysis of this outcome was not prespecified in the protocol.
o
There is no information on the methods used to assess PVR, which is a clinically reported outcome measure. The ultrasound method could imply some subjectivity from
the assessor.
p
Only descriptive statistics were used to report these outcomes. There is no clear explanation for the handling of missing IPSS data and no explanation for the handling
of missing IIEF and periprocedural pain data.
q
Data missing for 8/79 patients in the intervention group and 5/48 in the control group (10% in both groups) for IPSS and IPSS -QoL at 6 months. Data missing for 11/79
(14%) patients in the intervention group and 18/48 (38%) in the control group for IIEF at 6 months.
r
Patients from the control group who crossed over (25%) are likely to have been influenced by the knowledge of their treatment assignment when answering these self-
administered questionnaires.
s
It can be assumed that this outcome is available for all or nearly all participants.
t
Surgeons were not blinded to the type of treatment; this might have biased their assessment of the clinical status of the pa tient regarding the three components of this
composite safety outcome.
u
As prespecified in the protocol, only descriptive statistics were used to report this outcome.
Source: Appendix D.
Abbreviations: CI=confidence interval; CSR=clinical study report; IIEF=International Index of Erectile Function; IPSS=International Prostate Symptom Score; PVR=postvoid residual volume; Qmax=maximum
flow rate; QoL=quality of life.
The overall risk of bias is considered high for all outcomes in the ROBUST III study.
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4.4.1.3 Health outcome results

Table 21 presents relative effectiveness results for the stricture-free rate from the ROBUST III study and Table 22 lists the sensitivity
analysis results for this outcome. Table 23, Table 24 and Table 25 present relative effectiveness results for the other outcomes in ROBUST
III.
Table 21. Relative effectiveness results (dichotomous outcome) from direct comparison: Optilume DCB versus dilation or DVIU
Time point Optilume DCB Dilation or DVIU Optilume DCB vs. dilation or DVIU
Outcome N Patients with N Patients RD [95% CI] Hypothesis
Study reference/ID event, n (% ) with p value testing
events, n
(% )
6 months
Stricture-free rate a
ROBUST III 67 b 50 (74.6) 41 b,c 11 (26.8) 44.4 d [27.6; 61.1] S-P-C
p < 0.0001
Reading the “Hypothesis testing” columns:
1. statistical significance: S=statistically significant against the alpha level specified in the study SAP, NS = non-significant, NO = nominal p-value.
2. Prespecification: P=statistical test was prespecified according to the study SAP, NP = Not prespecified.
3. Multiple hypothesis testing: C=appropriate control for multiplicity according to the study SAP and clinical study report, NC = not controlled.
a
Proportion of participants in whom a 16 Fr flexible cystoscope or a 14 Fr catheter could be atraumatically passed through the treated area.
b
Data were missing for 12/79 (15%) patients in the Optilume DCB group and 7/48 (15%) patients in the dilation or DVIU group for this outcome (missing
cystoscopy).
c
Some 12/48 (25%) patients from the control group crossed over to the Optilume DCB group. These patients were considered a failure for this endpoint.
d
Estimated difference using multiple imputation of mis sing data.
Abbreviations: CI=confidence interval; DCB=drug-coated balloon; DVIU=direct vision internal urethrotomy; Fr=French; N=number of patients considered in the analysis for calculation of the
effect estimation; n: number of patients with event; RD=risk difference; SAP=statistical analysis plan.
As prespecified in the ROBUST III study protocol, a sensitivity analysis was conducted using the methods detailed in Table 22 to assess the
impact of the handling of missing data in the primary analysis for the stricture-free rate.
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Table 22. Sensitivity analysis for the stricture-free rate

Attribute Analysis method Optilume DCB Dilation or DVIU Risk difference, % [95% CI]
N=79, n/N (% ) N=48, n/N (% )
Missing data Observed a 50/67 (74.6) 11/41 (26.8) 47.8 [28.7; 66.9]
b
Missing data Worst case imputation 50/79 (63.3) 18/48 (37.5) 25.8 [6.8; 44.8]
c
Missing data Late cystoscopy as observed 53/72 (73.6) 12/44 (27.3) 46.3 [27.9; 64.8]
Missing data IPSS responder status at 6 months d 53/71 (74.6) 13/44 (29.5) 45.1 [26.4; 63.8]
e
Missing data IPSS responder status at last visit 58/79 (73.4) 16/47 (34.0) 39.4 [21.0; 57.8]
a
Only observed values were used for this analysis.
b
Including all patients randomised to the investigation group with missing data as failures and all patients randomised to the control group with missing data as successes.
c
Carries back the next available cystoscopy results captured after the 6-month visit cutoff (240 days) if the 6-month cystoscopy is missing.
d
Subjects missing 6-month cystoscopy with a documented improvement in IPSS ≥50% at 6 months are treated as a success and subjects with a documented improvement
<50% as a failure. Subjects with missing IPSS data at 6 months are censored in this analysis.
e
Subjects with missing 6-month cystoscopy and a documented improvement in IPSS ≥50% at their last visit before 6 months are treated as a success and subjects with a
documented improvement <50% as a failure. Subjects with no measured IPSS results are censored in this analysis.
Abbreviations: CI=confidence interval; DCB=drug-coated balloon; DVIU=direct vision internal urethrotomy; n/N=number of patients with overall endpoint success/number of randomised patients.
Results from the sensitivity analysis have the same directionality as for results from the primary analysis.
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Table 23. Relative effectiveness results (time-to-event outcomes) from direct comparison: Optilume DCB versus dilation or DVIU
Time point Optilume DCB Dilation or DVIU Optilume DCB versus dilation or DVIU
Outcome N Median time to event N Median time to event HR [95% CI] Log-rank test Hypothesis
Study reference/ID [95% CI] [95% CI] p value p value testing a
Patients with event Patients with event (% )
(% )
1 year
Freedom from repeat intervention rate
ROBUST III 79 83.2 a,b 48 21.7 a,b ND p <0.0001 c NO-NP-NC d

1. Statistical significance: S = statistically significant against the alpha level specified in the study SAP, NS = non-significant, NO=nominal p value.
3. Multiple hypothesis testing: C = appropriate control for multiplicity according to the study SAP and clinical study report, NC = not controlled.
a
Only reported in the publication by Elliott et al. [9].
b
Median time to event not provided.
c
A Kaplan-Meier curve is provided in the paper by Elliott et al. [9]. The two curves for observed survival did not cross each other during follow-up.
d
According to the protocol, the statistical test was prespecified and controlled for multiplicity at 6-month follow-up, but no formal hypothesis statistical test was planned
at 12-month follow-up (ancillary endpoint). Results at 6 months are not reported in the paper. The clinical study report only shows the Kaplan-Meier curve, with no
values at 6 months provided.
Abbreviations: CI=confidence interval; DCB=drug-coated balloon; DVIU=direct vision internal urethrotomy; HR=hazard ratio; N: number of patients considered in the analysis for calculation of the effect
estimate; ND=no data; SAP=statistical analysis plan.
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Table 24. Relative effectiveness results (quantitative outcomes) from direct comparison: Optilume DCB versus dilation or DVIU
Time point Optilume DCB Dilation or DVIU Optilume DCB vs. dilation or DVIU
Outcome N Value at Value at N Value at Value at MD a [90% CI] b Hypothesis testing
Study reference/ID baseline 6 months baseline 6 months p value
Mean ± Mean ± SD Mean ± Mean ± SD
SD Median SD Median
Median (range) Median (range)
(range) (range)
6 months
Change in Qmax
(ml/s)
ROBUST III 67 7.6 ± 3.4 16.6 ± 8.9 44 7.4 ± 3.5 11.1 ± 7.6 +4.78 c,d [1.94; 7.61] S-P-C
7.2 15.0 7.9 9.8 p=0.0031
(0.0–14.9) (1.6–48.5) (0.0–14.5) (0.0–31.2)
1. Statistical significance: S = statistically significant against the alpha level specified in the study SAP, NS = non-significant, NO=nominal p value.
3. Multiple hypothesis testing: C = appropriate control for multiplicity according to the study SAP and clinical study report , NC = not controlled.
a
From the clinical study report only.
b
The 95% CI was not provided in the clinical study report.
c
Estimated MD using multiple imputation of missing data.
d
The estimated MD without multiple imputation of missing data was not provided for this outcome.
Abbreviations: CI=confidence interval; DCB=drug-coated balloon; DVIU=direct vision internal urethrotomy; MD=mean difference; SAP=statistical analysis plan; SD=standard deviation.
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Table 25. Relative effectiveness outcomes (continuous) from direct comparison: Optilume DCB versus dilation or DVIU
Outcome Optilume DCB Dilation or DVIU Optilume DCB vs
Study reference dilation or DVIU
Values Baseline 6 months 1 year Baseline 6 months 1 year Effect [95% CI]
p value
Qmax (ml/s) a
ROBUST III
Mean ± SD 7.6 ± 3.4 16.6 ± 8.9 15.5 ± 9.0 7.4 ± 3.5 11.1 ± 7.6 8.0 ± 4.6 ND
Median (range) 7.2 (0.0–14.9) 15.0 (1.6–48.5) 13.5 (1.6–48.8) 7.9 (0.0–14.5) 9.8 (0.0–31.2) 7.6 (0.0–23.0)
Number of patients 78 67 65 47 44 42
IPSS a
ROBUST III
Mean ± SD 22.0 ± 6.8 8.3 ± 6.2 9.0 ± 7.1 22.9 ± 6.9 15.4 ± 9.6 19.8 ± 7.4 ND
Median (range) 22.0 (11–35) 8.0 (0–26) 8.0 (0–26) 22.0 (12–35) 14.0 (1–35) 18.0 (7–35)
PVR urine (ml) a
ROBUST III
Mean ± SD 109.8 ± 116.9 73.1 ± 117.7 94.6 ± 121.8 133.7 ± 153.8 141.4 ± 194.1 179.2 ± 199.9 ND
Median (range) 60.0 (0.0–557.0) 30.0 (0.0– 50.5 (0.0– 80.0 (0.0–703.0) 90.5 (0.0– 118.0 (0.0–
634.0) 546.0) 999.0) 999.0)
IPSS-QoL a
ROBUST III
Mean ± SD 4.5 ± 1.3 1.7 ± 1.3 1.9 ± 1.5 4.7 ± 1.2 3.4 ± 1.8 4.0 ± 1.3 ND
Median (range) 5.0 (1–6) 2.0 (0–5) 2.0 (0–5) 5.0 (2–6) 3.0 (0–6) 4.0 (1–6)
IIEF overall
satisfaction
ROBUST III
Mean ± SD 5.8 ± 2.9 6.5 ± 2.8 6.9 ± 3.1 6.0 ± 3.2 6.6 ± 3.2 5.9 ± 2.6 ND
Median (range) 6.0 (2–10) 6.5 (2–10) 8.0 (2–10) 6.0 (2–10) 7.5 (2–10) 6.0 (2–10)
VAS pain score
ROBUST III
Mean ± SD 1.6 ± 2.2 2.5 ± 2.2 b 0.6 ± 1. 0 c 1.8 ± 2.3 2.1 ± 2.2 b 0.2 ± 0.5 c ND
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Median (range) 1.0 (0–8) 2.0 (0–9) 0.0 (0–6) 1.0 (0–8) 2.0 (0–8) 0.0 (0–2)
a
Failure-carried-forward analysis.
b
The time point is before discharge.
c
The time point is 30 days after the procedure.
Abbreviations: DCB=drug-coated balloon; DVIU=direct vision internal urethrotomy; IIEF=International Index of Erectile Function; IPSS=International Prostate Symptom Score; ND=no data; PVR=postvoid
residual volume; Qmax=maximum flow rate; QoL=quality of life; SD=standard deviation; VAS=Visual Analogue Scale.
Only descriptive statistics were used to report these outcome data.
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Table 26 presents relative safety outcomes from the ROBUST III study.
Table 26. Relative safety outcomes: direct comparison of the Optilume DCB versus dilation or DVIU
Time point Optilume DCB Dilation or DVIU
Study reference/ID N Number of patients N Number of patients with
Outcome with event / event /
randomised patients randomised patients
(%) (%)
3 months
ROBUST III
Composite of specific device- or 0 0/79 (0) 0 0/48 (0)
procedure-related serious complications a
2 years
ROBUST III
All-cause mortality b 2 2/79 (3) 0 0/48 (0)
Any AE 182 58/79 (73) 89 39/48 (81)
Serious AEs 12 11/79 (14) 8 8/48 (17)
Device-related AEs 35 28/79 (35) 5 4/48 (8)
c
Device-related serious AEs 1 1/79 (1) 0 0/48 (0)
Procedure-related AEs 12 10/79 (13) 10 6/48 (13)
Procedure-related serious AEs 1d 1/79 (1) 2 e,f 2/48 (4)
Severe AEs
CTCAE grade ≥3 ND h 26 / 79 (33) ND h 13 / 48 (27)
g h h
CTCAE grade 4 ND 3 / 79 (4) ND 2 / 48 (4)
g h h
CTCAE grade 5 ND 2 / 79 (3) ND 0 / 48 (0)
Treatment discontinuation due to AEs 1 1/79 (1) 0 0/48 (0)
Treatment interruption due to AEs ND ND ND ND
Suspected unexpected serious adverse 0 0/79 (0) 0 0/48 (0)
reaction
Perioperative and postoperative 6 12/79 (15) 13 3/48 (6)
complications i
Urinary tract infection 21 9/79 (11) 8 5/48 (10)
Urinary retention 9 7/79 (9) 4 4/48 (8)
Urinary incontinence 2 2/79 (3) 0 0/48 (0)
Erectile dysfunction 0 0/79 (0) 1 1/48 (2)
a
Composite of specific device- or procedure-related serious complications including urethral fistula, unresolved
de novo stress urinary incontinence and urethral rupture. Defined as the primary safety endpoint.
b
Difference 2.5%, 95% CI [−2.6%; 7.7%]. The p value was not reported in the clinical study report.
c
Urinary tract infection.
d
Aspiration pneumonia.
e
Sepsis.
f
Aspiration/choking during crossover procedure.
g
Calculated by the assessment team using data from the clinical study report.
h
The number of events is not reported, only the number of patients experiencing the adverse event.
i
Described in the clinical study report as “injury, poisoning and procedural complications”.
Abbreviations: AE=adverse event; CI=confidence interval; CTCAE=Common Terminology Criteria for Adverse Events; DCB=drug-coated
balloon; DVIU=direct vision internal urethrotomy; N=number of events.
Details for all adverse events are provided in Appendix C.
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4.4.2 Safety results from noncomparative studies

