Supplementary Appendix

Supplement to: Smolen JS, Feist E, Fatenejad S, et al. Olokizumab versus placebo or adalimumab in rheumatoid
arthritis. N Engl J Med 2022;387:715-26. DOI: 10.1056/NEJMoa2201302

This appendix has been provided by the authors to give readers additional information about the work.
 TABLE OF CONTENTS

TABLE OF CONTENTS ........................................................................................................................................ 1

STUDY INVESTIGATORS .................................................................................................................................... 2
METHODS ....................................................................................................................................................... 10
Randomization and blinding........................................................................................................................... 10
Criteria for evaluation, determination of sample size and selection of non-inferiority margin .................... 11
Missing data ................................................................................................................................................... 14
Patient inclusion criteria ................................................................................................................................ 14
Patient exclusion criteria ................................................................................................................................ 15
Premature subject study withdrawal ............................................................................................................. 20
Premature subject treatment withdrawal ..................................................................................................... 20
Prior and concomitant treatments ................................................................................................................. 21
Sensitivity analyses ......................................................................................................................................... 25
Efficacy assessments ...................................................................................................................................... 26
FIGURES AND TABLES ..................................................................................................................................... 28
Figure S1. Gate-keeping strategy ................................................................................................................... 28
Figure S2. Non-inferiority testing details ....................................................................................................... 29
Figure S3. Core components of ACR response criteria (ITT population) ........................................................ 30
Figure S4. CDAI low disease activity and DAS28-CRP remission (ITT population) ......................................... 31
Figure S5. Mean changes in laboratory values (safety population) ............................................................... 32
Table S1. The numbers of randomized patients from each country (ITT population) ................................... 33
Table S2. Reasons for discontinuation at Week 12 (ITT population) ............................................................. 34
Table S3. Representativeness of study participants ...................................................................................... 35
Table S4. Rheumatoid arthritis reference values of disease activity scores as per disease severity ............. 35
Table S5. Status at Week 12 for ACR20 (ITT population) ............................................................................... 36
Table S6. ACR20 response rates by visit and treatment (ITT population)...................................................... 37
Table S7. ACR20 response rate at Week 12 by visit, treatment and region (ITT population)........................ 38
Table S8. ACR20 response rate at Week 12 by anti-CCP and RF status (ITT population) .............................. 39
Table S9. ACR20 response rate at Week 12 by time since diagnosis (ITT population) .................................. 41
Table S10. Main efficacy results for other endpoints (ITT population).......................................................... 42
Table S11. Treatment-emergent adverse events (safety population) ........................................................... 43
Table S12. Key serious treatment-emergent adverse events (safety population)......................................... 45
Table S13. Selected hematology assessments outside of the normal ranges (safety population) ................ 47
Table S14. Selected chemistry assessments outside of the normal ranges (safety population) ................... 49
Contributorship .............................................................................................................................................. 51
REFERENCES: .................................................................................................................................................. 51

1
 STUDY INVESTIGATORS

Principal Investigator Institution Location

HRF Hamburger Rheuma
Dr Andrea Everding Hamburg; Germany
Forschungszentrum
Klinische Forschung Berlin-Mitte
Dr Andrei Khariouzov Berlin; Germany
GmbH
Dr Ramona Koenig Kerckhoff-Klinik GmbH Bad Nauheim; Hessen; Germany
Magdeburg; Sachsen Anhalt;
Dr Cornelia Kuehne SMO.MD GmbH
Germany
Ratingen; Nordrhein Westfalen;
Dr Siegfried Wassenberg Studienambulanz Dr. Wassenberg
Germany
Rheumapraxis Dr. med. Reiner Aachen; Nordrhein Westfalen;
Dr Reiner Kurthen
Kurthen Germany
Ostrava – Trebovice; Czech
Dr Ladislav Bortlik ARTROSCAN s.r.o.
Republic
Dr Eva Dokoupilova Medical Plus s.r.o. Uherske Hradiste; Czech Republic

Dr Rudolf Horvath Fakultni nemocnice v Motole Praha; Czech Republic

Dr Angelika Lapcikova iMedica s.r.o. Brno; Czech Republic

Dr Leona Prochazkova Revmatologie s.r.o. Brno; Czech Republic

MUDR. Gabriela Simkova ordinace
Dr Gabriela Simkova lekare specialisty interna Kladno; Czech Republic
revmatologie
MUDR. Zuzana URBANOVA
Dr Zuzana Urbanova Praha; Czech Republic
Revmatologie
Dr Petr Vitek PV Medical Services s.r.o. Zlin; Czech Republic

Dr Marcela Svobodova CCR Czech, a.s. Pardubice; Czech Republic

Dr Michaela Blahova CCR Brno, s.r.o. Brno; Czech Republic

Dr Alena Petrikova CTCenter MaVe s.r.o. Olomouc; Czech Republic

Dr Olga Sleglova Revmatologicky Ustav Praha; Czech Republic

Dr Martina Machkova CCR Prague s.r.o. Praha; Czech Republic

Affidea Praha s.r.o.
Dr Jan Rosa Praha; Czech Republic
Sustova
Dr Libor Novosad Vesalion s.r.o. Ostrava; Czech Republic

Dr Andrea Houzarova Nemocnice Jihlava p.o. Jihlava; Czech Republic

MUDR. Zuzana Urbanova
Dr Zuzana Stejfova Praha; Czech Republic
Revmatologie
Dr Vlasta Gollerova CLINTRIAL s.r.o. Praha; Czech Republic

Dr Zdenek Dvorak ARTHROHELP s.r.o. Pardubice; Czech Republic

2
Dr Edit Drescher Vital-Medicina Kft. Veszprem; Hungary

Dr Magdolna Nagy Obudai Egeszsegugyi Centrum Kft. Budapest; Hungary

Dr Eszter Simoncsics Clinexpert Kft. Budapest; Hungary

DRC Gyogyszervizsgalo Kozpont
Dr Gabriella Sulyok Balatonfured; Hungary
Kft.
Dr Eva Somos Principal SMO Kft. Baja; Hungary

Dr Katalin Takacs Kiskunhalasi Semmelweis Korhaz Kiskunhalas; Hungary

Dr Attila Kovacs MAV Korhaz es Rendelointezet Szolnok; Hungary

Dr Ildiko Rapolthy DRC Szekesfehervar Szekesfehervar; Hungary

Associação de Assistência à
Dr Morton Aaron Scheinberg São Paulo; Brazil
Criança Deficiente – AACD
CCBR Brasil Centro de Pesquisas e
Dr Ana Claudia Cauceglia Melazzi Rio de Janeiro; Brazil
Análises Clínicas Ltda
Dr Flora Maria D'Andrea CPCLIN - Centro de Pesquisas
São Paulo; Brazil
Marcolino Clínicas Ltda
Centro Multidisciplinar de Estudos Sao Bernardo Do Campo (Sao
Dr Anna Maura Ferreira Fernandes
Clínicos – CEMEC Paulo); Brazil
Lajeado (Rio Grande do Sul);
Dr Jussara Marilu Bohn Hospital Bruno Born
Brazil
CETI - Centro de Estudos em
Dr Sebastiao Cezar Radominski Curitiba (Paraná); Brazil
Terapias Inovadoras Ltda
Juiz de For a (Minas Gerais);
Dr Antonio Scafuto Scotton CMiP - Centro Mineiro de Pesquisa
Brazil
Dr Mauro LMK Serviços Médicos S/S Ltda Porto Alegre (Rio Grande do Sul);
Waldemar Keiserman Avenida Carlos Gomes Brazil
CIP – Centro Internacional de
Dr Antonio Carlos Ximenes Goiânia (Goiás); Brazil
Pesquisa
Clinilive - Clínica do Idoso e
Dr Antônio Carlos da Silva Maringá (Paraná); Brazil
Pesquisa Clínica
Dr Celso Ricardo Emerich de CEDOES - Diagnóstico e Pesquisa
Vitória (Espírito Santo); Brazil
Abreu João da Silva
HUWC - UFC - Hospital
Dr Vanessa de Vasconcelos Universitário Walter Cantídio - Fortaleza (Ceará); Brazil
Universidade Federal do Ceará
Dr Sonia Maria Lima Faculdade de Medicina do ABC Santo André (Sao Paulo); Brazil

Dr Filipe Martins de Mello Clínica de Neoplasias Litoral Ltda Santa Catarina; Brazil
Spitalul Clinic Judetean de Urgenta
Dr Ana Maria Mihaela Ramazan Constanta; Romania
"Sf Apostol Andrei" Constanta
Ciudad Autonoma Buenos Aires;
Dr Cecilia Asnal Instituto Centenario
Argentina
Dr Gisela Constanza Subils Instituto Medico DAMIC Cordoba; Argentina
Instituto de Investigaciones Mar del Plata; Buenos Aires;
Dr Juan Pablo Gulin
Clinicas Argentina
Dr Eleonora del Valle Centro de Investigaciones San Miguel de Tucumán; Tucuman;
Lucero Reumatológicas Argentina
3
Dr Pablo Alejandro Mannucci APRILLUS Asistencia e Ciudad Autonoma Buenos Aires;
Walter Investigacion Argentina
CER San Juan Centro Polivalente
Dr Jose Luis Cristian Moreno Este; San Juan; Argentina
de Asistencia e Inv. Clinica
Centro Medico Privado de San Miguel de Tucuman; Tucuman;
Dr Alberto Jorge Spindler
Reumatologia Argentina
Centro de Investigaciones Medicas Mar del Plata; Buenos Aires;
Dr Gladys Alicia Testa
Mar del Plata Argentina
Atencion Integral en Reumatologia Ciudad Autonoma Buenos Aires;
Dr Horacio Oscar Venarotti
(AIR) Argentina
Dr Benito Jorge Velasco Zamora Instituto Medico CER Quilmes; Buenos Aires; Argentina
Hospital General de Agudos Dr. J. Ciudad Autonoma Buenos Aires;
Dr Eduardo Kerzberg
M. Ramos Mejia Argentina
Organizacion Medica de Ciudad Autonoma Buenos Aires;
Dr Patricio Tate
Investigacion (OMI) Argentina
Instituto de Investigaciones
Dr Jose Luis Velasco Zamora Quilmes; Buenos Aires; Argentina
Clinicas Quilmes
Venado Tuerto; Santa Fe;
Dr Rosana Gallo Sanatorio San Martin
Argentina
Clinica de Higado y Aparato
Dr Judith Carrio Rosario Santa Fe; Argentina
Digestivo
Hospital Privado Centro Medico de
Dr Alejandro Jose Alvarellos Cordoba; Argentina
Cordoba S.A
Siauliai Republican Hospital,
Dr Vida Basijokiene Siauliai; Lithuania
Public Institution
Klaipeda University Hospital,
Dr Loreta Bukauskiene Klaipeda; Lithuania
Public Institution
Center Outpatient Clinic, Public
Dr Ruta Lauciuviene Vilnius; Lithuania
Institution
Alytus Regional S. Kudirkos
Dr Rita Kvedaraviciene Alytus, Lithuania
Hospital
Republican Kaunas Hospital,
Dr Joana Dambrauskiene Kaunas; Lithuania
Public Institution
Vilnius University Hospital
Dr Jelena Ranceva Santariskiu Clinics, Public Vilnius; Lithuania
Institution
Dr Hung-An Chen Chi Mei Medical Center Tainan; Taiwan, Republic of China
Chang Gung Memorial Hospital, Guishan District; Taoyuan; Taiwan,
Dr Lieh-Bang Liou
Linkou Republic of China
Fundacion Instituto de
Dr Monique Rose Chalem Choueka Bogota; Colombia
Reumatologia Fernando Chalem
Dr Alvaro Arbelaez Cortes Clinica de Artritis Temprana S.A.S Cali; Colombia
Centro de Investigacion en
Dr Patricia Julieta Velez Sanchez Reumatologia y Especialidades Bogotá; Colombia
Medicas SAS. CIREEM
Centro de Investigacion Medico
Dr Juan Jose Jaller Raad Barranquilla; Colombia
Asistencial S.A.S
Dr Diego Luis Saaibi Solano Medicity S.A.S Bucaramanga; Colombia