4.4.2.1 Safety outcomes available from the ROBUST I and ROBUST II studies
Table 27 provides an overview of the endpoints available in the studies presented for safety
outcomes from noncomparative evidence.
Table 27. Matrix of outcomes in the ROBUST I and ROBUST II single-arm studies
Outcomes Study reference/ID Study reference/ID
ROBUST I (4-year results) ROBUST II (3-year results)
Any adverse events and device-related adverse Yes a Yes a,b
events including but not limited to: perioperative

and postoperative complications, urinary tract
infection, urinary retention, incontinence and
Drug-related adverse events No c No c
Serious adverse events Yes Yes
a
Data for perioperative and postoperative complications were not recorded.
b
Erectile dysfunction was not reported in the safety results but was reported in the efficacy results as part of
the erectile symptom score.
c
Data not recorded.
4.4.2.2 Risk of bias

No formal RoB assessment was conducted because the overall conclusion on the internal
validity of single-arm studies is considered to be very limited, which is very unlikely to be
changed by a formal RoB assessment.
4.4.2.3 Health outcome results

Table 28 presents the safety outcomes from the ROBUST I and ROBUST II studies.
Table 28. Safety outcomes for the Optilume urethral drug-coated balloon from noncomparative evidence
(single-arm studies)
N Patients with N Patients with N Patients
Outcome event, n (% ) event, n (% ) with
Study reference/ID event, n
(% )
Time frame 3 months 3 years 4 years
All-cause mortality
ROBUST I 0 0 0
ROBUST II 0 1 NA
At least one AE
ROBUST I ND ND 73 35/53 (66) 80 36/53
(68)
ROBUST II 21 10/16 (63) 46 13/16 (81) NA NA
Serious AEs
ROBUST I ND ND 6 5/53 (9) 6 5/53 (9)
ROBUST II 0 0/16 (0) 11 6/16 (38) NA NA
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Severe AEs
ROBUST I
CTCAE grade ≥3 ND ND 3 ND 8 ND
CTCAE grade 3 ND ND 2 ND ND ND
CTCAE grade 4 ND ND 1 ND ND ND
CTCAE grade 5 ND ND 0 ND 0 0
ROBUST II
Clavien-Dindo grade 3a 1 1/16 (6) ND ND NA NA
Clavien-Dindo grade 3b 2 1/16 (6) ND ND NA NA
Treatment discontinuation due to AEs
ROBUST I ND ND ND ND ND ND
ROBUST II ND ND ND ND NA NA
Treatment interruption due to AEs
Suspected unexpected serious adverse
reaction
ROBUST I 0 0/53 (0) 0 0/53 (0) 0 0/53 (0)
ROBUST II 0 0/16 (0) 0 0/16 (0) NA NA
Perioperative and postoperative
complications
Urinary tract infection
ROBUST I ND ND ND ND 12 11/53
(21)
ROBUST II 4 2/16 (13) ND ND NA NA
Urinary retention
ROBUST I ND ND ND ND 6 5/53 (9)
ROBUST II 1 1/16 (6) ND ND NA NA
Incontinence
ROBUST I 0a 0/53 (0) ND ND ND ND
ROBUST II 0a 0/16 (0) ND ND NA NA
Erectile dysfunction
ROBUST I ND ND ND ND 1 1/53 (2)
ROBUST II ND b ND ND ND NA NA
a
Incontinence was part of the composite primary safety endpoint and did not occur in any case during 3-month
follow-up.
b
Reported in the study as no negative impact on sexual function up to 1 year.
Abbreviations: AE=adverse event; CTCAE=Common Terminology Criteria for Adverse Events; N=number of events; NA=not
applicable; ND=no data.
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4.4.3 Summary table including the uncertainty of evidence

A summary table including the uncertainty of evidence is presented in Table 29.
Table 29. Uncertainty of evidence from the main studies from clinical development programme
Outcome Design Factors that may affect the certainty of evidence Effect estimate
p value
All outcomes 1 RCT Internal validity of individual studies NA
 ROBUST III is a prospective, interventional RCT that
included 127 patients (79 in the intervention group vs 48 in
the control group) with short follow-up duration (6 months)
for outcomes with prespecified hypothesis testing.
 The randomisation was planned at a 2:1 allocation to
treatment vs control, stratified by investigational centre and
by prior radiation treatment and number of prior dilation
treatments using randomly permuted blocks (block size not
reported). There is no specific information on the
concealment of the allocation sequence.
 Only the patients were blinded to the treatment.
 The study was designed with a primary objective of
demonstrating superiority.
 There were no major differences in baseline characteristics
between the treatment groups in the study.
 The risk of bias was considered high for all outcomes.
 Only descriptive statistics were used to report most of the
outcomes apart from the stricture free rate, the freedom from
repeat intervention rate at 12 months and the change in Qmax
at 6 months.
 Patients could cross over to the Optilume group after
6 months according to the study protocol and, if medically
necessary (recurrent stricture requiring intervention) before
6 months. Some 25% (12/48) of patients from the control
group crossed over to the Optilume group before 6 months.
 There is no agreed single outcome measure that defines
urethral stricture recurrence.
Applicability
 The population of the study was in line with the population
defined in the assessment scope.
The anatomic location of the anterior strictures was mainly
bulbar in the study.
The study was conducted in North America, not in Europe.
 Optilume treatment included predilation, which is not
standard according to the IFU; this step was only carried out
in the study and it might have influenced the results.
Optilume is proposed for second-line treatment after stricture
recurrence, but the majority of patients included in ROBUST
III had more than 3 endoscopic treatments before the
Optilume procedure.
 The comparator for ROBUST III does not match any of the
comparators defined in PICO 1, PICO 2 or PICO 3.
 The comparator in the study was standard-of-care endoscopic
management as determined by the treating physician. It
included different procedures (rigid rod dilation, DVIU,
balloon dilation or a combination) which was a mix of the
PICO 1 (urethrotomy) and PICO 2 (dilatation) comparators.
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 No data were reported for the drug-related adverse events

requested in the PICO question. All other outcomes were
reported in this study.
Heterogeneity and inconsistency
No heterogeneity or inconsistency issue was raised as only

1 RCT was available and included for assessing the relative
effectiveness and relative safety of Optilume.
Stricture-free rate  Data for this outcome were missing for 12/79 (15%) patients RD for
at 6 months in the Optilume group and 7/48 (15%) patients in the control Optilume vs
group. dilation or
 A sensitivity analysis comprising 5 different subanalyses DVIU: 44.4%
yielded results with the same directionality as for the primary 95% CI [27.6;
analysis. 61.1]
 Patients in the control group who crossed over to the p < 0.0001 * , #,$
Optilume group were considered a failure for this outcome.
 The surgeons and investigators were not blinded to the
intervention and the study authors noted that this might have
biased their interpretation of cystoscopic findings or the
decision to proceed with repeat treatment. Therefore, the
assessment of this clinically reported outcome may have been
subject to measurement bias.
Freedom from 1 RCT  A nominal p value is provided because analysis of this Optilume vs
repeat outcome was prespecified in the protocol at 6 months and not dilation or
intervention rate at 12 months, but Kaplan-Meier estimates for each group are DVIU
at 12 months only reported at 12 months in the publication. p < 0.0001
 No difference in the median time to event or hazard ratio was
provided.
intervention over the entire study period and the study
authors noted that this might have biased their interpretation
of cystoscopic findings or the decision to proceed with repeat
treatment. Therefore, the assessment of this clinically
reported outcome may have been subject to measurement
bias.
Change in Qmax 1 RCT  Only reported in the CSR. MD for
(ml/s) at 6  The 95% CI for this effect measure was not provided in the Optilume vs
months CSR. dilation or
 No sensitivity analysis was conducted for this outcome. DVIU: +4.78
ml/s 90% CI
[1.94; 7.61]
p = 0.0031 * ,#,$
Qmax at 30 days 1 RCT  Only descriptive statistics were used to report this outcome. NA
and 3, 6 and 12  There is no clear explanation for handling of missing data.
months
PVR at 30 days 1 RCT  Only descriptive statistics were used to report this outcome. NA
months
IPSS at 30 days 1 RCT  Assessment of this outcome was not prespecified in the NA
and 3 and 6 protocol.
months  Only descriptive statistics were used to report this outcome.
 There is no clear explanation for handling of missing data.
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IPSS-QoL at 30 1 RCT  The protocol prespecified the assessment of the QoL outcome NA
days and 3 and 6 but did not indicate any measurement instrument or follow-
months up length.
 Only descriptive statistics were used to report these
outcomes.
IIEF (overall 1 RCT  Assessment of this outcome was not prespecified in the NA
satisfaction) at 30 protocol.
days and 3 and 6  Only descriptive statistics were used to report this outcome.
months  There is no explanation for missing data.
Freedom from a 1 RCT As prespecified in the protocol, only descriptive statistics were NA
composite of used to report this outcome.
serious device- or
procedure related
events including:
– Urethral fistula
– Unresolved de
novo stress
urinary
incontinence
– Urethral rupture
up to 3 months
Periprocedural 1 RCT  Assessment of this outcome was not prespecified in the NA
pain (VAS) protocol.
 Only descriptive statistics were used to report this outcome.
All-cause 1 RCT,  Assessment of this outcome was not prespecified in the NA
mortality 2 single- protocols.
arm  Only descriptive statistics were used to report this outcome.
studies
Other adverse 1 RCT, Only descriptive statistics were used to report these outcomes. NA
events 2 single-
arm
studies
* Statistically significant according to a prespecified alpha level.
#
Prespecified analysis according to the statistical analysis plan (for individual studies) or the evidence synthesis
protocol.
$
Control for multiplicity.
Abbreviations: CI=confidence interval; CSR=clinical study report; DVIU=direct vision internal urethrotomy; IFU=instructions for use;
IIEF=International Index of Erectile Function; IPSS=International Prostate Symptom Score; MD=mean difference; NA=not applicable;
PICO=Population, Intervention, Comparator, Outcome; PVR=postvoid residual volume; Qmax=maximum flow rate; QoL=quality of life;
RCT=randomised controlled trial; RD=risk difference; VAS=Visual Analogue Scale.
A version of this table using categories according to partial use of GRADE 6 is provided in
Appendix E.
6
EUnetHTA-GRADE-framework-paper.pdf
44
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5 REFERENCES
1. Santucci RA, Joyce GF, Wise M. Male urethral stricture disease. J Urol 2007;177(5):1667–74.
https://doi.org/10.1016/j.juro.2007.01.041
2. Palminteri E, Berdondini E, Verze P, De Nunzio C, Vitarelli A, Carmignani L. Contemporary urethral stricture
characteristics in the developed world. Urology 2013;81(1):191–6. https:// doi.org/10.1016/j.urology.2012.08.062
3. Lumen N, Hoebeke P, Willemsen P, De Troyer B, Pieters R, Oosterlinck W. Etiology of urethral stricture disease
in the 21st century. J Urol 2009;182(3):983–7. https:// doi.org/10.1016/j.juro.2009.05.023
4. Lumen N, Campos-Juanatey F, Dimitropoulos K, Greenwell T, Martins FE, et al. EAU Guidelines on Urethral
Strictures. Arnhem: European Association of Urology; 2022.
5. Lumen N, Campos-Juanatey F, Dimitropoulos K, Greenwell T, Martins FE, et al. EAU Guidelines on Urethral
Strictures. Arnhem: European Association of Urology; 2023.
https://d56bochluxqnz.cloudfront.net/documents/full-guideline/EAU-Guidelines-on-Urethral-Strictures-2023.pdf
6. Al Taweel W, Seyam R. Visual internal urethrotomy for adult male urethral stricture has poor long-term results.
Adv Urol 2015;2015:656459. https://doi.org/10.1155/2015/656459
7. Heyns CF, Steenkamp JW, De Kock ML, Whitaker P. Treatment of male urethral strictures: is repeated dilation
or internal urethrotomy useful? J Urol 1998;160(2):356–8. https://doi.org/10.1016/s0022-5347(01)62894-5
8. Urotronic Inc. ROBUST III – Re-establishing Flow via Drug Coated Balloon for the Treatment of Urethral
Stricture Disease (ROBUST-III). ClinicalTrials.gov register.
9. Elliott SP, Coutinho K, Robertson KJ, D'Anna R, Chevli K, Carrier S, et al. One-year results for the ROBUST
III randomized controlled trial evaluating the Optilume ® drug-coated balloon for anterior urethral strictures. J Urol
2022;207(4):866–75. https://doi.org/10.1097/ju.0000000000002346
10. Urotronic Inc. ROBUST I Pilot Study (ROBUST). ClinicalTrials.gov register.
https://clinicaltrials.gov/ct2/show/NCT03014726
11. Virasoro R, DeLong JM, Estrella RE, Pichardo M, Rodriguez Lay R, Espino G, et al. A drug-coated balloon
treatment for urethral stricture disease: three-year results from the ROBUST I study. Res Rep Urol 2022;14:177–
83. https://doi.org/10.2147/rru.S359872
12. Mann RA, Virasoro R, DeLong JM, Estrella RE, Pichardo M, Lay RR, et al. A drug-coated balloon treatment
for urethral stricture disease: two-year results from the ROBUST I study. Can Urol Assoc J 2021;15(2):20–5.
https://doi.org/10.5489/cuaj.6661
13. Virasoro R, DeLong JM, Mann RA, Estrella RE, Pichardo M, Lay RR, et al. A drug-coated balloon treatment
for urethral stricture disease: interim results from the ROBUST I study. Can Urol Assoc J 2020;14(6):187–91.
https://doi.org/10.5489/cuaj.6323
14. Urotronic Inc. Re-establishing Flow via Drug Coated Balloon for the Treatment of Urethral Stricture Disease
(ROBUST-II) ClinicalTrials.gov register. https://clinicaltrials.gov/ct2/show/NCT03270384
15. DeLong JM, Ehlert MJ, Erickson BA, Robertson KJ, Virasoro R, Elliott SP. One-year outcomes of the
ROBUST II study evaluating the use of a drug-coated balloon for treatment of urethral stricture. Soc Int Urol J
2022;3(1):21–7. https://siuj.org/index.php/siuj/article/view/159
16. Fujita-Rohwerder N. One-year results for the ROBUST III randomized controlled trial evaluating the
Optilume® drug-coated balloon for anterior urethral strictures. Letter. J Urol 2022;207(4):941–2.
https://doi.org/10.1097/ju.0000000000002426
17. Elliott SP. One-year results for the ROBUST III randomized controlled trial evaluating the Optilume ® drug-
coated balloon for anterior urethral strictures. Reply. J Urol 2022;207(4):942.
https://doi.org/10.1097/ju.0000000000002427
18. Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen. [H23-02] Medikamentenbeschichteter
Ballondilatationskatheter zur transurethralen Behandlung von Harnröhrenstrikturen - 3. Addendum zum Auftrag
H20-02. Köln: IQWIG; 2023. https://www.iqwig.de/projekte/h23-02.html
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6 SUMMARY REPORT
The Optilume urethral drug-coated balloon (DCB) is a urethral balloon coated with an
antiproliferative medicinal product (paclitaxel).
It is intended for the treatment of strictures in the anterior urethra in adult males. It is designed
to be used as a dilation balloon for a single, tandem, or diffuse anterior urethral stricture of
≤3 cm in length or used as an adjunctive therapy with other dilation devices and/or procedures.
In males, a urethral stricture is a narrowing of the anterior urethra lumen. It is a relatively

common medical condition among men that adversely impacts physical health and quality of
life. Left untreated, strictures can lead to serious complications such as recurrent urinary tract
infections, urinary retention and eventual renal impairment.
The aim of this joint clinical assessment (JCA) was to assess the relative clinical effectiveness
and safety of the Optilume urethral DCB medical device in the target patient population against
relevant comparators defined before the start of the assessment in the assessment scope
(Population, Intervention, Comparator, Outcome; PICO) and according to the requirements of
EUnetHTA 21 members.
Stakeholders and external experts were consulted early in the JCA scoping process to support
the development of the PICO question. Input was received from two healthcare professional
organisations, one patient organisation and one clinical expert.
The consolidated assessment scope including the PICO questions is presented in Table 30.
Table 30. Assessment scope including the consolidated PICO questions

of PICO
elements
Population According to the intended use: The same as for PICO 1 The same as for PICO 1
Men aged ≥18 years with
bothersome urinary symptoms
associated with recurrent
anterior urethral strictures
≤3 cm in length.
Intervention According to the intended use*: The same as for PICO 1 The same as for PICO 1
Optilume urethral drug-coated
balloon catheter used as a
dilation balloon for a single,
tandem or diffuse anterior
urethral stricture ≤3 cm in
length or used as an adjunctive
therapy with other dilation
devices and/or procedures.
Comparator Urethrotomy a Dilation Urethroplasty
Outcomes The following outcomes are assessed across all PICO question(s):
– All-cause mortality
– Urinary function (lower urinary tract symptoms related to stricture) measured using:
International Prostatic Symptom Score, Post-Void Residual urine volume, maximum flow
rate
– Erectile function measured using: International Index of Erectile Function
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of PICO
elements
– Pain
– Treatment success, preferably measured as: stricture-free rate, recurrence rate,
reintervention or time to treatment failure (preferably at a minimum of 6 months, 1 year, 2
years and in the long term)
– Anatomical success, preferably measured in terms of stricture tightness
– Health-related quality of life (generic and disease- or population specific measure), any
other patient-centred outcome and health status measured using PROMs
- Safety, including a description of each adverse event included in the following categories:
 Any AEs and device-related AEs including but not limited to: perioperative and
postoperative complications, urinary tract infection, urinary retention, incontinence,
 Drug-related AEs
 Serious AEs
* The other dilation devices and/or procedures used with the Optilume DCB will have to be specified in the
description of the procedure used in the clinical study/studies in the “Characteristics of the studies included”
section of the health technology developer’s submission dossier, if relevant.
a
Urethrotomy and direct vision internal urethrotomy (DVIU) are used indistinctly in this report.
Source: EUnetHTA 21 Committee for Scientific Consistency and Quality.
Abbreviations: AE=adverse event; DCB=drug-coated balloon; PICO=Population, Intervention, Comparator, Outcome; PROM=patient-
reported outcome measure.
The three PICO questions only differed from each other in the comparator.
There was no evidence to address PICO 1, PICO 2 and PICO 3 separately. However, one RCT
(ROBUST III) from the clinical development programme for the intervention under assessment
is presented in the report. It addresses the assessment scope in terms of population, intervention
and outcomes, but includes several comparators defined as standard endoscopic management
by the treating physician, mixing the comparators from PICO 1 (urethrotomy) and PICO 2
(dilation).
In addition, two single-arm studies (ROBUST I and ROBUST II) with longer follow-up were
included in the report for safety outcomes.
A summary-of-evidence table including the uncertainty of the evidence is presented in Table

31.
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Table 31. Uncertainty of evidence from the main studies from the clinical development programme
Outcome Design Factors that may affect the certainty of evidence Effect estimate
p value
All outcomes 1 RCT Internal validity of individual studies NA
 ROBUST III is a prospective, interventional RCT that
included 127 patients (79 in the intervention group vs 48 in
the control group) with short follow-up duration (6 months)
for outcomes with prespecified hypothesis testing.
 The randomisation was planned at a 2:1 allocation to
treatment vs control, stratified by investigational centre and
by prior radiation treatment and number of prior dilation
treatments using randomly permuted blocks (block size not
reported). There is no specific information on the
concealment of the allocation sequence.
 Only the patients were blinded to the treatment.
 The study was designed with a primary objective of
demonstrating superiority.
 There were no major differences in baseline characteristics
between the treatment groups in the study.
 The risk of bias was considered high for all outcomes.
 Only descriptive statistics were used to report most of the
outcomes apart from the stricture free rate, the freedom from
repeat intervention rate at 12 months and the change in Qmax
at 6 months.
 Patients could cross over to the Optilume group after
6 months according to the study protocol and, if medically
necessary (recurrent stricture requiring intervention) before
6 months. Some 25% (12/48) of patients from the control
group crossed over to the Optilume group before 6 months.
 There is no agreed single outcome measure that defines
urethral stricture recurrence.
Applicability
 The population of the study was in line with the population
defined in the assessment scope.
The anatomic location of the anterior strictures was mainly
bulbar in the study.
The study was conducted in North America, not in Europe.
 Optilume treatment included predilation, which is not
standard according to the IFU; this step was only carried out
in the study and it might have influenced the results.
Optilume is proposed for second-line treatment after stricture
recurrence, but the majority of patients included in ROBUST
III had more than 3 endoscopic treatments before the
Optilume procedure.
 The comparator for ROBUST III does not match any of the
comparators defined in PICO 1, PICO 2 or PICO 3.
 The comparator in the study was standard-of-care endoscopic
management as determined by the treating physician. It
included different procedures (rigid rod dilation, DVIU,
balloon dilation or a combination) which was a mix of the
PICO 1 (urethrotomy) and PICO 2 (dilatation) comparators.
 No data were reported for the drug-related adverse events
requested in the PICO question. All other outcomes were
reported in this study.
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Heterogeneity and inconsistency
No heterogeneity or inconsistency issue was raised as only

1 RCT was available and included for assessing the relative
effectiveness and relative safety of Optilume.
Stricture-free rate  Data for this outcome were missing for 12/79 (15%) patients RD for
at 6 months in the Optilume group and 7/48 (15%) patients in the control Optilume vs
group. dilation or
 A sensitivity analysis comprising 5 different subanalyses DVIU: 44.4%
yielded results with the same directionality as for the primary 95% CI [27.6;
analysis. 61.1]
 Patients in the control group who crossed over to the p < 0.0001 * , #,$
Optilume group were considered a failure for this outcome.
intervention and the study authors noted that this might have
biased their interpretation of cystoscopic findings or the
decision to proceed with repeat treatment. Therefore, the
assessment of this clinically reported outcome may have been
subject to measurement bias.
Freedom from 1 RCT  A nominal p value is provided because analysis of this Optilume vs
repeat outcome was prespecified in the protocol at 6 months and not dilation or
intervention rate at 12 months, but Kaplan-Meier estimates for each group are DVIU
at 12 months only reported at 12 months in the publication. p < 0.0001
 No difference in the median time to event or hazard ratio was
provided.
intervention over the entire study period and the study
authors noted that this might have biased their interpretation
of cystoscopic findings or the decision to proceed with repeat
treatment. Therefore, the assessment of this clinically
reported outcome may have been subject to measurement
bias.
Change in Qmax 1 RCT  Only reported in the CSR. MD for
(ml/s) at 6  The 95% CI for this effect measure was not provided in the Optilume vs
months CSR. dilation or
 No sensitivity analysis was conducted for this outcome. DVIU: +4.78
ml/s 90% CI
[1.94; 7.61]
p = 0.0031 * ,#,$
Qmax at 30 days 1 RCT  Only descriptive statistics were used to report this outcome. NA
months
PVR at 30 days 1 RCT  Only descriptive statistics were used to report this outcome. NA
months
IPSS at 30 days 1 RCT  Assessment of this outcome was not prespecified in the NA
and 3 and 6 protocol.
months  Only descriptive statistics were used to report this outcome.
IPSS-QoL at 30 1 RCT  The protocol prespecified the assessment of the QoL outcome NA
days and 3 and 6 but did not indicate any measurement instrument or follow-
months up length.
 Only descriptive statistics were used to report these
outcomes.
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IIEF (overall 1 RCT  Assessment of this outcome was not prespecified in the NA
satisfaction) at 30 protocol.
days and 3 and 6  Only descriptive statistics were used to report this outcome.
months  There is no explanation for missing data.
Freedom from a 1 RCT As prespecified in the protocol, only descriptive statistics were NA
composite of used to report this outcome.
serious device- or
procedure related
events including:
– Urethral fistula
– Unresolved de
novo stress
urinary
incontinence
– Urethral rupture
up to 3 months
Periprocedural 1 RCT  Assessment of this outcome was not prespecified in the NA
pain (VAS) protocol.
 Only descriptive statistics were used to report this outcome.
All-cause 1 RCT,  Assessment of this outcome was not prespecified in the NA
mortality 2 single- protocols.
arm  Only descriptive statistics were used to report this outcome.
studies
Other adverse 1 RCT, Only descriptive statistics were used to report these outcomes. NA
events 2 single-
arm
studies
* Statistically significant according to a prespecified alpha level.
#
Prespecified analysis according to the statistical analysis plan (for individual studies) or the evidence synthesis
protocol.
$
Control for multiplicity.
Abbreviations: CI=confidence interval; CSR=clinical study report; DVIU=direct vision internal urethrotomy; IFU=instructions for use;
IIEF=International Index of Erectile Function; IPSS=International Prostate Symptom Score; MD=mean difference; NA=not applicable;
PICO=Population, Intervention, Comparator, Outcome; PVR=postvoid residual volume; Qmax=maximum flow rate; QoL=quality of life;
RCT=randomised controlled trial; RD=risk difference; VAS=Visual Analogue Scale.
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Appendix A Input from external experts

Input from stakeholder organisations and from clinical expert obtained via the open call for input are presented in this appendix.
Q uestion 1 2 3
Please state the country where the T he Netherlands Belgium Germany