Dr Voon Ong Royal Free Hospital London; UK

Dr Angela Pakozdi Whipps Cross University Hospital London; UK

4
 Basingstoke and North Hampshire
Dr Emma Williams Basingstoke; Hampshire; UK
Hospital
Dr Emmanuel George Arrowe Park Hospital Wirral; Merseyside; UK

Dr Catherine Gwynne Torbay Hospital Torquay; Devon; UK

Dr Michael Batley Maidstone Hospital Maidstone; Kent; UK

Dr Triin Savi East Tallinn Central Hospital Tallinn; Estonia

Dr Raili Müller Meditrials OU Tartu; Estonia

The Catholic University of Korea,
Dr Ji Hyeon Ju Gyeonggi-do; Korea, Republic of
Seoul St. Mary’s Hospital
Chonnam National University
Dr Shin-Seok Lee Gwangju; Korea, Republic of
Hospital
Severance Hospital, Yonsei
Dr Yong-Beom Park Seoul; Korea, Republic of
University
JeSelf-Governing Province; Korea,
Dr Jinseok Kim Jeju National University Hospital
Republic of
CHA Bundang Medical Center,
Dr Sang Youn Jung Gyeonggi-do; Korea, Republic of
CHA University
Seo-gu Daejeon; Korea, Republic
Dr Mi-Kyoung Lim Eulji University Hospital
of
Dr Edmundo Hector De la Garza
Accelerium S de RL de CV Monterrey; Nuevo León; Mexico
Ramos
Centro de Estudios de Investigacion
Dr Ignacio Garcia Valladares Guadalajara; Jalisco; Mexico
Basica y Clinica S.C
Centro de Investigacion Clínica
Dr Luis Jara Quezada Distrito Federal; Mexico
GRAMEL S.C
Clinica de Investigacion en
Dr Sergio Duran Barragan Guadalajara; Jalisco; Mexico
Reumatologia y Obesidad S.C
Dr Veronica Vicente Vicente
Clinicos Asociados BOCM S.C Mexico; Distrito Federal; Mexico
Gonzalez
Ciudad de México; Distrito
Dr Favio Edmundo Enriquez Sosa Clinstile, S.A. de C.V
Federal; Mexico
Dr Erika Maria Vera Perez Cryptex Investigacion Clinica S.C Mexico; Distrito Federal; Mexico
Universidad Autonoma de Nuevo
Dr Diana Elsa Flores Alvarado Leon, Hospital Universitario Dr. Monterrey; Nuevo León; Mexico
Jose Eleuterio Gonzalez
Centro de Alta Especialidad en
Dr Juan Cruz Rizo Rodriguez Reumatología e Investigación del San Luis Potosi; Mexico
Potosí S.C
Dr Sandra Munoz Lopez Clinical Research Institute S.C. México city; Mexico
Investigacion y Biomedicina de
Dr Cesar Pacheco Tena Chihuahua; Mexico
Chihuahua, S.C
Dr.Saulite-Kandevica Private
Dr Daina Saulite-Kandevica Liepaja; Latvia
Practice
Rheumatology Clinic of Houston,
Dr Qaiser Rehman Houston; Texas; USA
P.A
East Bay Rheumatology Medical
Dr C Michael Neuwelt San Leandro; California ;USA
Group, Inc
Oklahoma City; Oklahoma
Dr William Schnitz Lynn Health Science Institute
USA
5
Dr Mark Kutner Suncoast Research Group, LLC Miami; Florida; USA
Glacier View Research Institute-
Dr Roger Diegel Kalispell; Montana; USA
Rheumatology
Accurate Clinical Management.,
Dr Sabeen Najam Baytown; Texas; USA
LLC
Dr Prashanth Sunkureddi Accurate Clinical Research, Inc League City; Texas; USA

Dr Philip Waller Accurate Clinical Research, Inc Houston; Texas; USA

Dr Kwabena Ayesu Omega Research Consultants Orlando; Florida; USA

Dr Tina Bunch Austin Regional Clinic, P.A Austin; Texas; USA

Dr Sanford Wolfe STAT Research Dayton; Ohio; USA

Dr Michael Pick Springfield Clinic, LLP Springfield; Illinois; USA

The Arthritis & Diabetes Clinic,
Dr Jyothi Mallepalli Monroe; Louisiana; USA
Inc.
Dr Arthur Mabaquiao TriWest Research Associates, LLC El Cajon; California; USA

Dr Henry Paez Pharmax Research Clinic Miami; Florida; USA

Summerville; South Carolina
Dr Colin Edgerton Low Country Rheumatology, P.A
USA
Dr Melvin Churchill Physician Research Collaboration Lincoln; Nebraska; USA

Dr Joseph Forstot RASF - Clinical Research Center Boca Raton; Florida; USA
Arizona Arthritis & Rheumatology
Dr Saima Chohan Phoenix; Arizona; USA
Associates, P.C
Dr Pooja Bhadbhade University of Kansas Hospital Kansas City; Kansas; USA

Dr Howard Kenney Arthritis Northwest, PLLC Spokane; Washington; USA

Dr. Alex De Jesus Rheumatology,
Dr Alex De Jesus San Antonio; Texas; USA
P.A
Accurate Clinical Management -
Dr Michelle Eisenberg Houston; Texas; USA
Partner
Arthritis & Osteoporosis
Dr Hisham El-Kadi Freehold; New Jersey; USA
Associates, P.A
Dr David Goddard NYU Langone Ambulatory Care Brooklyn; New York; USA
Amarillo Center for Clinical
Dr Constantine Saadeh Amarillo; Texas; USA
Research
Dr Edward Goldberger Clinical Research Source, Inc Toledo; Ohio; USA

Dr Asad Fraser Graves Gilbert Clinic Bowling Green; Kentucky; USA

Dr Craig Scoville Institute of Arthritis Research Idaho Falls; Idaho; USA

Dr Mary Howell Klein and Associates, M.D., P.A Hagerstown; Maryland; USA

Dr Elmer Thomas Arne Lovelace Scientific Resources, Inc Venice; Florida; USA

Dr Kimberly Smith AdventHealth Medical Group Tampa; Florida; USA

6
Dr Chandrakant Mehta Southland Arthritis - Hemet Hemet; California; USA
New England Research Associates
Dr Geoffrey Gladstein Bridgeport; Connecticut; USA
LLC
Wilmington; North Carolina
Dr Mark Harris Carolina Arthritis Associates
USA
The Center for Rheumatology and
Dr Herbert Baraf Wheaton; Maryland; USA
Bone Research
Greensboro; North Carolina
Dr Nilamadhab Mishra Medication Management, LLC
USA
Health Research of Oklahoma, Oklahoma City; Oklahoma
Dr Christine Codding
PLLC USA
Inland Rheumatology Clinical
Dr Eric Lee Upland; California; USA
Trials, Inc
Los Alamitos; California
Dr Rebekah Neal-Kraal Valerius Medical Group
USA
Dr Robert LaGrone Center for Inflammatory Disease Nashville; Tennessee; USA

Dr Samy Metyas Medvin Clinical Research Covina; California; USA

Altoona Center for Clinical Duncansville; Pennsylvania
Dr Frederick Murphy
Research, P.C USA
Dr Andre Babajanians Riverside Medical Clinic Riverside; California; USA

Dr Christopher Antolini Denver Arthritis Clinic Denver; Colorado; USA

Dr Jeanne-Elyse Cedeno Family Clinical Trials, LLC Pembroke Pines; Florida; USA
Marietta Rheumatology Associates,
Dr Roel Querubin Marietta; Georgia; USA
P.C
Dr Jitendra Vasandani West Texas Clinical Research Lubbock; Texas; USA

Dr Charles King North MS Medical Clinics, Inc Tupelo; Mississippi; USA

Dr David Snow Cape Fear Arthritis Care Leland; North Carolina; USA

Dr Nayvis Iglesias Medical Research Center of Miami Miami; Florida; USA

Dr Erdal Diri Trinity Medical Group Minot; North Dakota; USA

Dr Nazanin Firooz Center for Rheumatology Research West Hills; California; USA
AA MRC LLC Ahmed Arif
Dr Ali Karrar Grand Blanc; Michigan; USA
Medical Research Center
Advanced Rheumatology of
Dr Tamar Brionez The Woodlands; Texas; USA
Houston
Dr Shaikh Arif Ali DM Clinical Research Tomball; Texas; USA

Dr Amber Khan Accurate Clinical Research, Inc Houston; Texas; USA

Arizona Arthritis & Rheumatology
Dr Nehad Soloman Sun City; Arizona; USA
Research, PLLC
Dr Luis Diaz-Secades Reliable Clinical Research, LLC Hialeah; Florida; USA
Arizona Arthritis & Rheumatology
Dr Daniel Kreutz Mesa; Arizona; USA
Associates, P.C

7
 Precision Comprehensive Clinical
Dr Dhiman Basu Colleyville; Texas; USA
Research Solutions
Dr Tania Rivera Rheumatology Center of San Diego San Diego; California; USA

Dr Karen Zagar Arthritis Center Palm Harbor; Florida; USA

Dr Vijay Kumar Pioneer Research Solutions, Inc Beaumont; Texas; USA

Dr Tien-I Karleen Su Medvin Clinical Research Whittier; California; USA

Javed Rheumatology Associates
Dr Sheerin Javed Newark; Delaware; USA
INC
Dr Marta Bognar Arthritis Center of North Georgia Gainesville; Georgia; USA
Medizinski Zentar-1-Sevlievo,
Dr Krasimira Tsoneva Sevlievo; Bulgaria
EOOD
Dr Stoyan Todorov MHAT - Shumen, AD Shumen; Bulgaria

Dr Antoaneta Toncheva NMTH "Tsar Boris III" Sofia; Bulgaria

Dr Emil Dimitrov MHAT "Lyulin", EAD Sofia; Bulgaria

Dr Nadezhda Kapandjieva MHAT - Ruse, AD Ruse; Bulgaria

MDHAT 'Dr. Stefan Cherkezov',
Dr Svetla Kopcheva Veliko Tarnovo; Bulgaria
AD
Dr Daniela Bichovska MC "Synexus - Sofia", EOOD Sofia; Bulgaria

Dr Rumen Stoilov UMHAT "Sv. Ivan Rilski", EAD Sofia; Bulgaria

Dr Dimitar Penev UMHAT "Pulmed", OOD Plovdiv; Bulgaria

Dr Tsvetanka Petranova Medical Center "Excelsior", OOD Sofia; Bulgaria

Dr Agnieszka Zielinska Medycyna Kliniczna Warszawa; Poland

Rheuma Medicus Zaklad Opieki
Dr Maria Rell-Bakalarska Warszawa; Poland
Zdrowotnej
Santa Familia Centrum Badan,
Dr Jadwiga Burczynska Zgierz; Poland
Profilaktyki i Leczenia
Dr Slawomir Jeka Nasz lekarz Przychodnie Medyczne Torun; Poland
ETYKA Osrodek Badan
Dr Agnieszka Pawtel Olsztyn; Poland
Klinicznych
Szpital Uniwersytecki nr 2 im.dr J.
Dr Iwona Dankiewicz-Fares Bydgoszcz; Poland
Biziela
Dr Anna Dudek Centrum Medyczne AMED Lodz; Poland
KO-MED Centra Kliniczne
Dr Krystyna Dworak Staszow; Poland
Staszow
Szpital Wojewodzki im. Prymasa
Dr Robert Kolacinski Sieradz; Poland
Kardynala Stefana Wyszynskiego
Dr Artur Racewicz ZDROWIE Osteo-Medic Bialystok; Poland