HCP organisation/clinical society
that you are representing is based
Please name the HCP European Association of Urology European Union of General Practitioners UEMO
organisation/clinical society you are
representing
What role do you have in the President/Vice President/ Board Member Member with mandate to speak on behalf of I am a self employed medical
organisation? organisation consultant
How many members does your Approx 19 000 individual members 24 national medical Organisations
organisation have?
How is your organisation funded? See link for 2021: https://uroweb.org/european-medicine- Funding by annual cotisations coming from No funding from medical industry
agency-ema For 2020: As part of the evaluation for national medical organisations according the during the last three years
eligibility, the European Association of Urology has number of GPs / Family doctors. No industry
provided the following financial information (2020) to be funding. Ireland, UK, Belgium, NL, Luxemburg,
assessed by the parameters as set by the European Portugal, Spain, France, Italy, Switzerland,
Medicine Agency: •Royalties EAU scientific journal: Germany, CZ, Slovenia, Slovakia, HR, HU,
26,08% – 50% non-industry – 50% industry •Membership Austria, RO, Lituanua, Norway, Sweden, Finland,
fees 22.96% – 100% non-industry •Registration fees Serbia, T urkey. Budget: previsional 2023 More
9.12% – 100% non-industry •Results EAU meeting & informations: [email protected]
education 33.15% – 100% industry •Accounting and
management consulting 1.49% – 100% non-industry
•Sold guidelines 1.98% – 100% non-industry •Other
income 5.22% – 100% non-industry Overall proportion of
industry and non-industry:46.19% vs 53.81% The
following pharmaceutical companies provide funding to
EAU: •Astellas Pharma Europe Ltd •Intuitive Surgical
Sarl •Janssen Pharmaceutical N.V. •Bayer Consumer Care
AG •GSK Services Unlimited •IPSEN innovation •BMS
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Bristol Myers Squibb •Ferring International Center S.A
•Bayer Healthcare Pharmaceuticals, Inc. •Pfizer Inc. For
2019: As part of the evaluation for eligibility, the
European Association of Urology has provided the
following financial information (2019) to be assessed by
the parameters as set by the European Medicine Agency:
•Royalties EAU scientific journal: 8.33% – 50% non-
industry – 50% industry •Membership fees 8.21% – 100%
non-industry •Registration fees 42.36% – 100% non-
industry •Results EAU meeting & education 40.22% –
100% industry •Accounting and management consulting
0.59% – 100% non-industry •Sold guidelines 0.22% –
100% non-industry •Other income 0.06% – 100% non-
industry Overall proportion of industry and non-
industry:44.79% vs 55.21% Funding Resources: The
following pharmaceutical companies provide funding to
EAU: •IPSEN innovation •Janssen Pharmaceutical N.V.
•Karl Storz SE & Co. KG •Bayer •Olympus Europa SE &
CO. KG •Intuitive Surgical Sarl •Astellas Pharma
•Bristol-Myers Squibb •Boston Scientific •Cook Medical
Europe Ltd.
Please state the geographical spread '+ Uk, Norway, Switzerland, Serbia, T urkey
of the organisation’s membership
Please state the health condition(s) All diseases in the field of Urology, Pediatric Urology, Family medicine/general practice
represented by the organisation Renal T ransplantation, and Andrology
and/or the remit of the organisation
Population Male patients who suffer from significant lower urinary In general practice our patients are certainly in Primary or repeated urethral
Please state relevant patient tract symptoms induced by a ureteral stricture. Lower majority old men with BPH, less with recurent stricture Work status: company
sociodemographic (e.g., age, urinary symptoms may include weak urine flow, dysuria, UT I. T his technique could be useful in medical employed, self employed, retired
ethnicity, socioeconomic st atus) and pollakisuria, recurrent urinary infection, residual post home for old persons or in palliative care units, if Eligibility criteria: Age,
clinical baseline characteristics (e.g., voiding urine and even urinary retention. T he highest the use is simple and comfortable. Patients who concomitant diseases
severity of condition, comorbidities) available evidence regarding optilume is obtained from need a dilatation are generally referred to the
which may contribute to differences the Robust III trial: Elliot et al. J Urol 2022; 207, 866-75 urologist. According to our numerous
in treatment outcomes or treatment Key inclusion criteria were: -at least 2 prior (failed) investigations of UEMO GPs practices around
preferences. endoscopic procedures -anterior urethral stricture (92% of Europe, in some rural or remote areas the GP can
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What are the relevant eligibility included patients had a bulbar stricture; therefore, the have the possibility to make such medical acts
criteria for treatment decisions made results predominantly apply to the bulbar urethra and this when no specialist is at disposal. But such a
by HCPs? device should only be endorsed for that part of the urethra technique needs a training. T he technique can be
only -stricture length ≤ 3cm (generally spoken „short“
stricture) -stricture diameter ≤ 12Fr (generally spoken
„high grade“ stricture) -IPSS ≥11 (although not validated
for urethral stricture disease, IPSS is often used for this
condition; we can state that they included patients with
moderate to severe LUT S -Q max <15ml/s (this is what
you expect in a high grade stricture) Key exclusion
criteria: -prior urethroplasty -hypospadias -Lichen
sclerosus In summary the device has been tested in: Male
adult patients with short, high-grade bulbar urethral
stricture with moderate to severe LUT S and who
underwent at least to endoscopic procedures but no prior
urethroplasty.
Intervention Are there contextual factors, (e.g., prior, concurrent or Consider the intervention by the GP if no urologist First line therapy versus repeated
Are there contextual factors, (e.g., subsequent treatments, training on administration, etc.) at disposal but training is necessary. Certainly treatments Professional experience
prior, concurrent or subsequent which may affect the safety and/or effectiveness of the needs the experience of GP or trained doctor. of the HCP/team Possibility of
treatments, training on intervention? Does the specific (professional) experience T reatment discontinuation if allergy to the outclinic treatment Multiple
administration, etc.) which may of the treating HCP or medical staff play a relevant role in medicine involved, lesions (perforation), pain or repeated treatment would imply
affect the safety and/or effectiveness the decision to use the intervention? Yes, any intervention recurent use higher drug exposure T here is a
of the intervention? should be performed by a certified urologist Would the strong interest in definite "cure"
Does the specific (professional) decision to use the intervention in clinical practice be after single intervention
experience of the treating HCP or affected by its route and/or frequency of administ ration?
medical staff play a relevant role in Yes, the surgeon (urologist) should have sufficient
the decision to use the intervention? experience in performing the respective procedure. What
Would the decision to use the would be relevant criteria for treatment discontinuation?
intervention in clinical practice be Is there a specific time point at which you check the
affected by its route and/or therapeutic effect? 1/ T reatment discontinuation: -if pre-
frequency of administration? operatively, the stricture cannot be dilated or incised
What would be relevant criteria for endoscopically, the procedure should be aborted -if after
treatment discontinuation? Is there a dilation/endoscopic incision, a false passage is present, the
specific time point at which you procedure should be aborted 2/ follow-up -> I propose to
check the therapeutic effect? take over the follow-up protocol from the study which is
not different to clinical practice -2-5 days (i.e. catheter
removal) (-30 days: not really necessary) -3 months -6
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Where does the intervention fit in the months -12 months -annually until 5 years Where does the
current treatment landscape? intervention fit in the current treatment landscape? The
current treatment does NOT fit in the current treatment
landscape according to the EAU guidelines. T here there is
a ST RONG recommendations for this guideline: „Do not
perform repetitive (>2) direct vision internal
urethrotomy/dilatations if urethroplasty is a viable
option.“ Nevertheless, repetitive DVIU/dilatations are
still routinely performed by many urologists. T he panel
would only endorse the DCB dilatation for patients with
recurrent bulbar strictures who are not fit to undergo
urethroplasty or who refuse urethroplasty (this is also
stated in the conclusion of the Robust III trial)
Comparator(s) What is the standard of care in your country? Are you Many old men in medical home can have an in situ Surgical treatment with termino-
What is the standard of care in your aware of the standard of care most commonly used in remaining urethral catheter. Some can make self terminal anastomosis is the
country? Are you aware of the Europe? T he SOC for a recurrent short bulbar stricture is regular catheterism. recommended procedure However,
standard of care most commonly open urethroplasty. DVIU or dilatation can only be repeated dilatation is preferred in
used in Europe?
Are there different treatment options considered SOC for an untreated short bulbar stricture. In clinical practise Comparison needs
for different patient groups case of a short bulbar stricture treatment options should be to be fair: Not single procedure
depending on severity, previous discussed: One trial urethrotomy/dilatation or against muli-modal treatment (i.e.
treatment, biomarker levels, etc.? urethroplasty. Highest success rate with the last treatment. pre-dilatation or DIVU followed by
What are the goals of current Are there different treatment options for different patient balloon dilatation and local
treatments? groups depending on severity, previous treatment, chemotherapy)
Are there contextual factors (e.g.,
biomarker levels, etc.? -For short obliterative strictures or
prior, concurrent or subsequent
treatments) which may affect the strictures with full thickness spongiofibrosis, the EAU
safety and/or effectiveness of the guidelines recommend transecting excision and primary
comparators? anastomosis -For short bulbar strictures not related to
Would the decision to use straddle injury, the EAU guidelines recommend non-
comparators in clinical practice be transecting excision and primary anastomosis or free graft
affected by their route and/or urethroplasty. -For longer strictures, the EAU guidelines
frequency of administration? recommend free graft urethroplasty. What are the goals of
current treatments? T o re-establish an open and not
stenotic urethra and thus cure the existing lower urinary
tract symptom. Are there contextual factors (e.g., prior,
concurrent or subsequent treatments) which may affect the
safety and/or effectiveness of the comparators? No, all
existing techniques are safe and effective, but the new
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device offers a minimally invasive approach. Would the
decision to use comparators in clinical practice be affected
by their route and/or frequency of administration? Yes, the
comparator in the Robust III trial is not the gold standard.
T he device should have been tested against open
urehtroplasty and not against the (mal)practice of
repetitive dilatations/DVIU
Outcome(s) Possible intraoperative complications are: Bleeding, pain, Outcome seems first the comfort of the patient: Safety: Need for hospitalisation for
Please define relevant safety, infection, urinary retention, injury of the urethra; Possible self management of symptoms, more freedom, no any reason Efficacy: Bladder
efficacy and patient -centred late complications are recurrent formation of the stricture, pain. emptying without significant
outcomes (e.g., quality of life) which
obstruction and dislodgement of the device requiring residual volume Most important:
should be assessed.
further interventions. Anatomical succes at 6 months was Long term patient reported outcome
What safety and efficacy outcomes
are used in clinical practice to inform 74.6% for DCB dilatation versus 26.8% for
clinical decisions regarding DVIU/dilatation. No serious device related adverse events
treatment and how are they were reported with DCB dilatation. Adverse events that
measured? were more frequent with DCB dilatation versus control
If surrogate outcomes (e.g., were: hematuria and dysuria. Pacitaxel remained
laboratory parameters) are relevant detectable in semen up to 6mo after procedure:
to the indication given, do you contraception warranted in case of fertile partner What
consider them to be clinically safety and efficacy outcomes are used in clinical practice
meaningful?
to inform clinical decisions regarding treatment and how
are these measured? Follow-up schedule mentioned
above. Every follow-up visit should include: -history
taking -Questionnaire evaluating LUT S and QoL Uroflow
-Residual volume In case of obstructive symptoms or
signs, further examinations with urethography or
urethroscopy are needed. If surrogate outcomes (e.g.,
laboratory parameters, etc.) are relevant to the indication
given, do you consider them to be clinically meaningful?
Residual urine, Urine peak flow, Urine culture
If you have any further comments or No further comments. For the GP it is certainly a technique needing All three clinical studies were
remarks, please add them here specialist competencies, but we are also the person performed in patients with recurrent
where the patient come back if there is a problem. urethral strictures; there are no
We have to discuss the options reports on first line intervention.
T his would be very interesting (if
55
16 June 2023
not absolutely necessary) for real
life use.
Input from patient organisation is provided in the following table.
Q uestion
Website of your organisation: www.prostatakrebs-bps.de
Where have you sourced information on patients’ own individual experience, individual patient stories, leader of a patient support group, patient group helpline, one-to-one
experiences? If relevant, how did you gather information discussions with patients
about the experiences of patients?
How does urinary symptoms associated with urethral male patients with prostate cancer may devellop urethral strictures some month after radical prostatectomy or some years after
stricture affect patient's daily life? radiation therapy. the symptoms are very different, pain during urination, urinary retention etc.. treatment options are ur ethral
dilation, urethrotomy etc. but often patients have recurrent urethral stricture.
How does urinary symptoms associated with urethral partners of prostate cancer patients suffer especially when the patient is depressiv, incontinent or impotent etc.
stricture affect carers?
Please provide your answer to the above question here. recurrent urethral stricturs are a big problem, i.e. after urethrotomy. many patients wish a minimal invasive treatment.
Please provide your answer to the above question here. Expectations for the treatment with Urethral Drug Coated Balloon: less recurrent urethral strictures less symptoms less side
effects of the paclitaxel coat
For those with experience using Urethral Drug Coated no or less urinary retention. no or less pain during urination etc. better sleep.
Balloon what difference does/did it make to their lives?
In no more than ten statements, please try to summarise main patient expectations are to avoid radical surgery and recurrence of urethral strictures
your submission by listing the most important points.
However, please note that all information you provide in
the template will be considered by the EUnetHT A (Co)-
Assessors.
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16 June 2023
Appendix B Assessment of information retrieval
The evidence base with regard to the health technology under assessment, the Optilume Urethral Drug-
coated Balloon (DCB), provided by the HTD was reviewed by the assessment team. Search strategies
were checked for appropriateness, and the results of information retrieval included in the HTD
submission dossier were checked for completeness of studies against a search of study registries and in
the Medline bibliographic database.
The documentation of searches conducted by the assessment team for the verification of the
completeness of studies included in the assessment is provided below.
No concerns regarding the information retrieval in the submission dossier were raised during
this completeness check.
Search strategy of the search conducted in study registries and in Medline by the
assessment team for study completeness check
1. ClinicalTrials.gov
Provider: U.S. National Institutes of Health
 URL: https://www.clinicaltrials.gov
 Interface: Expert Search
Search syntax
Optilume
2. Clinical Trials Information System (CTIS)

Provider: European Medicines Agency
 URL: https://euclinicaltrials.eu/search-for-clinical-trials/
 Interface: Basic Criteria (Contain any of these terms)
Search syntax
Optilume
3. International Clinical Trials Registry Platform Search Portal

Provider: World Health Organization
 URL: https://trialsearch.who.int/
 Interface: Standard Search
Search syntax
Optilume
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16 June 2023
4. Medline
Provider: National Library of Medicine
 Interface: ProQuest
Search Query
#1 Search ti,ab,if("optilume")
#2 Search tndev("Optilume")
#3 Search #1 OR #2
5. Embase
Provider: Elsevier
 Interface: ProQuest
Search Query
#1 Search ti,ab,if("optilume")
#2 Search tndev("Optilume")
#3 Search #1 OR #2
#4 Search EMB.EXACT(conference abstract)
#5 Search #3 AND #4
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16 June 2023
Appendix C Additional safety data from the ROBUST III CSR