Dr Sylwia Olechnowicz-Tietz Clinmed Research Skierniewice; Poland

Dr Andrzej Kaminski Samodzielny Publiczny ZOZ Tomaszow Lubelski; Poland

8
Dr Krystyna Kuc CERMED Bialystok; Poland

Dr Anna Strzelecka CCBR - Lodz - PL Lodz; Poland

POLIMEDICA CENTRUM
Dr Mirella Wojtecka-Grabka BADAŃ, PROFILAKTYKI I Kielce; Poland
LECZENIA
Dr Agnieszka Rapa KO-MED Centra Kliniczne Zamosc Zamosc; Poland
MCBK Iwona Czajkowska Anna
Dr Anna Malys Brylka Grodzisk Mazowiecki; Poland
Podrażka- Szczepaniak S.C
Dr Anna Rowinska-Osuch MCM POLIMEDICA Warszawa,Mazowieckie; Poland

Dr Monika Wronisz RCMed Sochaczew; Poland

SBHI of Republic of Karelia
Dr Natalia Vezikova "Republican Hospital named after Petrozavodsk, RussianFederation
V.A.Baranov"
State Budgetary Healthcare
Institution "City Clinical Hospital #
Prof Ivan Gordeev Moscow, Russian Federation
15 n.a O.M. Filatov" of Moscow
Healtheare Department
State Budgetary Healthcare
Institution of Sverdlovsk Region
Dr Ludmila Evstigneeva Ekaterinburg, Russian Federation
"Sverdlovsk Regional Clinical
Hospital #1"
SBEI HPE "Ural State Medical
University" of MoH of RF based
Dr Nadezhda Izmozherova Ekaterinburg, Russian Federation
MBI "Central City Clinical
Hospital #6"
Republican Hospital named after
Dr Rimma Kamalova Ufa, Russian Federation
G.G. Kuvatov
Non-govarnmental Healtheare
Institution "Regional Clinical
Dr Diana Krechikova Smolensk, Russian Federation
Hospital at Smolensk station of
OJSC "Russian Railways"
SPb SBHI "Clinical
Saint-Petersburg, Russian
Dr Galina Matsievskaya Rheumatological Hospital #25",
Federation
Fourth Rheumatology Unit
SBHI of Nizhny Novgorod Region
"Nizhny Novgorod Regional
Dr Tatyana Plaksina Novgorod, Russian Federation
Clinical Hospital named after N.A.
Semashko"
FSBEI HE "FMSMU named after
I.M. Sechenov of MoH of RF",
Dr Elena Smolyarchuk University Hospital #2, Moscow, Russian Federation
Departament of New Drugs
Introduction
SRI of Rheumatology named after
Dr Marina Stanislav Moscow, Russian Federation
V.I. Nasonova

9
 METHODS

Randomization and blinding

After eligibility had been confirmed, subjects were randomized in a 2:2:2:1 ratio in 4 treatment groups
(olokizumab [OKZ] 64 mg once every 2 weeks [q2w], OKZ 64 mg once every 4 weeks [q4w],
adalimumab [ADA] 40 mg q2w and placebo [PBO]) by blinded study staff using the IWRS (an
automated web randomization system). The IWRS allocated the treatment group and assigned the study
treatment. This system also managed drug supply management and visit dispensation. Blinded study
staff requested study treatment assignments via the IWRS for all subsequent treatment study visits.
Cenduit Interactive Response Technology (C.I.R.T) system (Cenduit, LLC) was used in the study for
this purpose.

The treatment each subject received was not disclosed to the blinded study site staff, including the
Investigators, study coordinators, subjects, R-Pharm (Sponsor), or R-Pharm’s designee. Since the study
treatments were distinguishable, they were prepared by the unblinded pharmacist (or their unblinded
designee) and administered by a trained, unblinded study team member who was not involved in the
management of study subjects. An independent unblinded pharmacist (or designee) prepared OKZ and
PBO in syringes of 0.4 mL for subcutaneous (SC) injection, and ADA was supplied from a central
vendor in a prefilled, single-dose syringe of either 0.4 or 0.8 mL for SC injection. In order to maintain
the blind, OKZ and PBO were prepared in blinded SC syringes as per the instructions in the study-
specific manual prior to dispensing, in a manner that both treatments were identical in appearance.
ADA was also masked; however, as ADA was supplied in a larger SC syringe, the size of the masked
syringe was distinguishable from OKZ and PBO. A qualified unblinded study team member who was
not involved in the management of study subjects administered the assigned study treatment as a single
SC injection q2w or q4w at the relevant time points. Subjects were dosed individually and away from
other subjects to ensure that differences between OKZ, ADA, and PBO were not observed. To maintain
the blind, the unblinded study site staff was trained in methods that must be followed and documented
to prevent subjects from observing which SC injection they receive. Guidance on specific blinding
procedures were provided in the study-specific manual.

Access to randomization codes were restricted. The treatment codes were held by the IWRS. Only the
unblinded pharmacist (or their unblinded designee) or dedicated unblinded study staff who were not
directly involved in subject management were aware of the randomized drug assignment. The storage
and preparation of the study treatment were at a secured location that was not accessible to blinded
study staff. Additional measures to ensure that both Investigators and participants remained blinded to
study treatment included the following:

10
  Joint assessments were made by an independent assessor, blinded to both the dosing
regimen and all other study assessments. Training video was provided to the assigned assessors
in the beginning of the study.
 Laboratory results for C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)
samples collected during the treatment period were not available to blinded study site staff. As
ESR was tested locally, the testing was performed, reviewed, registered and reported by
unblinded study site staff who was not responsible for managing subjects.
 Certain efficacy assessments (American College of Rheumatology 20% improvement response
criteria ACR20, ACR50, ACR70, Disease Activity Score 28-joint count CRP (DAS28-CRP),
DAS28-ESR, Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index
(CDAI)) were not calculated by the Investigator during the course of the study, but were
computed in the statistical database for analysis purposes further.
 All blinding procedures were respected.
Members of the independent Data Safety Monitoring Board (DSMB) reviewed separately safety data
during the study. In the event that ongoing safety monitoring had uncovered an issue needed to be
addressed by unblinding at the treatment group level, only members of the DSMB were permitted to
conduct additional analysis of the safety data.

Criteria for evaluation, determination of sample size and selection of non-

inferiority margin

Primary efficacy endpoint

The primary efficacy endpoint was the ACR20 response at Week 12, where a responder was defined
as any subject satisfying ACR20 criteria and remaining on randomized treatment and in the study at
Week 12. This endpoint served to demonstrate that the efficacy of OKZ was superior to PBO.

Secondary efficacy endpoints

The secondary efficacy endpoints were:

 ACR20 response at Week 12, where a responder was defined as any subject satisfying ACR20
criteria and remaining on randomized treatment and in the study at Week 12; was used to
demonstrate that the efficacy of OKZ was non-inferior to ADA, provided that superiority of
ADA to PBO (assay sensitivity) was demonstrated concurrently based on the same endpoint.

 Percentage of subjects achieving DAS28-CRP<3.2, and remaining on randomized treatment

and in the study at Week 12. This endpoint served to demonstrate that the efficacy of OKZ
was superior to PBO.

11
  Percentage of subjects achieving DAS28-CRP<3.2, and remaining on randomized treatment
and in the study at Week 12; served to demonstrate that the efficacy of OKZ was non-inferior
to ADA, provided that superiority of ADA to PBO (assay sensitivity) was demonstrated
concurrently based on the same endpoint.

 Improvement of physical ability from baseline to Week 12, as measured by the Health
Assessment Questionnaire-Disability Index (HAQ-DI).

 Percentage of subjects achieving an ACR50 response and remaining on randomized treatment

and in the study at Week 24.

 Percentage of subjects with CDAI ≤2.8 (remission) and remaining on randomized treatment
and in the study at Week 24.

Other efficacy endpoints

Other efficacy (exploratory) endpoints included but were not limited to proportion of subjects
achieving an ACR20, ACR50, and ACR70 response and remaining on randomized treatment and in
the study, assessed at all other applicable time points; proportion of subjects with
SDAI ≤3.3 (remission) and remaining on randomized treatment and in the study, assessed at all other
applicable time points; proportion of subjects with CDAI ≤2.8 (remission) and remaining on
randomized treatment and in the study, assessed at all other applicable time points; proportion of
subjects with DAS28-CRP<3.2 and remaining on randomized treatment and in the study at all other
applicable time points.

Determination of sample size

Sample size requirements were calculated to provide sufficient disjunctive power to evaluate the
primary endpoint (superiority of OKZ relative to PBO with respect to the ACR20 response rate at
Week 12) as well as 3 secondary endpoints (non-inferiority of OKZ relative to ADA with respect to
the ACR20 response rate at Week 12, superiority of OKZ relative to PBO with respect to the proportion
of subjects with DAS28-CRP<3.2 at Week 12, and non-inferiority of OKZ relative to ADA with
respect to the proportion of subjects with DAS28-CRP<3.2 at Week 12).

Sample size was estimated taking into account a multiplicity control procedure and the resulting α
adjustment that was used to control an overall Type I error rate in the strong sense at a 1-sided α =
0.025 across the primary and secondary endpoints. More specifically, the α-control strategy was based
on using the Bonferroni adjustment for the tests related to each of the 2 OKZ dose regimens (ie, using
the 1-sided α = 0.0125 for each dose). A gate-keeping strategy was used for tests associated with the
primary and secondary endpoints for each OKZ dose regimen independently, with a fixed order of
hypothesis tests for the primary and secondary endpoints within each OKZ dose regimen.
12
Sample size was estimated based on simulation that implemented the above α adjustment and gate-
keeping procedure including the primary endpoint of ACR20 response rate at Week 12 (superiority of
OKZ to PBO) and the 3 secondary endpoints as detailed. Based on this simulation, an adequate sample
size was selected to provide sufficient disjunctive power for the primary endpoint as well as sufficient
disjunctive power for testing non-inferiority of OKZ relative to ADA with respect to the ACR20
response rate at Week 12, superiority of OKZ relative to PBO with respect to the proportion of subjects
with DAS28-CRP<3.2 at Week 12, and non-inferiority of OKZ relative to ADA with respect to the
proportion of subjects with DAS28-CRP<3.2 at Week 12. For each secondary endpoint, the disjunctive
power represents a probability of establishing a significant treatment effect for 1 or 2 OKZ dose
regimens for the primary endpoint and a significant treatment effect for 1 or 2 OKZ dose regimens for
a given secondary endpoint, conditional on the fact that each dose regimen tested for the secondary
endpoint must have null hypothesis previously rejected for all endpoints (primary and secondary) that
precede this endpoint in a fixed order of testing as per the gate-keeping procedure.