Table 32: Adverse Events Categorised by Common Terminology Criteria for Adverse Events (CTCAE)
Severity for the Randomised Cohort (Adjudicated) - ROBUST III
Control Arm Optilume Arm
(N=48) (N=79)
System Organ Class/

CTCAE Term Grade 1-2 Grade 3+ Grade 1-2 Grade 3+
Renal and urinary disorders 25/48 (52.1%) 6/48 (12.5%) 32/79 (40.5%) 8/79 (10.1%)
Urethral stricture 17/48 (35.4%) 3/48 (6.3%) 10/79 (12.7%) 3/79 (3.8%)
Urinary retention 1/48 (2.1%) 3/48 (6.3%) 5/79 (6.3%) 1/79 (1.3%)
Dysuria 1/48 (2.1%) 0/48 (0.0%) 7/79 (8.9%) 0/79 (0.0%)
Post procedural hematuria 0/48 (0.0%) 0/48 (0.0%) 6/79 (7.6%) 1/79 (1.3%)
Bladder spasm 1/48 (2.1%) 0/48 (0.0%) 4/79 (5.1%) 0/79 (0.0%)
Poor urinary stream 2/48 (4.2%) 0/48 (0.0%) 3/79 (3.8%) 0/79 (0.0%)
Hematuria 1/48 (2.1%) 0/48 (0.0%) 3/79 (3.8%) 0/79 (0.0%)
Lower urinary tract symptoms 2/48 (4.2%) 0/48 (0.0%) 0/79 (0.0%) 1/79 (1.3%)
Post micturition dribble 0/48 (0.0%) 0/48 (0.0%) 3/79 (3.8%) 0/79 (0.0%)
Voiding difficulty 0/48 (0.0%) 0/48 (0.0%) 3/79 (3.8%) 0/79 (0.0%)
Urinary incontinence 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 1/79 (1.3%)
Bladder neck contracture 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Detrusor sphincter dyssynergia 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Frequency of micturition 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Kidney stone 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Overactive bladder 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Renal calculi 0/48 (0.0%) 0/48 (0.0%) 0/79 (0.0%) 1/79 (1.3%)
Urethral bleeding 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Urethritis 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Urge incontinence 1/48 (2.1%) 0/48 (0.0%) 0/79 (0.0%) 0/79 (0.0%)
Infections and infestations 6/48 (12.5%) 2/48 (4.2%) 11/79 (13.9%) 2/79 (2.5%)
Urinary tract infection 5/48 (10.4%) 0/48 (0.0%) 9/79 (11.4%) 0/79 (0.0%)
Bacteriuria 2/48 (4.2%) 0/48 (0.0%) 5/79 (6.3%) 0/79 (0.0%)
COVID-19 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 1/79 (1.3%)
COVID-19 pneumonia 0/48 (0.0%) 1/48 (2.1%) 0/79 (0.0%) 0/79 (0.0%)
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16 June 2023

(N=48) (N=79)
System Organ Class/

Conjunctivitis infective 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Fungal skin infection 1/48 (2.1%) 0/48 (0.0%) 0/79 (0.0%) 0/79 (0.0%)
Kidney infection 0/48 (0.0%) 0/48 (0.0%) 0/79 (0.0%) 1/79 (1.3%)
Sepsis 0/48 (0.0%) 1/48 (2.1%) 0/79 (0.0%) 0/79 (0.0%)

Staphylococcal infection 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Upper respiratory infection 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Wound infection 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Respiratory, thoracic and 7/48 (14.6%) 0/48 (0.0%) 8/79 (10.1%) 2/79 (2.5%)
mediastinal disorders
Cough 2/48 (4.2%) 0/48 (0.0%) 2/79 (2.5%) 0/79 (0.0%)
Bronchitis 3/48 (6.3%) 0/48 (0.0%) 0/79 (0.0%) 0/79 (0.0%)
Cold symptoms 1/48 (2.1%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Pneumonia 0/48 (0.0%) 0/48 (0.0%) 2/79 (2.5%) 0/79 (0.0%)
Upper respiratory tract infection 0/48 (0.0%) 0/48 (0.0%) 2/79 (2.5%) 0/79 (0.0%)
Lung adenocarcinoma metastatic 0/48 (0.0%) 0/48 (0.0%) 0/79 (0.0%) 1/79 (1.3%)
Lung nodule 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Pulmonary embolism 0/48 (0.0%) 0/48 (0.0%) 0/79 (0.0%) 1/79 (1.3%)
Rhinorrhea 1/48 (2.1%) 0/48 (0.0%) 0/79 (0.0%) 0/79 (0.0%)
Rhonchi 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Gastrointestinal disorders 3/48 (6.3%) 1/48 (2.1%) 7/79 (8.9%) 4/79 (5.1%)
Abdominal pain 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 1/79 (1.3%)
Constipation 0/48 (0.0%) 0/48 (0.0%) 2/79 (2.5%) 0/79 (0.0%)
Nausea 1/48 (2.1%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Umbilical hernia 0/48 (0.0%) 0/48 (0.0%) 0/79 (0.0%) 2/79 (2.5%)
Abdominal discomfort 1/48 (2.1%) 0/48 (0.0%) 0/79 (0.0%) 0/79 (0.0%)
Acute gastroenteritis 0/48 (0.0%) 1/48 (2.1%) 0/79 (0.0%) 0/79 (0.0%)
Bowel infarction 0/48 (0.0%) 0/48 (0.0%) 0/79 (0.0%) 1/79 (1.3%)
Esophageal acid reflux 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
GI bleed 1/48 (2.1%) 0/48 (0.0%) 0/79 (0.0%) 0/79 (0.0%)
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(N=48) (N=79)
System Organ Class/

Left inguinal hernia 0/48 (0.0%) 0/48 (0.0%) 0/79 (0.0%) 1/79 (1.3%)
Opioid induced constipation 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Pelvic pain 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Tooth infection 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Xerostomia 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Reproductive system and breast 2/48 (4.2%) 0/48 (0.0%) 9/79 (11.4%) 0/79 (0.0%)
disorders
Prostatitis 0/48 (0.0%) 0/48 (0.0%) 3/79 (3.8%) 0/79 (0.0%)
Penile pain 0/48 (0.0%) 0/48 (0.0%) 2/79 (2.5%) 0/79 (0.0%)
Testicular pain 1/48 (2.1%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Balanitis candida 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Benign prostatic hyperplasia 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Erectile dysfunction 1/48 (2.1%) 0/48 (0.0%) 0/79 (0.0%) 0/79 (0.0%)
Perineal pain 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Peyronie's disease 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Retracted penis 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Injury, poisoning and procedural 2/48 (4.2%) 1/48 (2.1%) 5/79 (6.3%) 1/79 (1.3%)
complications
Medical device site extravasation 1/48 (2.1%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Pulmonary aspiration during 0/48 (0.0%) 1/48 (2.1%) 0/79 (0.0%) 1/79 (1.3%)
anaesthetic induction
Achilles tendon sprain 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Catheter site irritation 1/48 (2.1%) 0/48 (0.0%) 0/79 (0.0%) 0/79 (0.0%)
Exposure to toxic agent (non- 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
occupational)
Fall 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Insect bite, nonvenomous, of hip, 1/48 (2.1%) 0/48 (0.0%) 0/79 (0.0%) 0/79 (0.0%)
thigh, leg, and ankle, without mention
of infection
Post procedural hematuria 1/48 (2.1%) 0/48 (0.0%) 0/79 (0.0%) 0/79 (0.0%)
Postoperative hemorrhage 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
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(N=48) (N=79)
System Organ Class/

Musculoskeletal and connective 3/48 (6.3%) 1/48 (2.1%) 4/79 (5.1%) 1/79 (1.3%)
tissue disorders
Low back pain 1/48 (2.1%) 1/48 (2.1%) 2/79 (2.5%) 0/79 (0.0%)
Bone spur 0/48 (0.0%) 0/48 (0.0%) 2/79 (2.5%) 0/79 (0.0%)
Arthritis 0/48 (0.0%) 0/48 (0.0%) 0/79 (0.0%) 1/79 (1.3%)
Bursitis 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Myalgia 1/48 (2.1%) 0/48 (0.0%) 0/79 (0.0%) 0/79 (0.0%)
Osteoarthritis aggravated 1/48 (2.1%) 0/48 (0.0%) 0/79 (0.0%) 0/79 (0.0%)
Pain knee 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Shoulder pain 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
General disorders and 4/48 (8.3%) 0/48 (0.0%) 2/79 (2.5%) 1/79 (1.3%)
administration site conditions
Chest pain (non-cardiac) 1/48 (2.1%) 0/48 (0.0%) 1/79 (1.3%) 1/79 (1.3%)
Fever 1/48 (2.1%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Adverse reaction to antibiotics 1/48 (2.1%) 0/48 (0.0%) 0/79 (0.0%) 0/79 (0.0%)
Alcoholic withdrawal symptoms 1/48 (2.1%) 0/48 (0.0%) 0/79 (0.0%) 0/79 (0.0%)
Edema of lower extremities 1/48 (2.1%) 0/48 (0.0%) 0/79 (0.0%) 0/79 (0.0%)
Fatigue 1/48 (2.1%) 0/48 (0.0%) 0/79 (0.0%) 0/79 (0.0%)
Pain-left side 1/48 (2.1%) 0/48 (0.0%) 0/79 (0.0%) 0/79 (0.0%)
Skin and subcutaneous tissue 1/48 (2.1%) 0/48 (0.0%) 6/79 (7.6%) 0/79 (0.0%)
disorders
Actinic keratosis 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Herpes zoster 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Lower extremities ulcers of 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Penile rash 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Pruritus 1/48 (2.1%) 0/48 (0.0%) 0/79 (0.0%) 0/79 (0.0%)
Skin and subcutaneous tissue 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
disorders - other, specify
Smelly feet 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Vascular disorders 2/48 (4.2%) 1/48 (2.1%) 1/79 (1.3%) 2/79 (2.5%)
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(N=48) (N=79)
System Organ Class/

Hypertension 1/48 (2.1%) 0/48 (0.0%) 0/79 (0.0%) 1/79 (1.3%)
Aneurysm cerebral 0/48 (0.0%) 1/48 (2.1%) 0/79 (0.0%) 0/79 (0.0%)
Dizziness 1/48 (2.1%) 0/48 (0.0%) 0/79 (0.0%) 0/79 (0.0%)
Hematoma 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)

Hypertension exacerbated 0/48 (0.0%) 0/48 (0.0%) 0/79 (0.0%) 1/79 (1.3%)
Cardiac disorders 1/48 (2.1%) 0/48 (0.0%) 2/79 (2.5%) 1/79 (1.3%)
Atrial fibrillation 0/48 (0.0%) 0/48 (0.0%) 0/79 (0.0%) 1/79 (1.3%)
Coronary artery disease 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Myocardial infarction 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Sinus bradycardia 1/48 (2.1%) 0/48 (0.0%) 0/79 (0.0%) 0/79 (0.0%)
Surgical and medical procedures 1/48 (2.1%) 0/48 (0.0%) 2/79 (2.5%) 1/79 (1.3%)
Cataract operation 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Colectomy 0/48 (0.0%) 0/48 (0.0%) 0/79 (0.0%) 1/79 (1.3%)

Surgical and medical procedures - 1/48 (2.1%) 0/48 (0.0%) 0/79 (0.0%) 0/79 (0.0%)
other, specify
Total knee replacement 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Immune system disorders 3/48 (6.3%) 0/48 (0.0%) 0/79 (0.0%) 0/79 (0.0%)
Allergic reaction 3/48 (6.3%) 0/48 (0.0%) 0/79 (0.0%) 0/79 (0.0%)
Psychiatric disorders 0/48 (0.0%) 0/48 (0.0%) 3/79 (3.8%) 0/79 (0.0%)
Attention deficit disorder 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Bipolar disorder 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Depression 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Blood and lymphatic system 0/48 (0.0%) 0/48 (0.0%) 2/79 (2.5%) 0/79 (0.0%)
disorders
Anemia 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Swollen lymph nodes 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Endocrine disorders 1/48 (2.1%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Diabetic ulcer right foot 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Worsening of diabetes 1/48 (2.1%) 0/48 (0.0%) 0/79 (0.0%) 0/79 (0.0%)
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(N=48) (N=79)
System Organ Class/

Nervous system disorders 0/48 (0.0%) 1/48 (2.1%) 1/79 (1.3%) 0/79 (0.0%)
Headache 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Thalamus hemorrhage 0/48 (0.0%) 1/48 (2.1%) 0/79 (0.0%) 0/79 (0.0%)
Ear and labyrinth disorders 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Vertigo 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Eye disorders 1/48 (2.1%) 0/48 (0.0%) 0/79 (0.0%) 0/79 (0.0%)
Double vision 1/48 (2.1%) 0/48 (0.0%) 0/79 (0.0%) 0/79 (0.0%)
Hepatobiliary disorders 0/48 (0.0%) 0/48 (0.0%) 0/79 (0.0%) 1/79 (1.3%)
Gallstones 0/48 (0.0%) 0/48 (0.0%) 0/79 (0.0%) 1/79 (1.3%)
Investigations 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Alanine aminotransferase increased 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)

Aspartate aminotransferase increased
Metabolism and nutrition disorders 0/48 (0.0%) 0/48 (0.0%) 0/79 (0.0%) 1/79 (1.3%)
Hyperkalemia 0/48 (0.0%) 0/48 (0.0%) 0/79 (0.0%) 1/79 (1.3%)
Neoplasms benign, malignant and 0/48 (0.0%) 0/48 (0.0%) 0/79 (0.0%) 1/79 (1.3%)
unspecified (incl. cysts and polyps)
Neoplasms benign, malignant and 0/48 (0.0%) 0/48 (0.0%) 0/79 (0.0%) 1/79 (1.3%)
unspecified (incl. cysts and polyps) -
other, specify
Penile and scrotal disorders (excl. 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
infections and inflammations)
Hydrocele 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Respiratory, thoracic and 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
mediastinal disorders
Dyspnea 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Respiratory disorders NEC 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)
Cough 0/48 (0.0%) 0/48 (0.0%) 1/79 (1.3%) 0/79 (0.0%)

Only the AE terms before crossover were included.
Each subject is counted once within each System Organ Class and CTCAE Term according to the maximum
intensity for all AEs within that System Organ Class or CTCAE Term.
Effect measures and p values were not provided by the HTD.
AE: adverse events; CTCAE: Common Terminology Criteria for Adverse Events; GI: gastrointestinal; HTD: Health Technology Developper;
NEC: not elsewhere classifiable
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Table 33: Reasons for Study Exit ROBUST III

Control Optilume Crossovera Total
Measure % (n/N) % (n/N) % (n/N) % (n/N)
Total Study Exit 25.0% 38.0% 37.5% 38.3%
(12/48) (30/79) (12/32) (54/141)
All required follow-up completed 4.2% 0.0% 0.0% 1.4%
(2/48) (0/79) (0/32) (2/141)
Investigator discretion 4.2% 2.5% 0.0% 2.8%
(2/48) (2/79) (0/32) (4/141)
Subject withdrew consent 6.3% 6.3% 0.0% 5.7%
(3/48) (5/79) (0/32) (8/141)
Lost to follow-up 4.2% 2.5% 9.4% 5.0%
(2/48) (2/79) (3/32) (7/141)
Adverse Event 0.0% 1.3% 0.0% 0.7%
(0/48) (1/79) (0/32) (1/141)
Treatment Failure – Subject 6.3% 21.5% 28.1% 20.6%
Received Alternative Therapy (3/48) (17/79) (9/32) (29/141)
Death 0.0% 2.5% 0.0% 1.4%
(0/48) (2/79) (0/32) (2/141)
Other 0.0% 1.3% 0.0% 0.7%
(0/48) (1/79) (0/32) (1/141)
a: crossover subjects were enrolled in the Control arm and are not included in denominator for ‘Total’.
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Appendix D RoB 2.0 tables
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Revised Cochrane risk-of-bias tool for randomized trials (RoB 2)

TEMPLATE FOR COMPLETION
Edited by Julian PT Higgins, Jelena Savović, Matthew J Page, Jonathan AC Sterne
on behalf of the RoB2 Development Group
Version of 22 August 2019
The development of the RoB 2 tool was supported by the MRC Network of Hubs for Trials Methodology Research (MR/L004933/2- N61), with the
support of the host MRC ConDuCT-II Hub (Collaboration and innovation for Difficult and Complex randomised controlled Trials In Invasive procedures -
MR/K025643/1), by MRC research grant MR/M025209/1, and by a grant from The Cochrane Collaboration.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
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Study details
Elliott SP, Coutinho K, Robertson KJ, D'Anna R, Chevli K, Carrier S, Aube-Peterkin M, Cantrill CH, Ehlert MJ, Te AE, Dann J,
DeLong JM, Brandes SB, Hagedorn JC, Levin R, Schlaifer A, DeSouza E, DiMarco D, Erickson BA, Natale R, Husmann DA,
Reference Morey A, Olsson C, Virasoro R. One-Year Results for the ROBUST III Randomized Controlled Trial Evaluating the
Optilume Drug-Coated Balloon for Anterior Urethral Strictures. J Urol. 2022 Apr;207(4):866-875. doi:
10.1097/JU.0000000000002346. Epub 2021 Dec 2. PMID: 34854748.
Study design
X Individually-randomized parallel-group trial
 Cluster-randomized parallel-group trial
 Individually randomized cross-over (or other matched) trial
For the purposes of this assessment, the interventions being compared are defined as
Experimental: OPTILUME DCB Comparator: Standard of care endoscopic
management as determined by
the treating physician, including
rigid rod dilation, DVIU, uncoated
balloon dilation or a combination
Specify which outcome is being assessed for risk of bias Primary efficacy end point: % Stricture-free at 6 months
Specify the numerical result being assessed. In case of multiple alternative Difference (OPTILUME vs control) = 44.4% (95% CI 27.6 to 61.1)
analyses being presented, specify the numeric result (e.g. RR = 1.52 (95% CI In Table 2
0.83 to 2.77) and/or a reference (e.g. to a table, figure or paragraph) that
uniquely defines the result being assessed.
Is the review team’s aim for this result…?
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x to assess the effect of assignment to intervention (the ‘intention-to-treat’ effect)

 to assess the effect of adhering to intervention (the ‘per-protocol’ effect)
If the aim is to assess the effect of adhering to intervention, select the deviations from intended intervention that should be addressed (at least one
must be checked):
 occurrence of non-protocol interventions
 failures in implementing the intervention that could have affected the outcome
 non-adherence to their assigned intervention by trial participants
Which of the following sources were obtained to help inform the risk-of-bias assessment? (tick as many as apply)
x Journal article(s) with results of the trial
x Trial protocol
 Statistical analysis plan (SAP)
x Non-commercial trial registry record (e.g. ClinicalTrials.gov record)
 Company-owned trial registry record (e.g. GSK Clinical Study Register record)
 “Grey literature” (e.g. unpublished thesis)
 Conference abstract(s) about the trial
x Regulatory document (e.g. Clinical Study Report, Drug Approval Package)
 Research ethics application
 Grant database summary (e.g. NIH RePORTER or Research Councils UK Gateway to Research)
 Personal communication with trialist
 Personal communication with the sponsor
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(1) Risk of bias assessment

Responses underlined in green are potential markers for low risk of bias, and responses in red are potential markers for a risk of bias. Where questions
relate only to sign posts to other questions, no formatting is used.
Do main 1: Risk o f b ias arisin g fro m th e ran d o miz atio n p ro cess

Signalling questions Comments Response options
1.1 Was the allocation sequence random? From the protocol: “Subjects will be randomized in a 2:1 allocation of treatment vs Y
control. Randomization will be stratified by investigational center and by prior
radiation treatment (yes or no) and number of prior dilation treatments (i.e. less than
5 prior dilations versus ≥ 5prior dilations). Each treatment group will have its own
1.2 Was the allocation sequence concealed randomization schedule within each participating center. For each randomization PY
until participants were enrolled and schedule, randomization will be performed using randomly permuted blocks.”
assigned to interventions?
There is no specific information on the concealment of the allocation sequence.
1.3 Did baseline differences between N
intervention groups suggest a problem with
the randomization process?
Risk-of-bias judgement Low risk
Optional: What is the predicted direction of NA

bias arising from the randomization process?
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Domain 2: Risk of bias due to deviations from the intended interventions ( effect of assignment to intervention )
2.1. Were participants aware of their Some participants were unblinded before 6 months if they experienced recurrent PN
assigned intervention during the trial? stricture requiring intervention.
2.2. Were carers and people delivering the Y
interventions aware of participants' Surgeons and investigators were not blinded to the intervention over the entire
assigned intervention during the trial? study period.
2.3. If Y/PY/NI to 2.1 or 2.2: Were there PN
deviations from the intended intervention
that arose because of the trial context?
2.4 If Y/PY to 2.3: Were these deviations NA
likely to have affected the outcome?
2.5. If Y/PY/NI to 2.4: Were these NA
deviations from intended intervention
balanced between groups?
2.6 Was an appropriate analysis used to Intention-to-treat analysis with multiple imputation of missing data was Y
estimate the effect of assignment to prespecified and conducted.
intervention?
2.7 If N/PN/NI to 2.6: Was there potential NA
for a substantial impact (on the result) of
the failure to analyse participants in the
group to which they were randomized?
Risk-of-bias judgement Low
bias due to deviations from intended
interventions?
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Domain 2: Risk of bias due to deviations from the intended interventions ( effect of adhering to intervention )
2.1. Were participants aware of their Y / PY / PN / N / NI
assigned intervention during the trial?
2.2. Were carers and people delivering the Y / PY / PN / N / NI
interventions aware of participants'
2.3. [If applicable:] If Y/PY/NI to 2.1 or 2.2: NA / Y / PY / PN / N / NI
Were important non-protocol interventions
balanced across intervention groups?
2.4. [If applicable:] Were there failures in NA / Y / PY / PN / N / NI
implementing the intervention that could
have affected the outcome?
2.5. [If applicable:] Was there non- NA / Y / PY / PN / N / NI
adherence to the assigned intervention
regimen that could have affected
participants’ outcomes?
2.6. If N/PN/NI to 2.3, or Y/PY/NI to 2.4 or NA / Y / PY / PN / N / NI
2.5: Was an appropriate analysis used to
estimate the effect of adhering to the
intervention?
Risk-of-bias judgement Low / High / Some concerns
Optional: What is the predicted direction of NA / Favours experimental /

bias due to deviations from intended Favours comparator /
interventions? Towards null /Away from
null / Unpredictable
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Domain 3: Missing outcome data
3.1 Were data for this outcome available 67 out 79 for OPTILUME group and 41 out of 48 for the control group: 15% N
for all, or nearly all, participants patients in both groups were not evaluable=> missing data for them.
randomized?
3.2 If N/PN/NI to 3.1: Is there evidence that A sensitivity analysis was conducted with 5 different analyses (Observed, Worst PY
the result was not biased by missing Case Imputation, Late Cystoscopy as Observed, IPSS Responder Status at 6m, IPSS
outcome data? Responder Status at Last Visit) that were all in the same directionality as the
primary analysis.
3.3 If N/PN to 3.2: Could missingness in the NA
outcome depend on its true value?
3.4 If Y/PY/NI to 3.3: Is it likely that NA

missingness in the outcome depended on
its true value?

bias due to missing outcome data?
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Domain 4: Risk of bias in measurement of the outcome
4.1 Was the method of measuring the This outcome is measured by the ability to pass a 16Fr flexible cystoscope or 14Fr N
outcome inappropriate? rubber catheter through the treated area by the surgeon. It’s measured as
prespecified in the protocol.
4.2 Could measurement or ascertainment The same measurement method was probably used in both groups. PN
of the outcome have differed between
intervention groups?
4.3 If N/PN/NI to 4.1 and 4.2: Were Surgeons were unblinded to the treatment over the entire study period. Y
outcome assessors aware of the
intervention received by study
participants?
4.4 If Y/PY/NI to 4.3: Could assessment of One limitation of the study stated by the authors “surgeons were not blinded to PY
the outcome have been influenced by the type of treatment; this might bias their interpretation of cystoscopic findings
knowledge of intervention received? or the decision to proceed with repeat treatment.”
4.5 If Y/PY/NI to 4.4: Is it likely that PY
assessment of the outcome was influenced
by knowledge of intervention received?
Risk-of-bias judgement High risk
Optional: What is the predicted direction of Favours experimental

bias in measurement of the outcome?
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Domain 5: Risk of bias in selection of the reported result
5.1 Were the data that produced this result There are several revisions of the protocol and it’s not clear if the analysis plan PY
analysed in accordance with a pre-specified was finalised before the outcome data were unblinded for analysis.
analysis plan that was finalized before
unblinded outcome data were available for
analysis?
Is the numerical result being assessed likely
to have been selected, on the basis of the
results, from...
5.2. ... multiple eligible outcome There was only one defined outcome measurement for the “stricture free” N
measurements (e.g. scales, definitions, outcome.
time points) within the outcome
domain?
5.3 ... multiple eligible analyses of the There is only one way in which the outcome measurement can be analysed. N
data? Analysis reported in the CSR is consistent with what was planned in the protocol.

bias due to selection of the reported result?
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Overall risk of bias
Optional: What is the overall predicted Favours experimental

direction of bias for this outcome?
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Study details
Optilume® Drug-Coated Balloon for Anterior Urethral Strictures. J Urol. 2022 Apr;207(4):866-875. doi:
10.1097/JU.0000000000002346. Epub 2021 Dec 2. PMID: 34854748
Study design
Experimental: OPTILUME Comparator: Standard of care endoscopic
Specify which outcome is being assessed for risk of bias Freedom from repeat intervention rate (also referred to as Time to
treatment failure rate) at 12 months
Specify the numerical result being assessed. In case of multiple alternative 83.2% vs 21.7% (logrank test p<0.0001) from figure 3 in Elliott
analyses being presented, specify the numeric result (e.g. RR = 1.52 (95% CI publication
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must be checked):
x Trial protocol
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assigned intervention during the trial? stricture requiring intervention: 12/48 (25%) patients of the control group
2.2. Were carers and people delivering the crossed over. Y
assigned intervention during the trial? Surgeons and investigators were not blinded to the intervention over the entire
study period.
2.6 Was an appropriate analysis used to If a Kaplan-Meier curve is available as well as the p-value of a log rank test, no PY
estimate the effect of assignment to difference in medians (point estimate and confidence interval), nor a hazard ratio
intervention? (point estimate and confidence interval), are available, while they could have been
estimated.
interventions?
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intervention?

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3.1 Were data for this outcome available According to the Kaplan-Meier curve available in the publication, for most of the PY
for all, or nearly all, participants follow-up, there is a low rate of lost-to follow up in both groups. However,
randomized? between 340 and 360 days (the last 20 days of follow-up), more patients are
censored in the Optilume group than in the control group.
3.2 If N/PN/NI to 3.1: Is there evidence that NA
the result was not biased by missing
outcome data?


its true value?