Selection of non-inferiority margin

Based on the treatment effect assumptions and the methodology for estimating sample size via
simulation to ensure sufficient disjunctive power as described, a sample size of 1575 subjects
randomized in a 2:2:2:1 ratio (450, 450, 450, and 225 subjects per group, respectively) would yield
100% disjunctive power for testing the primary hypothesis (superiority of OKZ to PBO with respect
to ACR20 at Week 12), 92% disjunctive power for testing the secondary hypothesis of non-inferiority
of OKZ to ADA with respect to ACR20 rate at Week 12, 92% disjunctive power for the evaluation of
the secondary endpoint of superiority of OKZ to PBO with respect to DAS28-CRP<3.2 at Week 12,
and 88% disjunctive power for testing the secondary hypothesis of non-inferiority of OKZ to ADA
with respect to DAS28-CRP<3.2 at Week 12.

For selection of non-inferiority margin the following assumptions were used: in a meta-analysis of two
key pivotal clinical studies for registration of ADA,1,2 the difference between the ACR20 response rate
at Week 12 for ADA in combination with methotrexate (MTX) with N=280 and PBO in combination
with MTX with N=262 was equal to 35% (95% confidence interval: 27.3% to 42.6%). Therefore,
27.3% was estimated as the absolute largest non-inferiority margin that could be justified. Using an
assumption of 55% ACR20 response rate at Week 12 for ADA and a more conservative minimum
lower bound of 43% for OKZ was considered to be clinically meaningful. As a result, a non-inferiority
margin of 12% for the ACR20 response rate at Week 12 was used in this study.

In a meta-analysis of 2 clinical studies of ADA,3,4 the difference between the DAS28-CRP<3.2

response rate at Week 12 for ADA+MTX (N=537) and PBO+MTX (N=688) was equal to 20% (95%
confidence interval: 15.3% to 24.6%). Therefore, 15.3% is the absolute largest non-inferiority margin
13
that could be justified. Using an assumption of 27% for DAS28-CRP<3.2 response rate at Week 12 for
ADA and a more conservative minimum lower bound of 19.5% for OKZ is considered to be clinically
meaningful. As a result, we use a non-inferiority margin of 7.5% for DAS28-CRP<3.2 response rate at
Week 12.

Missing data

The main method for handling missing data resulting from premature withdrawal of a subject from the
study was based on a clinical approach where no treatment benefit was attributed to study treatment at
any time point post study withdrawal, if the subject was unable to complete the study for the planned
duration.

Therefore, for all binary primary and secondary endpoints (ACR20 at Week 12, DAS28-CRP32 at
Week 12, ACR50 at Week 24 and CDAI28 at Week 24), all subjects who discontinue prematurely,
regardless of reason, were considered as non-responders with respect to the definition of the
corresponding endpoint.

Similarly, for all endpoints that are continuous in nature (such as HAQ-DI at Week 12), a return to
baseline values was performed and was implemented using multiple imputation accounting for the
uncertainty of missing data according to the methodology of Rubin.5

Missing data could be also result from missed intermediate visits. For all binary endpoints, missing
intermediate responder status was imputed from the surrounding visits. If the status at visits both before
and after the missed visit was classified as responder, the subject was considered a responder at the
missed visit. Otherwise, the subject was considered a non-responder. If an assessment for a given
binary endpoint at the last visit was missing for a completing subject, data from the 2 previous visits
were used with the same logic for determining the response status.

For the ACR20/50/70 endpoints, if only some components of the response criteria were missing but
the available components allowed classifying the subject as a responder, the responder category was
used. Otherwise, the method based on surrounding visits as described above was applied.

Similarly, for all continuous endpoints, an average of values from the surrounding visits was imputed
for the missing visit. In the event that some visits remained missing, either due to sequential missing
visits, the preceding visit being baseline, or the missing visit being the last scheduled visit, then these
were imputed using the Markov chain Monte Carlo method.

Patient inclusion criteria

Subjects were enrolled in the study only if they met all of the following criteria:

14
1. Male or female subjects ≥18 years of age.
2. Subjects willing and able to sign informed consent.
3. Subjects had to have a diagnosis of adult-onset RA classified by American College of
Rheumatology (ACR)/ European Alliance of Associations for Rheumatology (EULAR) 2010
revised classification criteria for rheumatoid arthritis (RA)6 for at least 12 weeks prior to Screening.
 If the subject was diagnosed according to ACR 1987 criteria previously, the Investigator could
classify the subject per ACR 2010 retrospectively, using available source data.
4. Inadequate response to treatment with oral, SC, or intramuscular MTX for at least 12 weeks prior
to Screening at a dose of 15 to 25 mg/week (or ≥10 mg/week if intolerant to higher doses); a lower
dose of MTX (≥7.5 mg/week) was permitted for subjects with intolerant to higher doses enrolled
in the Republic of Korea, consistent with local clinical practice.
 The dose and means of administering MTX had to have been stable for at least 6 weeks prior
to Screening.
5. Subjects had to be willing to take folic acid or equivalent throughout the study.
6. Subjects had to have moderately to severely active RA disease as defined by all of the following:
a) ≥6 tender joints (68-joint count) at Screening and baseline; and
b) ≥6 swollen joints (66-joint count) at Screening and baseline; and
c) CRP above upper limit of normal (ULN) at Screening based on the central laboratory results.

Patient exclusion criteria

Subjects who met any of the following criteria were not eligible for the study:

1. Diagnosis of any other inflammatory arthritis or systemic rheumatic disease (eg, gout, psoriatic or
reactive arthritis, Crohn’s disease, Lyme disease, juvenile idiopathic arthritis, or systemic lupus
erythematosus)
 Subjects could have secondary Sjogren’s syndrome or hypothyroidism.
2. Subjects who were Steinbrocker class IV functional capacity (incapacitated, largely or wholly
bed-ridden or confined to a wheelchair, with little or no self-care).
3. Prior exposure to any licensed or investigational compound directly or indirectly targeting IL-6 or
IL-6R (including tofacitinib or other Janus kinase(JAK) and spleen tyrosine kinase (SYK)
inhibitors)
4. Prior treatment with cell-depleting therapies, including anti-CD20 or investigational agents (eg,
Campath, anti-CD4, anti-CD5, anti-CD3, and anti-CD19).
5. Prior use of biological disease-modifying antirheumatic drugs (bDMARDs).
6. Use of parenteral and/or intra-articular (IA) glucocorticoids within 4 weeks prior to baseline.

15
7. Use of oral glucocorticoids greater than 10 mg/day prednisone (or equivalent) or change in dosage
within 2 weeks prior to baseline.
8. Prior documented history of no response to hydroxychloroquine and sulfasalazine.
9. Prior use of conventional DMARDs (cDMARDs) other than MTX within the following windows
prior to baseline (cDMARDs should not be discontinued to facilitate a subject’s participation in the
study, but should instead have been previously discontinued as part of a subject’s medical
management of RA):
 Four weeks for sulfasalazine, azathioprine, cyclosporine, hydroxychloroquine, chloroquine,
gold, penicillamine, minocycline, or doxycycline
 Twelve weeks for leflunomide, unless the subject had completed the following elimination
procedure at least 4 weeks prior to baseline: сholestyramine at a dosage of 8 g 3 times daily for
at least 24 hours, or activated charcoal at a dosage of 50 g 4 times daily for at least 24 hours
 Twenty-four weeks for cyclophosphamide
10. Vaccination with live vaccines in the 6 weeks prior to baseline or planned vaccination with live
vaccines during the study.
11. Participation in any other study of investigational drug within 30 days or 5 times the terminal
half-life of the investigational drug, whichever was longer, prior to baseline.
12. Other treatments for RA (eg, Prosorba Device/Column) within 6 months prior to baseline
13. Use of IA hyaluronic acid injections within 4 weeks prior to baseline.
14. Use of non-steroidal anti-inflammatory drugs (NSAIDs) on unstable dose or switching of NSAIDs
within 2 weeks prior to baseline.
15. Previous participation in this study (randomized) or another study of OKZ.
16. Abnormal laboratory values, as defined below:
 Creatinine level ≥1.5 mg/dL (132 µmol/L) for females or ≥2.0 mg/dL (177 µmol/L) for males
 Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥1.5× ULN
 Platelets <100×109/L (<100,000/mm3)
 White blood cell (WBC) count <3.5×109/L
 Neutrophil count <2000×106/L (<2000/mm3)
 Hemoglobin (Hb) level ≤80 g/L
 Glycosylated Hb level ≥8%
17. Subjects with concurrent acute or chronic viral hepatitis B or C infection as detected by blood tests
at Screening (eg, positive for hepatitis B surface antigen [HBsAg], total hepatitis B core antibody
[anti-HBc], or hepatitis C virus antibody [HCV Ab])
 Subjects who were positive for hepatitis B surface antibodies (anti-HBs), but negative for
HBsAg and anti-HBc, were eligible.
16
18. Subjects with human immunodeficiency virus (HIV) infection.
19. Subjects with:
 Suspected or confirmed current active tuberculosis (TB) disease or a history of active TB
disease
 Close contact (ie, sharing the same household or other enclosed environment, such as a social
gathering place, workplace, or facility, for extended periods during the day) with an individual
with active TB within 1.5 years prior to Screening.
 History of untreated latent TB infection (LTBI), regardless of interferon-gamma release assay
(IGRA) result at Screening
 Subjects with a history of untreated LTBI could be re-screened and enrolled if they fulfilled
all 3 of the following criteria:
 Active TB was ruled out by a certified TB specialist or pulmonologist who was familiar
with diagnosing and treating TB (as acceptable per local practice);
 The subject had completed at least 30 days of LTBI-appropriate prophylaxis prior to
baseline with agents recommended as preventative therapy for LTBI according to
country-specific/Centers for Disease Control and Prevention (CDC) guidelines
(treatment with isoniazid for 6 months was not an appropriate prophylactic regime for
this study and was not used); and
 The subject was willing to complete the entire course of recommended LTBI therapy.
 Positive IGRA result at Screening. If indeterminate, the IGRA could be repeated once during
the Screening Period. If there was a second indeterminate result, the subject was excluded.
 Subjects with a positive IGRA result at Screening could be re-screened and enrolled if:
 Active TB was ruled out by a certified TB specialist or pulmonologist who was familiar
with diagnosing and treating TB (as acceptable per local practice);
 The subject had completed at least 30 days of LTBI-appropriate prophylaxis prior to
baseline with agents recommended as preventative therapy for LTBI according to
country-specific/CDC guidelines (treatment with isoniazid for 6 months was not an
appropriate prophylactic regime for this study and was not used); and
 The subject was willing to complete the entire course of recommended LTBI therapy.
 If a subject with a positive IGRA result at Screening had documented evidence of
completing treatment for LTBI with a treatment regime and treatment duration that were
appropriate for this study, the subject could be enrolled without further prophylaxis if
recommended by a certified TB specialist or pulmonologist who was familiar with
diagnosing and treating TB (as acceptable per local practice) and no new exposure in close

17
 contact with an individual with active TB after completing the prophylactic treatment was
suspected.
20. Concurrent malignancy or a history of malignancy within the last 5 years (with the exception of
successfully treated carcinoma of the cervix in situ and successfully treated basal cell carcinoma
and squamous cell carcinoma not less than 1 year prior to Screening [and no more than 3 excised
skin cancers within the last 5 years prior to Screening]).
21. Subjects with any of the following cardiovascular (CV) conditions:
 Uncompensated congestive heart failure, or class III or IV heart failure defined by the New
York Heart Association classification7
 Untreated or resistant arterial hypertension Grade II-III (systolic blood pressure [BP]
>160 mm Hg and/or diastolic BP >100 mm Hg)
 History or presence of concurrent severe and/or uncontrolled CV disorder (including but not
limited to acute coronary syndrome or stroke/transient ischemic attack in the previous 3 months
before Screening) that would, in the Investigator’s judgment, have contraindicated subject
participation in the clinical study, or clinically significant enough in the opinion of the
Investigator to have altered the disposition of the study treatment, or constituted a possible
confounding factor for assessment of efficacy or safety of the study treatment
22. Subjects with a history or presence of any concurrent severe and/or uncontrolled medical condition
(including but not limited to respiratory, hepatic, renal, gastrointestinal, endocrinological,
dermatological, neurological, psychiatric, hematological [including bleeding disorder], or
immunologic/immunodeficiency disorder[s]) that would, in the Investigator’s judgment, have
contraindicated subject participation in the clinical study, or clinically significant enough in the
opinion of the Investigator to have altered the disposition of the study treatment, or constituted a
possible confounding factor for assessment of efficacy or safety of the study treatment.
23. Uncontrolled diabetes mellitus.
24. Subjects with any infection requiring oral antibiotic or antiviral therapy in the 2 weeks prior to
Screening or at baseline, injectable anti-infective therapy in the last 4 weeks prior to baseline, or
serious or recurrent infection with history of hospitalization in the 6 months prior to baseline.
25. Subjects with evidence of disseminated herpes zoster infection, zoster encephalitis, meningitis, or
other non-self-limited herpes zoster infections in the 6 months prior to baseline.
26. Subjects with planned surgery during the study or surgery ≤4 weeks prior to Screening and from
which the subject had not fully recovered, as judged by the Investigator.
27. Subjects with diverticulitis or other symptomatic GI conditions that could have predisposed the
subject to perforations, including subjects with history of such predisposing conditions (eg,
diverticulitis, GI perforation, or ulcerative colitis).