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4.1 Was the method of measuring the The measurement of the “freedom from repeat intervention” outcome is detailed PN
outcome inappropriate? in the protocol for treatment failure as: “Any subjects who have a second dilation
procedure, pursue surgical intervention, or otherwise seek alternative treatment
for the target stricture after the index procedure are considered treatment failures
for the primary analysis. Subjects who cross-over to receive treatment with the
Optilume device will be considered a treatment failure for the primary therapy. At
the 6 months follow up, if a 16F flexible cystoscope or a 14F rubber catheter cannot
cross the treated stricture, the subject will be considered a treatment failure. This
6 month follow-up urethral lumen test will be analyzed as occurring at 180 days
for time-to-event analyses.” This outcome is assessed by the surgeon (clinically-
reported outcome).
However, it can be assumed that the measuring method of the treatment failure
was not changed for measuring this outcome at 12 months.
participants?
4.4 If Y/PY/NI to 4.3: Could assessment of One limitation of the study stated by the authors “surgeons were not blinded to PY
the outcome have been influenced by the type of treatment; this might bias their interpretation of cystoscopic findings
knowledge of intervention received? or the decision to proceed with repeat treatment.”
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5.1 Were the data that produced this result This analysis of this outcome was prespecified in the hierarchical testing procedure N
analysed in accordance with a pre-specified at 6 months but not at 12 months. However, group Kaplan-Meier estimates are
analysis plan that was finalized before only reported at 12 months in the publication.
unblinded outcome data were available for Additionally, there are several revisions of the protocol and it’s not clear if the
analysis? analysis plan was finalised before the outcome data were unblinded for analysis.
results, from...
5.2. ... multiple eligible outcome See above. PY
measurements (e.g. scales, definitions,
domain?
5.3 ... multiple eligible analyses of the Several analyses are reported in the CSR (2 for 6 months) and in the publication PY
data? (1 at 12 months).

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Study details
10.1097/JU.0000000000002346. Epub 2021 Dec 2. PMID: 34854748
Study design
Specify which outcome is being assessed for risk of bias Change in Qmax at 6 months + 4.78 ml/s 90% CI 1.94 to 7.61
Specify the numerical result being assessed. In case of multiple alternative Change in Qmax at 6 months = + 4.78 ml/s 90% CI 1.94 to 7.61 (from
analyses being presented, specify the numeric result (e.g. RR = 1.52 (95% CI the CSR)
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must be checked):
x Trial protocol
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study period.
2.6 Was an appropriate analysis used to Change in Qmax at 6 months was assessed as the secondary endpoint #2, Y
estimate the effect of assignment to according to a prespecified hierarchical testing procedure. It was analysed in an
intervention? ITT analysis with multiple imputation for missing data.
interventions?
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intervention?

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3.1 Were data for this outcome available 67 out of 79 for OPTILUME group and 44 out of 48 for the control group for Qmax N
for all, or nearly all, participants at 6 months => missing data for 15% patients in OPTILUME group and 8% in control
randomized? group
3.2 If N/PN/NI to 3.1: Is there evidence that No sensitivity analysis was conducted for this outcome. N
outcome data?
3.3 If N/PN to 3.2: Could missingness in the This outcome is a Performance outcome (PerfO) and patients could be unblinded Y
outcome depend on its true value? before 6 months if they experienced recurrence symptoms and were unblinded
after 6 months. Therefore the missingness of this outcome data may depend on
its true value.
its true value?
Optional: What is the predicted direction of Unpredictable

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4.1 Was the method of measuring the This outcome is a performance outcome (clinician-reported outcome which PN
outcome inappropriate? requires active patient involvement to complete a standardised task) used in
routine care for assessing urological symptoms. However, the measurement tool
for this outcome is not detailed in the study.
participants?
4.4 If Y/PY/NI to 4.3: Could assessment of Even though the measurement tool for this outcome is not detailed in the study, PN
the outcome have been influenced by it can be assumed that, like in most routine care situations, uroflowmetry is
knowledge of intervention received? carried out in a fully automatic way without any need for medical staff to read
out the results.

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5.1 Were the data that produced this result There are several revisions of the protocol and it’s not clear if the analysis plan PY
analysed in accordance with a pre-specified was finalised before the outcome data were unblinded for analysis.
analysis?
results, from...
5.2. ... multiple eligible outcome Change in Qmax was defined for this outcome measurement in the protocol. PN
domain?
5.3 ... multiple eligible analyses of the There is only one way in which this outcome measurement can be analysed. N
data? Analysis reported in the CSR is consistent with what was planned in the protocol.

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97
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98
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Study details
10.1097/JU.0000000000002346. Epub 2021 Dec 2. PMID: 34854748
Study design
Specify which outcome is being assessed for risk of bias Qmax at 30 days, 3 months, 6 months and 12 months
Specify the numerical result being assessed. In case of multiple alternative Table 3 in Elliott at al.
analyses being presented, specify the numeric result (e.g. RR = 1.52 (95% CI Results at 30 days, 3 months, 6 months and 12 months
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must be checked):
x Trial protocol
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assigned intervention during the trial? stricture requiring intervention: 12/48 (25%) patients of the control group crossed
2.2. Were carers and people delivering the over. Y
study period.
2.6 Was an appropriate analysis used to The results for this outcome are only descriptive. N
estimate the effect of assignment to There is no clear explanation for the handling of missing data (it was only stated in
intervention? the CSR that failure carried forward analysis was performed).
2.7 If N/PN/NI to 2.6: Was there potential PY
interventions?
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intervention?

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3.1 Were data for this outcome available 67 out of 79 for OPTILUME group and 44 out of 48 for the control group for Qmax N
for all, or nearly all, participants at 6 months => missing data for 15% patients in OPTILUME group and 8% in control
randomized? group
3.2 If N/PN/NI to 3.1: Is there evidence that Only descriptive results provided for this outcome. N
outcome data?
3.3 If N/PN to 3.2: Could missingness in the There is no explanation for the missing data. Y
This outcome is a Performance outcome (PerfO) and patients could be unblinded
before 6 months if they experienced recurrence symptoms and were unblinded
3.4 If Y/PY/NI to 3.3: Is it likely that after 6 months. Therefore, the missingness of this outcome data may depend on PY
missingness in the outcome depended on its true value.
its true value?

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4.1 Was the method of measuring the This outcome is a performance outcome (clinician-reported outcome which PN
outcome inappropriate? requires active patient involvement to complete a standardised task) used in
routine care for assessing urological symptoms. However, the measurement tool
for this outcome is not detailed in the study.
participants?
4.4 If Y/PY/NI to 4.3: Could assessment of Even though the measurement tool for this outcome is not detailed in the study, PN
the outcome have been influenced by it can be assumed that, like in most routine care situations, uroflowmetry is
knowledge of intervention received? carried out in a fully automatic way without any need for medical staff to read
out the results.

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5.1 Were the data that produced this result The analysis of this outcome was not prespecified in the protocol, only change in N
analysed in accordance with a pre-specified Qmax was prespecified.
analysis?
results, from...
5.2. ... multiple eligible outcome See above. PN
domain?
5.3 ... multiple eligible analyses of the Change from baseline in Qmax was prespecified at 12, 24, 36, 48 and 60 months Y
data? as an ancillary endpoint, however not reported in the CSR nor in the publication,
only average Qmax over time was reported. Therefore, it could have been
selected from other eligible outcome measurements.

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Study details
10.1097/JU.0000000000002346. Epub 2021 Dec 2. PMID: 34854748
Study design
Specify which outcome is being assessed for risk of bias PVR at 30 days, 3 months, 6 months and 12 months
Specify the numerical result being assessed. In case of multiple alternative Table 3 in Elliott at al.
analyses being presented, specify the numeric result (e.g. RR = 1.52 (95% CI Results at 30 days, 3 months, 6 months and 12 months
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must be checked):
x Trial protocol
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study period.
2.6 Was an appropriate analysis used to The results for this outcome are only descriptive. N
estimate the effect of assignment to There is no clear explanation for the handling of missing data (it was only stated in
intervention? the CSR that failure carried forward analysis was performed).
interventions?
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intervention?

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3.1 Were data for this outcome available 67 out of 79 for OPTILUME group and 44 out of 48 for the control group for PVR N
for all, or nearly all, participants urine at 6 months => missing data for 15% patients in OPTILUME group and 8% in
randomized? control group
3.2 If N/PN/NI to 3.1: Is there evidence that Only descriptive results provided for this outcome. N
outcome data?
3.3 If N/PN to 3.2: Could missingness in the There is no explanation for the missing data. Y

its true value?

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4.1 Was the method of measuring the The method for measuring PVR urine is not detailed in the CSR. Therefore, it PN
outcome inappropriate? might have differed between centres in the study. There is no information on the
type of healthcare professional who measured this outcome.
4.2 Could measurement or ascertainment NI
4.3 If N/PN/NI to 4.1 and 4.2: Were Surgeons and investigators were not blinded to the intervention over the entire PY
outcome assessors aware of the study period.
participants?
4.4 If Y/PY/NI to 4.3: Could assessment of There is no information on the methods used to assess PVR urine. The ultrasound Y
the outcome have been influenced by method could imply some subjectivity from the assessor.
knowledge of intervention received?
4.5 If Y/PY/NI to 4.4: Is it likely that PN
Risk-of-bias judgement Some concerns

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5.1 Were the data that produced this result This outcome was not prespecified in the protocol. N
analysed in accordance with a pre-specified
analysis?
results, from...
5.2. ... multiple eligible outcome This outcome was not prespecified in the protocol. However, it was reported in Y
measurements (e.g. scales, definitions, the CSR and in the publication. Therefore, it could have been selected from other
time points) within the outcome eligible outcome measurements.
domain?
5.3 ... multiple eligible analyses of the This outcome was not prespecified in the protocol. However, it was reported in Y
data? the CSR and in the publication. Therefore, it could have been selected from other
eligible analyses.

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Study details
10.1097/JU.0000000000002346. Epub 2021 Dec 2. PMID: 34854748.
Study design
Specify which outcome is being assessed for risk of bias Patients reported outcomes at 30 days, 3 months and 6 months*:
- International Prostatic Symptom Score (IPSS)
- IPSS - QoL
- International Index of Erectile Function (IIEF)
- Periprocedural pain
*Patients were blinded to the treatment until 6 months. After this 6
months timepoint we assume that the risk of bias of these outcomes
will be higher.
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Specify the numerical result being assessed. In case of multiple alternative Table 3
analyses being presented, specify the numeric result (e.g. RR = 1.52 (95% CI Results at 30 days, 3 months and 6 months

If the aim is to assess the effect of adhering to intervention, select the deviations from intended intervention that should be addressed (at least one must be
checked):
x Trial protocol
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Risk of bias assessment



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study period.
2.6 Was an appropriate analysis used to Unclear how the analyses were conducted: ITT, per protocol, or other analysis? N
estimate the effect of assignment to There is no clear explanation for the handling of missing data, which vary along
intervention? time and are not the same for IPSS than for IIEF (slightly less patients at each
timepoint). It was only stated in the CSR that failure carried forward analysis was
performed for the IPSS outcomes.
interventions?
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Domain 2: Risk of bias due to deviations from the intended interventions ( effect of adhering to intervention)
intervention?

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3.1 Were data for this outcome available 71 out of 79 for OPTILUME group and 43 out of 48 for the control group for IPSS N
for all, or nearly all, participants and IPSS-QoL at 6 months => missing data for 10% patients in both groups
randomized?
68 out of 79 for OPTILUME group and 30 out of 48 for the control group for IIEF
at 6 months => missing data for 14% patients in OPTILUME group and for 38%
patients in the control group
3.2 If N/PN/NI to 3.1: Is there evidence that No sensitivity analysis was carried out for these outcomes. N
outcome data?
3.3 If N/PN to 3.2: Could missingness in the These outcomes are PROMS and patients could be unblinded before 6 months if Y
outcome depend on its true value? they experienced recurrence symptoms and were unblinded after 6 months.
Therefore the missingness of these outcome data may depend on its true value.
3.4 If Y/PY/NI to 3.3: Is it likely that Y
its true value?

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4.1 Was the method of measuring the These outcomes are PROMs measured with structured self-administered PN
outcome inappropriate? questionnaires used in routine care for assessing urological symptoms (IPSS, IIEF)
and for assessing pain (VAS).
4.2 Could measurement or ascertainment The same measurement methods were probably used in both groups. PN
4.3 If N/PN/NI to 4.1 and 4.2: Were Some participants (12/48, 25%) from the control group were unblinded before 6 Y
outcome assessors aware of the months if they experienced recurrent stricture requiring intervention.
participants?
4.4 If Y/PY/NI to 4.3: Could assessment of Even if patients were blinded to the intervention until 6 months, some patients Y
the outcome have been influenced by were unblinded in case of medical necessity (stricture recurrence).
knowledge of intervention received?
by knowledge of intervention received? The answer to 4.5 is “probably yes”, because it can be assumed that the patients
from control group who crossed over are likely to have been influenced by the
knowledge of their treatment assignment when answering these questionnaires.

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5.1 Were the data that produced this result IPSS: is stated as an additionnal outcome to the primary efficacy and safety N
analysed in accordance with a pre-specified endpoints in the publication, but it was not mentioned as such in the protocol
analysis plan that was finalized before where only “percent responder at 6 months (IPSS)” was indicated as the 3rd
unblinded outcome data were available for secondary endpoint but also as one the ancillary endpoints, at 12, 24, 36, 48 and
analysis? 60 months. The analyses at 30 days, 3 months and 6 months are not mentioned in
the protocol.
IPSS-QoL: is stated as an additionnal outcome to the primary efficacy and safety

endpoints in the publication, but it was not mentioned in the protocol where only
“QoL” was indicated as one the ancillary endpoints
IIEF is mentioned as an additionnal outcome to the primary efficacy and safety

endpoints in the publication, but it was not planned in the protocol
results, from...
5.2. ... multiple eligible outcome See above. PY
domain?
5.3 ... multiple eligible analyses of the NI
data?