18
28. Pre-existing central nervous system demyelinating disorders (eg, multiple sclerosis and optic
neuritis).
29. History of chronic alcohol or drug abuse as judged by the Investigator.
30. Female subjects who were pregnant, currently lactating, had lactated within the last 12 weeks, or
who were planning to become pregnant during the study or within 6 months of the last dose of
study treatment.
31. Female subjects of childbearing potential (unless permanent cessation of menstrual periods,
determined retrospectively after a woman had experienced 12 months of natural amenorrhea as
defined by the amenorrhea with underlying status [eg, correlative age] or 6 months of natural
amenorrhea with documented serum follicle-stimulating hormone levels >40 mIU/mL and
estradiol <20 pg/mL) who were not willing to use a highly effective method of contraception during
the study and for at least 6 months after the last administration of study treatment
OR
Male subjects with partners of childbearing potential not willing to use a highly effective method
of contraception during the study and for at least 3 months after the last administration of study
treatment
Highly effective contraception was defined as:
 Female sterilization surgery: hysterectomy, surgical bilateral oophorectomy (with or without
hysterectomy), or tubal ligation at least 6 weeks prior to the first dose of study treatment
 In the case of oophorectomy alone, only when the reproductive status of the woman had
been confirmed by documented follow-up hormone level assessment
 Total abstinence if that was the preferred and constant lifestyle of the subject. Thus, periodic
abstinence such as ovulation, symptothermal, postovulation, calendar methods, and withdrawal
were not acceptable methods of contraception.
 Male sterilization surgery: at least 6 months prior to Screening (with the appropriate
postvasectomy documentation of the absence of sperm in the ejaculate). For female subjects,
the vasectomized male had to be the only partner.
 Placement of established intrauterine device (IUD): IUD copper or IUD with progesterone.
 Barrier method (condom and intravaginal spermicide, cervical caps with spermicide,
diaphragm with spermicide) in combination with the following: established oral, injected, or
implanted hormone methods of contraception or contraceptive patch.
32. Subjects with a known hypersensitivity to any component of the OKZ drug product, ADA, or PBO.
33. Subjects with a known hypersensitivity or contraindication to any component of the rescue
medication.

19
34. History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal
antibodies.
35. Subject's unwillingness or inability to follow the procedures outlined in the protocol.
36. Other medical or psychiatric conditions or laboratory abnormalities that could have increased
potential risk associated with study participation and administration of investigational products, or
that could have affected study results interpretation and, as per the Investigator's judgment, made
the subject ineligible.

Premature subject study withdrawal

All subjects were free to withdraw from participation in the study at any time, for any reason, specified
or unspecified, and without prejudice to further treatment.

If premature withdrawal occurred for any reason, the Investigator made every effort to determine the
primary reason for a subject’s premature withdrawal from the study and record this information on the
source documents and appropriate electronic сase report form (eCRF).

Subjects were completely withdrawn from study treatment and all assessments in the following cases:

 Withdrawal of informed consent

 Death of subject
 Subject lost to follow-up

Premature subject treatment withdrawal

Protocol listed the reasons for premature treatment discontinuation. Among them there were the
following circumstances:

 Subject presented with any of the following elevated liver function tests (LFTs):

 ALT or AST elevations >8× ULN at any time, regardless of total bilirubin or accompanying
symptoms;
 ALT or AST >5× ULN for ≥2 weeks regardless of total bilirubin or accompanying
symptoms;
 ALT or AST elevations >3× ULN and total bilirubin value >2× ULN;
 ALT or AST elevations >3× ULN accompanied by symptoms consistent with hepatic
injury (fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, or rash);

 Subject presented with any of the following laboratory abnormalities:

 Absolute neutrophil count <500×106/L (<500 /mm3);

20
  Two sequential lymphocyte counts <500×106/L (<500 /mm3)’
 Platelet count <50×109/L (<50,000 /mm3 or <50,000×106/L);
 Two sequential Hb values ≤8.0 g/dL and decreased ≥20 g/L (2 g/dL) below Screening
value;
 Creatinine value >2× ULN.

 Subject had a GI perforation.

 Subject had a severe or life-threatening infection that required hospitalization (that was also a
Serious Adverse Event (SAE).
 Confirmed active TB (that was also an SAE).

The subjects who discontinued randomized study treatment early (ie, prior to Week 24) adhered to the
established double-blind treatment period visit schedule outlined in the study Schedule of Events, as if
they were still receiving study treatment. In addition, all subjects who discontinued study treatment
early were required to attend the End of Treatment (EoT) Visit 2 weeks after the last dose of the study
treatment, as well as Safety Follow-Up assessments 4, 8, and 22 weeks after the last dose of study
treatment.

Prior and concomitant treatments

Concomitant treatment with MTX was detailed in the protocol. Specifically, at the discretion of the
Investigator, the dose of MTX could be reduced once during the study for safety reasons. Concomitant
treatment with folic acid ≥5 mg per week or equivalent was required for all subjects starting by
Visit 2 (Week 0). Specific treatments prohibited prior to and during the course of the study are
described in the Table below. Other medications and non-drug therapies not listed within the Table
that were considered necessary for the subject’s safety and well-being could be given at the discretion
of the Investigator.

Prior MTX and all other treatments for RA for the 6 months prior to the Screening Visit were recorded
in the eCRF. All medications/treatments received within 4 weeks prior to the Screening Visit were also
recorded in the eCRF. Doses, route of applications, duration of treatment, and reasons for prescription
were also recorded.

21
 Prohibited medications

Treatment Restriction

cDMARDs other than

 Treatment with cDMARDs other than MTX was prohibited during
MTX
the entire study, with the exception of sulfasalazine and/or
hydroxychloroquine, which were permitted as rescue medication for
nonresponders starting at Week 14.
 Prior use of cDMARDs other than MTX within the following
windows prior to baseline was exclusionary (cDMARDs were not
discontinued to facilitate a subject’s participation in the study, but
were instead to have been previously discontinued as part of a
subject’s medical management of RA):
– 4 weeks for sulfasalazine, azathioprine, cyclosporine,
hydroxychloroquine, chloroquine, gold, penicillamine,
minocycline, or doxycycline;
– 12 weeks for leflunomide, unless the subject had completed the
following elimination procedure at least 4 weeks prior to
baseline: cholestyramine at a dosage of 8 g 3 times daily for at
least 24 hours, or activated charcoal at a dosage of 50 g 4 times
a day for at least 24 hours;
– 24 weeks for cyclophosphamide.

bDMARDs/ kinase
 Treatment with any licensed or investigational biologics directly or
inhibitors
indirectly targeting IL-6 or IL-6R (including tofacitinib or other JAK
or SYK inhibitors) was prohibited during the entire study and their
use prior to Screening was exclusionary.
 Treatment with cell-depleting therapies, including anti-CD20 agents
or investigational agents (e.g., CAMPATH, anti-CD4, anti-CD5,
anti-CD3, and anti-CD19), was prohibited during the entire study
and their use prior to Screening was exclusionary.
 Treatment with bDMARDs, including tumor necrosis factor
inhibitors, was prohibited during the entire study and their use prior
to Screening was exclusionary.

22
Treatment Restriction

Corticosteroids
 Treatment with an oral glucocorticoid greater than 10 mg/day
prednisone, or equivalent, or a change in dosage within 2 weeks prior
to baseline was exclusionary.
 Use of parenteral glucocorticoids within 4 weeks prior to baseline
was exclusionary. Use of parenteral glucocorticoids was strongly
discouraged during the entire study, but limited use was allowed in
the following circumstance:
– No more than 2 joints could be injected at or after Week 14 after
all study assessments for this time point were performed. The
injection must not exceed 40 mg methylprednisolone or
equivalent cumulative dose. Injected joints were rated as having
their pre-injection status for the remainder of the study.

NSAIDs
 NSAIDs were prohibited during the entire study with the following
exceptions:
– Stable doses of NSAIDs were permitted during the study if the
subject had received stable doses for ≥2 weeks prior to baseline.
Doses of NSAIDs were kept constant throughout the entire study
unless the Investigator changes the dose for safety reasons.
Switching of NSAIDs was not allowed. However, if the subject
had an AE that requires discontinuation of the NSAID, an
alternative NSAID could be initiated per the local label (if not
contraindicated).
 Aspirin used at daily doses up to 325 mg was permitted if indicated
for CV protection. At this dose, aspirin was not considered an
NSAID.

Analgesics
 Analgesics, including opioids, were prohibited during the entire
study with the exception of paracetamol/acetaminophen (maximum
2000 mg per day (maximum 1000 mg per dose).
Paracetamol/acetaminophen were not to be taken within 24 hours
prior to joint assessment, including baseline assessment.

23
 Treatment Restriction

Hyaluronic acid
 IA hyaluronic acid was prohibited during the entire study and its use
within 4 weeks prior to baseline was exclusionary.

Vaccination
 Live vaccinations were prohibited during the entire study and their
use within 6 weeks prior to baseline was exclusionary.

Abbreviations: AE, adverse event; bDMARD, biologic disease-modifying anti-rheumatic drug; cDMARD,
conventional disease-modifying anti-rheumatic drug; CV, cardiovascular; IA, intraarticular; IL-6,
interleukin-6; IL-6R, IL-6 receptor; JAK, Janus kinase; MTX, methotrexate; NSAID, non-steroidal
anti-inflammatory drug; RA, rheumatoid arthritis; SYK, spleen tyrosine kinase.

Allowed medications

The following medications were allowed (non-exhaustive list), including clarifications of the
prohibited medications listed previously:

 Inhaled corticosteroids

 Topical corticosteroids

 Oral corticosteroids

 Doses of ≤10 mg/day of prednisone or equivalent were permitted as long as the dose was
not changed within the 2 weeks prior to baseline; dose adjustments were not permitted
during the study unless the Investigator changed the dose for safety reasons.

 IA corticosteroids

 No more than 2 joints could be injected during the study at or after Week 14, after all study
assessments for this time point were performed. The cumulative dose for both injections did
not exceed 40 mg methylprednisolone or equivalent. Joints treated with IA corticosteroids
were rated with their pre-injection status for the remainder of the study and should be
omitted from all subsequent joint assessments.

 NSAIDs

 The subject was receiving a stable dose for ≥2 weeks prior to baseline, and the dose was
kept constant throughout the entire study unless the Investigator changed the dose for safety
reasons.

 Analgesic treatment with paracetamol/acetaminophen was permitted up to a maximum dose of

2000 mg per day (maximum 1000 mg per dose) or up to the maximum dose in the local label,
24
 whichever was lower. Paracetamol/acetaminophen were not allowed within 24 hours prior to
joint assessment, including baseline assessment.

Rescue medication starting at Week 14

Subjects were classified in terms of their response to study treatment at Week 14 with nonresponders
defined as all subjects who did not improve by at least 20% in both swollen and tender (66-68 joint
assessment). Nonresponders in all groups were prescribed sulfasalazine and/or hydroxychloroquine
according to the local label of the prescribed drug(s) as a rescue medication starting at or as close as
possible to Week 14, in addition to the assigned study treatment without unblinding.

The maximum allowed doses of sulfasalazine and hydroxychloroquine were:

 Sulfasalazine: 3 g per day

 Hydroxychloroquine: 400 mg per day

Nonresponders at Week 14 remained blinded to their assigned treatment. Rescue medication was
administered as open-label treatment. The choice of rescue medication (sulfasalazine,
hydroxychloroquine, or both) was made according to local practice, and the assigned rescue medication
regimen was maintained throughout the study.

For subjects who received rescue medication, periodic safety evaluations for toxicity resulting from
sulfasalazine and/or hydroxychloroquine were undertaken as per the drug label and local guidelines.

Sensitivity analyses

For the primary outcome sensitivity analyses were also conducted in which intermediate missing data
were multiply imputed within treatment, data after treatment discontinuation were included, and data
after discontinuing the study were multiply imputed based on the placebo group for all subjects in the
Intention-to-treat population (ITT) and in the Per protocol population (PP); in these analyses
differences in the response rates for the OKZ q2w group, the OKZ q4w group and the adalimumab
group compared with the placebo group were statistically significant (p<0.0001 for all comparisons).

In the tipping point analysis to demonstrate the robustness of the ACR20 response for OKZ q4w
compared with placebo, all points were statistically significant (p<0.0125). In the tipping point
analysis of the ACR20 response for OKZ q2w compared with placebo, all points were statistically
significant (p<0.0125). In the tipping point analysis of the ACR20 response for adalimumab compared
with placebo, all points were statistically significant (p<0.025).

25
For the secondary outcome: to further compare the efficacy of OKZ with that of adalimumab, analyses
were conducted in which data after treatment discontinuation were included, and intermediate missing
data and data after discontinuing the study were multiply imputed within treatment in the ITT
population and in the PP population; non-inferiority of OKZ relative to adalimumab was demonstrated.

In the tipping point analysis of the ACR20 response for OKZ q2w compared with adalimumab, all
points demonstrated non-inferiority of OKZ relative to adalimumab using a margin of -12%. In the
tipping point analysis of the ACR20 response for OKZ q4w compared with adalimumab, all points
demonstrated non-inferiority of OKZ relative to adalimumab using a margin of -12% .

Efficacy assessments

All efficacy assesments were computed in the statistical database for analysis purposes, icluding
DAS28-CRP that was kept blinded after Screening.
ACR20/50/70 Response Criteria

The calculations were based on a ≥20%, ≥50%, and ≥70% improvement from baseline in the swollen
joint count (SJC) assessed in 66 joints and in the tender joint count (TJC) assessed in 68 joints; and a
≥20%, ≥50%, and ≥70% improvement from baseline in at least 3 of the 5 remaining core set measures:
1) Patient Global Assessment of Disease Activity (VAS); 2) Patient Assessment of Pain (VAS); 3)
HAQ DI; 4) Physician Global Assessment (VAS) and 5) Level of acute phase reactant (level of CRP
in this study).

Disease Activity Score 28-Joint Count (C-Reactive Protein)

The DAS28-CRP was calculated using the SJC (28 joints), TJC (28 joints), CRP level, and the Patient
Global Assessment of Disease Activity (VAS) (in mm) according to the following formula:

DAS28 (CRP) = 0.56 × √(TJC) + 0.28 × √(SJC) + 0.36 × lognat (CRP+1) +

0.014 × Patient Global Assessment of Disease Activity (VAS) + 0.96.

Clinical Disease Activity Index

The CDAI was calculated using the SJC (28 joints), TJC (28 joints), the Patient Global Assessment of
Disease Activity (VAS) (in cm), and the Physician Global Assessment (VAS) (in cm) according to the
following formula:

CDAI = SJC + TJC + Patient Global Assessment of Disease Activity (VAS) + Physician Global
Assessment (VAS).

26
 Health Assessment Questionnaire – Disability Index

The HAQ-DI assessed the degree of difficulty experienced in 8 domains of daily living activities using
20 questions. The domains were dressing and grooming, arising, eating, walking, hygiene, reach, grip,
and common daily activities, and each domain (activity) consisted of 2 or 3 items. For each question,
the level of difficulty was scored from 0 to 3 where 0 = without any difficulty, 1 = with some difficulty,
2 = much difficulty, and 3 = unable to do. Each category was given a score by taking the maximum
score of each question (i.e., question in each category with the highest score for that category).

If the maximum score was 0 or 1, but a device related to that category was used, or help from another
person was provided for the category, then the category score was increased to 2. If the category score
was already a 2 (or above), the score in that category remained 2 with or without any aids or device
use. If the subject did not answer for any questions within a category, no score was provided for that
category. The HAQ DI was calculated by dividing the sum of the category scores by the number of
categories with at least 1 question answered. If fewer than 6 categories had responses, no disability
score was calculated. The HAQ DI was also include patient assessments of pain and health on a scale
of 0 to 100.

27
 FIGURES AND TABLES
Figure S1. Gate-keeping strategy

Notes: pSup, q2w and pSup, q4w represent p-values from a one-sided test of superiority versus placebo for OKZ dose
regimens 64 mg q2w and q4w respectively; 97.5% CLL OKZ q2w - Adb and 97.5% CLL OKZ q4w - Adb represent the
lower confidence limit of the 97.5% 2-sided CI for the difference between proportions versus ADA for OKZ
dose regimens 64 mg q2w and q4w respectively.
Abbreviations: ACR20, American College of Rheumatology 20% improvement response criteria; ACR50,
American College of Rheumatology 50% improvement response criteria; ADA, adalimumab; CDAI, Clinical
Disease Activity Index; CI, confidence interval; DAS28-CRP, Disease Activity Score 28 (based on C-reactive
protein data); HAQ-DI, Health Assessment Questionnaire-Disability Index; OKZ, olokizumab; PBO, placebo;
q2w, every 2 weeks; q4w, every 4 weeks; Wk, week
28
Figure S2. Non-inferiority testing details

Abbreviations: ACR20, American College of Rheumatology 20% improvement response criteria; ADA,
adalimumab; CI, confidence interval; DAS28-CRP, Disease Activity Score 28 (based on C-reactive protein
data); NI, non-inferiority; OKZ, olokizumab; q2w, every 2 weeks; q4w, every 4 weeks; Wk, week

29
Figure S3. Core components of ACR response criteria during the double‐blind treatment period (ITT population)

Abbreviations: ACR, American College of

Rheumatology response criteria; ADA,
adalimumab; CRP, C-reactive protein; ITT,
intention-to-treat; OKZ, olokizumab; PBO,
placebo; GA, global assessment of disease
activity; q2w, every 2 weeks; q4w, every 4
weeks; SJC, swollen joint count (66); TJC,
tender joint count (68); VAS, visual analogue
scale; wk, week

30
 Figure S4. CDAI low disease activity and DAS28-CRP remission during the double‐blind treatment period (ITT population)

60 60
50,2
50 50
47,0

DAS28 <2.6 , % of patients

CDAI <10, % of patients

39,6 46,8
40 40 35,1
37,6
37,3 31,9
30 30
24,3 25,6 25,1 28,6
20 17,7 20
20,8 10,7
7,0
10 10

0 0 0
0 4 8 12 16 20 24 0 4 8 12 16 20 24
Weeks since Baseline Weeks since Baseline

Abbreviations: ADA, adalimumab; CDAI, Clinical Disease Activity Index; DAS28 (CRP), Disease Activity Score 28 (based on C-reactive protein data); ITT, intention-
to-treat; OKZ, olokizumab; PBO, placebo; q2w, every 2 weeks; q4w, every 4 weeks

31
 Figure S5. Mean changes in laboratory values during double-blind treatment
period (safety population)
400 4,62

Erythrocyte count, 10*12/L

Platelet count, 10*9/L

350 4,56

300 4,5

250 4,44

200 4,38

150 4,32
7 150
Neutrophil count, 10*9/L

Hemoglobin level, g/L

6 145

5 140

4 135

3 130

2 125
5,8
40,0
Total сholesterol level, mmol/L

5,6
30,0
ALT, U/L

5,4
20,0
5,2
10,0
5
0,0

4,8

1,8 4

1,7 3,5
LDL level, mmol/L
HDL level, mmol/L

1,6 3

1,5 2,5

1,4 2

1,3 1,5
0 4 8 12 16 20 24 0 4 8 12 16 20 24
Weeks since baseline Weeks since baseline

Abbreviations: ADA, adalimumab; ALT, alanine aminotransferase; HDL, high density lipoproteins; LDL, low
density lipoproteins; OKZ, olokizumab; PBO, placebo; q2w, every 2weeks; q4w, every 4 weeks

32
 Table S1. The numbers of randomized patients from each country (ITT
population)
OKZ 64 mg OKZ 64 mg ADA 40mg
Placebo Total
q2wk q4wk q2wk
N=243 N=1648
N=464 N=479 N=462
Сountries, n (%)
Argentina 42 (9.1) 44 (9.2) 43 (9.3) 24 (9.9) 153 (9.3)
Bulgaria 20 (4.3) 18 (3.8) 19 (4.1) 8 (3.3) 65 (3.9)
Brazil 33 (7.1) 33 (6.9) 30 (6.5) 16 (6.6) 112 (6.8)
Colombia 17 (3.7) 18 (3.8) 16 (3.5) 8 (3.3) 59 (3.6)
Czech Republic 50 (10.8) 58 (12.1) 51 (11.0) 30 (12.3) 189 (11.5)
Germany 13 (2.8) 11 (2.3) 10 (2.2) 6 (2.5) 40 (2.4)
Estonia 3 (0.6) 4 (0.8) 5 (1.1) 1 (0.4) 13 (0.8)
United Kingdom 1 (0.2) 3 (0.6) 6 (1.3) 1 (0.4) 11 (0.7)
Hungary 13 (2.8) 15 (3.1) 13 (2.8) 10 (4.1) 51 (3.1)
South Korea 4 (0.9) 2 (0.4) 1 (0.2) 4 (1.6) 11 (0.7)
Lithuania 22 (4.7) 22 (4.6) 22 (4.8) 8 (3.3) 74 (4.5)
Latvia 3 (0.6) 1 (0.2) 0 0 4 (0.2)
Mexico 63 (13.6) 63 (13.2) 59 (12.8) 30 (12.3) 215 (13.0)
Poland 85 (18.3) 90 (18.8) 87 (18.8) 46 (18.9) 308 (18.7)
Romania 0 0 1 (0.2) 0 1 (<0.1)
Russia 21 (4.5) 20 (4.2) 25 (5.4) 11 (4.5) 77 (4.7)
Taiwan 3 (0.6) 2 (0.4) 2 (0.4) 1 (0.4) 8 (0.5)
United States 71 (15.3) 75 (15.7) 72 (15.6) 39 (16.0) 257 (15.6)
Regions, n (%)
Western 148 (31.9) 162 (33.8) 152 (32.9) 86 (35.4) 548 (33.3)
Latin America 155 (33.4) 158 (33.0) 148 (32.0) 78 (32.1) 539 (32.7)
Rest of the World 161 (34.7) 159 (33.2) 162 (35.1) 79 (32.5) 561 (34.0)

Note: Western region was defined as Czech Republic, Germany, Hungary, United Kingdom and United
States; Latin America: Argentina, Brazil, Columbia, Mexico, Rest of the World: Bulgaria, Estonia, Latvia,
Lithuania, Poland, Romania, Russia, South Korea and Taiwan.
Abbreviations: ADA, adalimumab; ITT, intention-to-treat; n, number of subjects; N, total number of subjects
in the population; OKZ, olokizumab; q2wk, every 2 weeks; q4wk, every 4 weeks; %, percentage of subjects
calculated relative to the total number of subjects in the population.