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Study details
10.1097/JU.0000000000002346. Epub 2021 Dec 2. PMID: 34854748.
Study design
Specify which outcome is being assessed for risk of bias Primary safety end point: freedom from a composite of serious
device- or procedure related events including urethral fistula,
unresolved de novo stress urinary incontinence or urethral rupture
through 3 months.
Specify the numerical result being assessed. In case of multiple alternative No subject experienced a primary safety end point event through 3
analyses being presented, specify the numeric result (e.g. RR = 1.52 (95% CI months (from the Elliott et al. publication).
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0.83 to 2.77) and/or a reference (e.g. to a table, figure or paragraph) that Table: Primary Safety Endpoint – Freedom from Composite
uniquely defines the result being assessed. Serious Complications (from the CSR)
Endpoint Control Arm Optilume Arm

Serious device / procedure related
complications at 3 months post- 0/48 (0%) 0/79 (0%)
treatment
Formation of Fistula 0/48 (0%) 0/79 (0%)
Unresolved De Novo Stress
0/48 (0%) 0/79 (0%)
Urinary Incontinence
Urethra Rupture or Burst 0/48 (0%) 0/79 (0%)

 to assess the effect of assignment to intervention (the ‘intention-to-treat’ effect)
x to assess the effect of adhering to intervention (the ‘per-protocol’ effect)
must be checked):
x non-adherence to their assigned intervention by trial participants
x Trial protocol
 Non-commercial trial registry record (e.g. ClinicalTrials.gov record)
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assigned intervention during the trial? stricture requiring intervention.
2.2. Were carers and people delivering the Y
Surgeons and investigators were not blinded to the intervention over the entire
study period.
2.3. [If applicable:] If Y/PY/NI to 2.1 or 2.2: NA
2.4. [If applicable:] Were there failures in NA
2.5. [If applicable:] Was there non- We consider crossovers as non-adherences. PY
2.6. If N/PN/NI to 2.3, or Y/PY/NI to 2.4 or NI
intervention?

interventions?
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3.1 Were data for this outcome available For this outcome, the protocol states “Unless there is evidence of occurrence of a PY
for all, or nearly all, participants primary safety endpoint, subjects with missing data for the primary safety
randomized? endpoint are presumed to not have experienced a primary safety endpoint.”
Therefore, we cannot be sure that this outcome is available for all, or nearly all,
participants.
3.2 If N/PN/NI to 3.1: Is there evidence that NA
outcome data?


its true value?

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4.1 Was the method of measuring the NI
outcome inappropriate?
4.2 Could measurement or ascertainment NI

4.3 If N/PN/NI to 4.1 and 4.2: Were Surgeons and investigators were not blinded to the intervention over the entire Y
outcome assessors aware of the study period.
participants?
4.4 If Y/PY/NI to 4.3: Could assessment of Surgeons were not blinded to the type of treatment; this might have biased their PY
the outcome have been influenced by assessment of the clinical status of the patient regarding formation of urethral
knowledge of intervention received? fistula, unresolved de novo stress urinary incontinence or urethral rupture through
3 months after intervention (the 3 components of this composite safety outcome).
4.5 If Y/PY/NI to 4.4: Is it likely that NI

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5.1 Were the data that produced this result The protocol planned a descriptive analysis of this primary safety outcome. PY
analysed in accordance with a pre-specified
analysis?
results, from...
5.2. ... multiple eligible outcome PN
domain?
5.3 ... multiple eligible analyses of the PN
data?

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Optional: What is the overall predicted Unpredictable

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Appendix E Partial use of GRADE

Table 34: Uncertainties of the evidence categorised according to the partial use of GRADE
Factors that may affect certainty of evidence Number of patients Effect estimate
Outcome Design
Dilation or p-valuea
Risk of bias Indirectness Inconsistency Imprecision Other Optilume DCB
DVIU
Risk difference
Optilume
Stricture-free Indirectness vs dilation or DVIU:
No issues are
rate at 6 1 RCT High b,c,d,e issues are 1 study None 79 48 44.4%, 95% CI 27.6
flagged. to 61.1
months flagged f
p-value: <0.0001*, #,$

Freedom from
repeat Indirectness Imprecision
intervention 1 RCT High b,e,g issues are 1 study issues are None 79 48 p-value: <0.0001
rate at 12 flagged f flagged h
months
Mean difference
Optilume vs dilation
Change in Indirectness or DVIU:+ 4.78 ml/s
No issues are
Qmax at 6 1 RCT High b,c,i,j,k issues are 1 study None 79 48 90% CI 1.94 to 7.61
flagged.
months (ml/s) flagged f
p-value: 0.0031*, #,$
Qmax at 30
Indirectness Imprecision
days, 3 months,
1 RCT High b,i,k,l issues are 1 study issues are None 79 48 NA
6 months and
flagged f flagged m
12 months
PVR at 30
days, 3 months,
1 RCT High b,i,k,l,n issues are 1 study issues are None 79 48 NA
6 months and
flagged f flagged m
12 months
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16 June 2023
IPSS at 30 Indirectness Imprecision
days, 3 months 1 RCT High b,j,l,o,q issues are 1 study issues are None 79 48 NA
and 6 months flagged f flagged m
IPSS-QoL at
30 days, 3
1 RCT High b,j,l,o,q issues are 1 study issues are None 79 48 NA
months and 6
flagged f flagged m
months
IIEF (overall
satisfaction) at Indirectness Imprecision
30 days, 3 1 RCT High b,j,l,p,q issues are 1 study issues are None 79 48 NA
months and 6 flagged f flagged m
months
Periprocedural
pain at 30 days, None
1 RCT High b,j,l,q issues are 1 study issues are 79 48 NA
3 months and 6
flagged f flagged m
months
Freedom from
a composite of
serious device-
or procedure
related events
including:
- urethral
fistula, Indirectness Imprecision
- unresolved de 1 RCT High b,e issues are 1 study issues are None 79 48 NA
novo stress flagged f flagged m
urinary
incontinence
or
- urethral
rupture
through 3
months
1 RCT, 2 Indirectness Imprecision
All-cause
single-arm NA issues are NA s issues are None NA NA NA
mortality
studies flagged f,r flagged m
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1 RCT, 2 Indirectness Imprecision
Other adverse
single-arm NA issues are NA s issues are None NA NA NA
events
studies flagged f,r,t flagged m
a: Use of an * indicates statistical significance versus a pre-specified alpha level, use of a # indicates a pre-specified analysis according to the SAP (for individual studies)
or evidence synthesis protocol, use of a $ indicates control for multiplicity.
b: According to the protocol, randomisation was planned in a 2:1 allocation of treatment vs control, stratified by investigational centre and by prior radiation treatment
and number of prior dilation treatments using randomly permuted blocks. There is no specific information on the concealment of the allocation sequence. Some
participants were unblinded before 6 months if they experienced recurrent stricture requiring intervention: 12/48 (25%) patie nts of the control group crossed over.
Surgeons and investigators were not blinded to the intervention over the entire study period.
c: Intention-to-treat analysis with multiple imputation of missing data was pre-specified and conducted.
d: 12 patients in the Optilume group and 7 patients in the control group (15% in each group) with missing data for this outcome. Sensitivity analysis was conducted with
5 different analyses that were all in the same directionality as the primary analysis.
e: As the surgeons and investigators were not blinded to the intervention over the entire study period, it might have biased their interpretation of findings or the decision
to proceed with repeat treatment. Therefore, the assessment of this clinically reported outcome may have been subject to meas urement bias.
f: The RCT was conducted in North America, not in Europe. Optilume treatment encompassed a pre-dilation, which is not standard according to the IFU, it was done in
the study only and it might have influenced the results. Optilume is proposed for second-line treatment after stricture recurrence, but the majority of patients included in
ROBUST III had more than 3 endoscopic treatments before having Optilume. The comparator in the study was standard of care endoscopic management as determined
by the treating physician. It included different procedures (rigid rod dilation, DVIU, balloon dilation or a combination) which was a mix of PICO 1 and PICO 2
comparators (urethrotomy and dilation respectively). Additionally, there is no internationally agreed on single outcome mea sure, which defines stricture recurrence.
g: According to the Kaplan-Meier curve, for most of the follow-up, there is a low rate of loss -to-follow-up in both groups. However, during the last 20 days of follow-
up, more patients were censored in the Optilume group than in the control group. The analysis of this outcome was prespecified in the protocol for 6 months but the 12-
month results are reported only (several analyses are reported in the CSR and in the publication).
h: Nominal p-value is reported. While a Kaplan-Meier curve is available, as well as a p-value of a log rank test, no difference in medians (point estimate and confidence
intervals), nor a hazard ratio (point estimate and confidence interval), are provided.
i: Missing data for 12/79 (15%) patients in intervention group and 4/48 (8%) in control group. No clear explanation for the handling of missing data for Qmax and PVR
(it was stated only that a “failure carried forward” analysis was conducted).
j: No sensitivity analysis was conducted for this outcome.
k: Even though the measurement tool for this performance outcome is not detailed in the study, it can be assumed that, like in most routine care situations, uroflowmetry
is carried out in a fully automatic way without any need for medical staff to read out the results.
l: The analysis of the outcome was not pre-specified in the protocol.
m: Only descriptive statistics used to report the outcome. No confidence interval was provided.
n: There is no information on the methods used to assess PVR urine which is a clinically reported outcome. The ultrasound method could imply some subjectivity from
the assessor.
o: Missing data for 8/79 patients in intervention group and 5/48 in control group: 10% in both groups for IPSS and IPSS-QoL at 6 months. No clear explanation provided
for the handling of missing data.
p: Missing data for 11/79 (14%) patients in intervention group and 18/48 (38%) in control group for IIEF at 6 months. No explanation provided for the handling of
missing data.
q: Patients from control group who crossed over (25%) are likely to have been influenced by the knowledge of their treatment assignment when a nswering these self-
administered questionnaires.
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r: The single-arm prospective, interventional studies included for safety outcomes only were conducted in Latin American and North America, not in Europe. Inclusion
criteria in these two studies are narrower than in the RCT, possibly resulting in more severe patients.
s: Variation in treatment effects between studies was not assessed, as only descriptive statistics were used to assess the outcome.
t: There was no data reported for the drug-related adverse events which were requested in the PICO question.
Abbreviations: CI=confidence interval; CSR=clinical study report; DVIU=direct vision internal urethrotomy; IFU=instructions for use; IIEF=International Index of Erectile Function; IPSS=International Prostate
Symptom Score; NA=not applicable; PICO=Population, Intervention, Comparator, Outcome; PVR=postvoid residual volume; Qmax=maximum flow rate; QoL=quality of life; RCT=randomised controlled trial;
SAP: statistical analysis plan; VAS=Visual Analogue Scale.
140

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JCAMD001 Assessment Report –

OPTILUME ® URETHRAL DRUG-COATED BALLOON

Version 1.1, 16/06/2023

Document history and contributors

Version Date Description

How to cite this assessment?

EUnetHTA 21 JCAMD001. Authoring Team. Optilume urethral drug-coated balloon. Joint

Document history and contributors .................................................................................. 2

Figure 1. The Optilume urethral drug-coated balloon. ........................................................................................ 15

1.1 Assessment team

1.2 Overview of procedural steps

1.3 Stakeholder and external expert involvement

Table 2. Contributors to the joint clinical assessment

2.1 Overview of the health condition

2.1.1 Epidemiology of the health condition

2.1.2 Characterisation of the health condition

The anterior urethra is made up of three segments (from proximal to distal):

 The bulbar urethra (segment fixed to the pelvic floor);

These different segments may be involved in strictures at varying frequency, as mentioned

2.1.3 Management of the health condition

Table 4. European Association of Urology guidelines on management of anterior urethral strictures in

As “repetitive dilatations/DVIU have no long-term freedom of recurrence and increase stricture

2.2 Characterisation of the health technology

2.2.1 Characteristics of the health technology

Table 5. Characteristics of the health technology under assessment

Figure 1. The Optilume urethral drug-coated balloon.

2.2.2 Requirements/instructions for use

Table 6. Characteristics of the use of the Optilume urethral drug-coated balloon

2.2.3 Regulatory status of the technology

Table 7. Regulatory information on the health technology under assessment

Further regulatory information is included in the submission dossier.5

3 RESEARCH QUESTION AND SCOPE

Table 8: Assessment scope including the consolidated PICO questions

4.1 Information retrieval

Sources provided by the HTD in the dossier were as follows:

 List of HTD-sponsored studies on the Optilume DCB (as of 1 March 2023).

4.1.1 Resulting list of studies included, overall and by PICO question

4.2 Characteristics of the studies included

4.3 Study results on relative effectiveness and relative safety

4.3.1.2 Outcomes for PICO 2

4.3.1.3 Outcomes for PICO 3

Study design and study populations

Table 16. Baseline patient characteristics in the ROBUST III study

Number of previous endoscopic treatments, mean ± SD ND 4.1 ± 4.9

The outcomes reported are presented in brief in Table 19.

Table 19. Outcomes reported and their measurement instruments

Outcome Outcome Outcome measurement instrument definition/ Interpretation

4.4.1.2 Risk of bias

Bias due to Bias due Bias in

4.4.1.3 Health outcome results

Table 22. Sensitivity analysis for the stricture-free rate

Reading the “Hypothesis testing” columns:

Only descriptive statistics were used to report these outcome data.

Details for all adverse events are provided in Appendix C.

4.4.2 Safety results from noncomparative studies

events including but not limited to: perioperative

4.4.2.2 Risk of bias

4.4.2.3 Health outcome results

4.4.3 Summary table including the uncertainty of evidence