33
Table S2. Reasons for discontinuation at Week 12 (ITT population)
OKZ 64 mg q2wk OKZ 64 mg q4wk ADA 40mg q2wk Placebo
Reason for discontinuation, n (%)
N=464 N=479 N=462 N=243
Discontinued treatment 26 (5.6) 29 (6.1) 34 (7.4) 26 (10.7)
Primary reason for premature discontinuation from treatment
Lack of efficacy (investigator perspective) 0 0 1 (0.2) 3 (1.2)
Adverse event 17 (3.7) 19 (4.0) 17 (3.7) 6 (2.5)
Pregnancy 0 0 0 0
Protocol violation 1 (0.2) 2 (0.4) 7 (1.5) 3 (1.2)
Consistent non-compliance with study drug dosing 0 0 1 (0.2) 0
Consistent non-compliance with study procedures 0 0 0 0
Use of prohibited concomitant medications 0 0 2 (0.4) 0
Violation of eligibility criteria 1 (0.2) 2 (0.4) 4 (0.9) 3 (1.2)
Other 0 0 0 0
Subject refusal 6 (1.3) 5 (1.0) 5 (1.1) 13 (5.3)
Lack of efficacy (subject perspective) 1 (0.2) 0 2 (0.4) 5 (2.1)
Withdrawal of informed consent 5 (1.1) 2 (0.4) 3 (0.6) 7 (2.9)
Other 0 3 (0.6) 0 1 (0.4)
Lost to Follow-Up 2 (0.4) 0 1 (0.2) 1 (0.4)
Discontinuation by sponsor 0 1 (0.2) 1 (0.2) 0
Study terminated by sponsor or investigator 0 0 0 0
Other 0 2 (0.4) 2 (0.4) 0
Abbreviations: ADA, adalimumab; ITT, intention-to-treat; n, number of subjects; N, total number of subjects in the population; OKZ, olokizumab; q2wk, every 2 weeks;
q4wk, every 4 weeks; %, percentage of subjects calculated relative to the total number of subjects in the population.

34
 Table S3. Representativeness of study participants7,8

Category Example

Disease, problem, or condition

under investigation Moderately to Severely Active Rheumatoid Arthritis (RA) Inadequately Controlled by Methotrexate Therapy

Special considerations related to

Sex and gender RA affects women more than men (ratio of 3:1).

Age Adult patients (RA usually manifested later 40 years)

Race or ethnic group RA affects predominantly Caucasians (White).

Geography Age of patients is about the same among countries (Western, Latin and Rest of the World), prevalence of RA in North Africa,
Middle East and Asia relatively low.

Other considerations MTX is the standard of start-up therapy and 1/3 - 1/2 received GCS

Overall representativeness of this Age distribution was the same among countries (adult patients was investigated). The proportion of Asian patients who
trial underwent randomization overall was small (1.5%), Black or African American patients was 4,0%. Health status was the same
between gender and region.

Table S4. Rheumatoid arthritis reference values of disease activity scores as per disease severity9

Scale Range RA remission Low activity Moderate RA Severe RA

DAS28CRP 0-9.4 ≤2.6 ≤3.2 > 3.2 ≤ 5.1 >5.1

CDAI 0-76 ≤2.8 ≤10 > 10 ≤ 22 > 22

SDAI 0-86 ≤3.3 ≤11 > 11 ≤ 26 > 26

Abbreviations: CDAI, Clinical Disease Activity Index; DAS28 (CRP), Disease Activity Score 28 (based on C-reactive protein data); SDAI, Simplified Disease Activity
Index
35
Table S5. Status at Week 12 for ACR20 (ITT population)

Question, n (%) OKZ 64 mg q2wk OKZ 64 mg q4wk ADA 40mg q2wk Placebo
N=464 N=479 N=462 N=243
How many didn’t complete 12 weeks?
(Including patients who discontinued treatment at 26 (5.6) 29 (6.1) 34 (7.4) 26 (10.7)
week 12)
How many didn’t complete 12 weeks?
(Patients discontinued treatment before week 12 (not 24 (5.2) 21 (4.4) 31 (6.7) 23 (9.5)
including week 12)

How many are non-responders? 138 (29.7) 137 (28.6) 153 (33.1) 135 (55.6)

How many were imputed? 59 (12.7) 56 (11.7) 67 (14.5) 42 (17.3)

Abbreviations: ADA, adalimumab; ITT, intention-to-treat; n, number of subjects; N, total number of subjects in the population; OKZ, olokizumab; q2wk, every 2 weeks;
q4wk, every 4 weeks; %, percentage of subjects calculated relative to the total number of subjects in the population.

36
 Table S6. ACR20 response rates by visit and treatment (ITT population)
Analysis (visit) OKZ 64 mg q4wk OKZ 64 mg q2wk ADA 40 mg q2wk Placebo
N = 479 N = 464 N=462 N=243
Week 8 (visit 7), Nx (%) 479 (100.0) 479 (100.0) 462 (100.0) 243 (100.0)
n (%) 317 (66.2) 318 (68.5) 302 (65.4) 93 (38.3)
Comparison vs. PBO risk difference (97.5% CI/95% CI)1 0.279 [0.192, 0.361] 0.303 [0.215, 0.384] 0.271 [0.194, 0.343]
Comparison vs ADA risk difference 97.5% CI 0.008 [-0.061, 0.077] 0.032 [-0.038, 0.100]
Week 12 (visit 9), Nx (%) 479 (100.0) 479 (100.0) 462 (100.0) 243 (100.0)
n (%) 342 (71.4) 326 (70.3) 309 (66.9) 108 (44.4)
Comparison vs. PBO risk difference (97.5% CI/95% CI)1 0.270 [0.183, 0.362] 0.268 [0.171, 0.341] 0.224 [0.148, 0.298]
P-value <0.0001 <0.0001 <0.0001
Comparison vs ADA 0.045 0.034
risk difference 97.5% CI -0.022, 0.112 -0.035, 0.102
Non-inferiority Achieved? Yes Yes

Note: Subjects discontinuing the treatment or the study are considered nonresponders; 197.5% CI was calculated for comparison of OKZ vs PBO, 95% CI was calculated for
comparison of ADA vs PBO.
Abbreviations: ACR20: American College of Rheumatology 20%; ADA, adalimumab; CI, confidence interval; ITT: Intent-to-Treat: OKZ: olokizumab; q2wk, every 2
weeks; q4wk, every 4 weeks.
Note: N = Number of subjects in the analysis population: Nx = Number of subjects contributing to the analysis at the corresponding time point; n = Number of responders;
% = For Nx the percentage of subjects is calculated relative to the total number of subjects in the population (N). For n the percentage is calculated relative to Nx.
Note: Intermediate missing data are imputed using surrounding visits.
Note: Response is calculated relative to baseline, the last available assessment prior to the first dose of the study treatment.
Note: Confidence Interval is calculated using Newcombe hybrid score method.
Note: P-values are 1-sided p-values from 2x2 chi-square test.
Note: Non-Inferiority for each OKZ dosing regimen versus Adalimumab is achieved if the lower limit of the 97.5% confidence interval is greater than the protocol defined
non-inferiority margin of -12%.

37
 Table S7. ACR20 response rate at Week 12 by visit, treatment and region (ITT population)

OKZ 64 mg q2wk OKZ 64 mg q4wk ADA 40mg q2wk PBO

N=464 N=479 N=462 N=243
Western
Nx (%) 148 (31.9) 162 (33.8) 152 (32.9) 86 (35.4)
n (%) 96 (64.9) 106 (65.4) 100 (65.8) 30 (34.9)
1
Comparison vs PBO risk difference (97.5% CI/95% CI) 30.0 [14.8, 43.2] 30.5 [15.7, 43.5] 30.9 [17.8, 42.5]
Comparison vs ADA risk difference 97.5% CI -0.9 [-13.1, 11.2] -0.4 [-12.2, 11.6]
Latin America
Nx (%) 155 (33.4) 158 (33.0) 148 (32.0 78 (32.1)
n (%) 110 (71.0) 114 (72.2) 97 (65.5) 43 (55.1)
1
Comparison vs PBO risk difference (97.5% CI/95% CI) 15.8 [1.1, 30.4] 17.0 [2.3, 31.5] 10.4 [-2.8, 23.6]
Comparison vs ADA risk difference 97.5% CI 5.4 [-6.5, 17.2] 6.6 [-5.2, 18.3]
Rest of the World
Nx (%) 161 (34.7) 159 (33.2) 162 (35.1) 79 (32.5)
n (%) 120 (74.5) 122 (76.7) 112 (69.1) 35 (44.3)
Comparison vs PBO risk difference (97.5% CI/95% CI)1 30.2 [15.2, 43.9] 32.4 [17.5, 46.0] 24.8 [11.6, 37.2]
Comparison vs ADA risk difference 97.5% CI 5.4 [-5.8, 16.4] 7.6 [-3.5, 18.5]
Notes: 197.5% CI was calculated for comparison of OKZ vs PBO, 95% CI was calculated for comparison of ADA vs PBO. Percentage for Nx is calculated relative to the
total number of subjects in the population, percentage for n is calculated relative to Nx.
Abbreviations: ACR20, American College of Rheumatology 20% improvement response criteria; ADA, adalimumab; CI, confidence interval; ITT, intent-to-treat; N,
number of subjects in the analysis population; Nx, number of subjects contributing to the analysis at the corresponding time point; n, number of responders; OKZ,
olokizumab; PBO, placebo; q2wk, every 2 weeks; q4wk, every 4 weeks.

38
 Table S8. ACR20 response rate at Week 12 by anti-CCP and RF status (ITT population)
OKZ 64 mg q2wk OKZ 64 mg q4wk ADA 40mg q2wk PBO
N=464 N=479 N=462 N=243
RF+ (≥ 20 IU/ml)
Nx (%) 352 (75.9) 355 (74.1) 343 (74.2) 181 (74.5)
n (%) 254 (72.2) 260.(73.2) 236 68.8) 77(42.5)
Comparison vs. PBO risk difference (97.5% CI/95% CI)1 29.6 [19.6, 39.0] 30.7 [20.7, 40.0] 26.3 [17.4, 34.7]
p-value <0.001 <0.001 <0.001
Comparison vs. ADA risk difference 97.5% CI 3.4 [-4.4, 11.1] 4.4 [-3.3, 12.1]
Anti-CCP+ (> 10 IU/ml)
Nx (%) 355 (76.5) 361 (75.4) 324 (70.1) 188 (77.4)
n (%) 257 (72.4) 262 (72.6) 225 (69.4) 85 (45.2)
Comparison vs. PBO risk difference (97.5% CI/95% CI)1 27.2 [17.3, 36.5] 27.4 [17.5, 36.7] 24.2 [15.4, 32.7]
p-value <0.001 <0.001 <0.001
Comparison vs ADA risk difference 97.5% CI 2.9 [-4.8, 10.7] 3.1 [-4.6, 10.9]
Either RF+ and/or Anti-CCP+
Nx (%) 383 (82.5) 391 (81.6) 367 (79.4) 203 (83.5)
n (%) 277 (72.3) 286 (73.1) 251 (68.4) 90 (44.3)
Comparison vs. PBO risk difference (97.5% CI/95% CI)1 28.0 [18.5, 37.0] 28.8 [19.3, 37.7] 24.1 [15.6, 32.1]
p-value <0.001 <0.001 <0.001
Comparison vs ADA risk difference 97.5% CI 3.9 [-3.5, 11.4] 4.8 [-2.6, 12.1]
Both RF+ and Anti-CCP+
Nx (%) 324 (69.8) 325 (67.8) 300 (64.9) 166 (68.3)
n (%) 234 (72.2) 236 (72.6) 210 (70.0) 72 (43.4)
Comparison vs. PBO risk difference (97.5% CI/95% CI)1 28.8 [18.4, 38.6] 29.2 [18.8, 39.0] 26.6 [17.3, 35.4]
p-value <0.001 <0.001 <0.001
Comparison vs ADA risk difference 97.5% CI 2.2 [-5.9, 10.3] 2.6 [-5.5, 10.7]
Seronegative
Nx (%) 79 (17.0) 87 (18.2) 95 (20.6) 40 (16.5)
n (%) 49 (62.0) 56 (64.4) 58 (61.1) 18 (45.0)

39
 OKZ 64 mg q2wk OKZ 64 mg q4wk ADA 40mg q2wk PBO
N=464 N=479 N=462 N=243
Comparison vs. PBO risk difference [97.5% CI/95% CI]* 17.0 [-4.3,36.6] 19.4 [-1.6, 38.5] 16.1 [-2.1, 33.0]
p-value 0.038 0.020 0.043
Comparison vs ADA risk difference 97.5% CI 1.0 [-15.4, 17.0] 3.3 [-12.6, 18.0]
Notes: 197.5% CI was calculated for comparison of OKZ vs PBO, 95% CI was calculated for comparison of ADA vs PBO. Percentage for Nx is calculated relative to
the total number of subjects in the population, percentage for n is calculated relative to Nx, p-values are 1-sided p-values from 2x2 chi-square test.
Abbreviations: ACR20, American College of Rheumatology 20% improvement response criteria; ADA, adalimumab; Anti-CCP, anti-cyclic citrullinated peptide; CI,
confidence interval; ITT, intent-to-treat; N, number of subjects in the analysis population; Nx, number of subjects contributing to the analysis at the corresponding time
point; n, number of responders; OKZ, olokizumab; PBO, placebo; q2wk, every 2 weeks; q4wk, every 4 weeks; RF, rheumatoid factor.

40
Table S9. ACR20 response rate at Week 12 by time since diagnosis (ITT population)
OKZ 64 mg q2wk OKZ 64 mg q4wk ADA 40mg q2wk Placebo
N=464 N=479 N=462 N=243
0 to < 2 Years
Nx (%) 127 (27.4) 123 (25.7) 130 (28.1) 70 (28.8)
n (%) 90 (70.9) 90 (73.2) 83 (63.8) 34 (48.6)
Comparison vs. PBO risk difference (97.5% CI/95% CI)1 22.3 [6.1, 37.5] 24.6 [8.3, 39.7] 15.3 [1.0, 29.0]
p-value <0.001 <0.001 0.018
Comparison vs ADA risk difference 97.5% CI 7.0 [-6.0, 19.7] 9.3 [-3.8, 21.9]
≥ 2 to < 5 Years
Nx (%) 111 (23.9) 116 (24.2) 112 (24.2) 57 (23.5)
n (%) 83 (74.8) 76 (65.5) 82 (73.2) 29 (50.9)
Comparison vs. PBO risk difference (97.5% CI/95% CI)1 23.9 [6.5, 40.3] 14.6 [-2.9, 31.6] 22.3 [7.0, 36.9]
p-value <0.001 0.032 0.002
1.6 -7.7
Comparison vs ADA risk difference 97.5% CI
[-11.5, 14.6] [-20.9, 6.0]
≥ 5 Years
Nx (%) 224 (48.3) 240 (50.1) 220 (47.6) 116 (47.7)
n (%) 153 (68.3) 176 (73.3) 144 (65.5) 45 (38.8)
Comparison vs. PBO risk difference (97.5% CI/95% CI)1 29.5 [16.8, 41.0] 34.5 [22.1, 45.7] 26.7 [15.5, 36.9]
p-value <0.001 <0.001 <0.001
Comparison vs ADA difference 97.5% CI 2.8 [-7.1, 12.7] 7.9 [-1.7, 17.4]
Notes: 197.5% CI was calculated for comparison of OKZ vs PBO, 95% CI was calculated for comparison of ADA vs PBO. Percentage for Nx is calculated relative
to the total number of subjects in the population, percentage for n is calculated relative to Nx, p-values are 1-sided p-values from 2x2 chi-square test.
Abbreviations: ACR20, American College of Rheumatology 20% improvement response criteria; ADA, adalimumab; CI, confidence interval; ITT, intent-to-treat;
N, number of subjects in the analysis population; Nx, number of subjects contributing to the analysis at the corresponding time point; n, number of responders; OKZ,
olokizumab; PBO, placebo; q2wk, every 2 weeks; q4wk, every 4 weeks.

41
Table S10. Main efficacy results for other endpoints (ITT population)
OKZ 64 mg q2wk OKZ 64 mg q4wk ADA 40mg q2wk PBO
N=464 N=479 N=462 N=243
DAS28 (CRP) <2.6†week 24, n (%) 148 (31.9) 168 (35.1) 132 (28.6) 26 (10.7)

Comparison vs. PBO risk difference (97.5% CI/95% CI)1 21.2 [14.2; 27.4]# 24.4 [17.3; 30.6]# 17.9 [11.9; 23.3]#

CDAI <10, n (%) week 242 211 (45.5) 224 (46.8) 227 (49.1) 59 (24.3)

Comparison vs. PBO risk difference (97.5% CI/95% CI)1 21.2 [12.8; 28.8]# 22.5 [14.1; 30.1]# 24.8 [17.5; 31.6]#

ACR70 response, n (%) week 24 133 (28.7) 129 (26.9) 119 (25.8) 27 (11.1)

Comparison vs. PBO risk difference (97.5% CI/95% CI)1 17.6 [10.6; 23.7]# 15.8 [9.0; 21.9]# 14.7 [8.7; 20.0]#

HAQ-DI <0.5, n (%) week 122 87 (18.8) 80 (16.7) 80 (17.3) 32 (13.2)

Comparison vs. PBO risk difference (97.5% CI/95% CI) 1 5.6 [-0.3; 10.9]* 3.5 [-3.1; 9.4] 4.1 [-1.6; 9.4]

HAQ-DI improvement of ≥0.22, n (%) week 12 322 (69.4) 340 (71.0) 313 (67.7) 130 (53.5)

Comparison vs. PBO risk difference (97.5% CI/95% CI)1 15.9 [7.3; 24.4]# 17.5 [8.9; 25.9]# 14.2 [6.5; 21.6]#

Footnotes: 1Risk difference in percentage points; 97.5% CI was calculated for comparison of OKZ vs. PBO; 95% CI was calculated for comparison of ADA vs. PBO;
†p≤0.05, ⱡp<0.001; #p<0.0001 compared with placebo.
Abbreviations: ACR, American College of Rheumatology response; ADA, adalimumab; CDAI, Clinical Disease Activity Index; CI, confidence interval; CRP, C-
reactive protein; DAS28-CRP, Disease Activity Score 28 based on CRP; HAQ-DI, Health Assessment Questionnaire Disability Index; NRI, non-responder imputation;
N, number of subjects; n, number of responders; OKZ, olokizumab; PBO, placebo; q2wk, every 2 weeks; q4wk, every 4 weeks; SE, standard error; Wk, week

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 Table S11. Treatment-emergent adverse events (safety population)
System Organ Class OKZ 64 mg q2wk OKZ 64 mg q4wk ADA 40 mg q2wk Placebo
Preferred Term (more than 4% in any group), n (%) N=463 N=477 N=462 N=243
Subjects with at Least One TEAE 324 (70.0) 338(70.9) 302(65.4) 154(63.4)
Infections and infestations 140 (30.2) 162 (34.0) 148 (32.0) 84 (34.6)
Nasopharyngitis 29 (6.3) 26 (5.5) 29 (6.3) 18 (7.4)
Upper respiratory tract infection 28 (6.0) 29 (6.1) 26 (5.6) 16 (6.6)
Urinary tract infection 7 (1.5) 14 (2.9) 20 (4.3) 9 (3.7)
Bronchitis 12 (2.6) 10 (2.1) 12 (2.6) 11 (4.5)
Investigations 108 (23.3) 127 (26.6) 53 (11.5) 26 (10.7)
ALT increased 42 (9.1) 53 (11.1) 9 (1.9) 4 (1.6)
AST increased 23 (5.0) 24 (5.0) 8 (1.7) 2 (0.8)
Metabolism and nutrition disorders 93 (20.1) 62 (13.0) 38 (8.2) 17 (7.0)
Hypercholesterolaemia 29 (6.3) 20 (4.2) 6 (1.3) 3 (1.2)
Dyslipidaemia 25 (5.4) 15 (3.1) 4 (0.9) 4 (1.6)
Hyperlipidaemia 22 (4.8) 10 (2.1) 5 (1.1) 2 (0.8)

Gastrointestinal disorders 57 (12.3) 55 (11.5) 53 (11.5) 21 (8.6)

Musculoskeletal and connective tissue disorders 46 (9.9) 48 (10.1) 60 (13.0) 21 (8.6)
General disorders and administration site conditions 35 (7.6) 34 (7.1) 54 (11.7) 17 (7.0)
Injection site erythema 8 (1.7) 8 (1.7) 20 (4.3) 2 (0.8)
Blood and lymphatic system disorders 42 (9.1) 38 (8.0) 28 (6.1) 19 (7.8)

43
System Organ Class OKZ 64 mg q2wk OKZ 64 mg q4wk ADA 40 mg q2wk Placebo
Preferred Term (more than 4% in any group), n (%) N=463 N=477 N=462 N=243
Skin and subcutaneous tissue disorders 44 (9.5) 37 (7.8) 22 (4.8) 15 (6.2)
Nervous system disorders 34 (7.3) 22 (4.6) 28 (6.1) 19 (7.8)
Headache 10 (2.2) 11 (2.3) 14 (3.0) 12 (4.9)
Vascular disorders 30 (6.5) 43 (9.0) 20 (4.3) 10 (4.1)
Hypertension 25 (5.4) 28 (5.9) 13 (2.8) 8 (3.3)
Respiratory, thoracic and mediastinal disorders 27 (5.8) 28 (5.9) 34 (7.4) 11 (4.5)

Injury, poisoning and procedural complications 27 (5.8) 27 (5.7) 20 (4.3) 13 (5.3)

Notes: AEs were collected from the signature of the informed consent form until the last visit of the subject in the study (up to 22 weeks after the last dose of study
treatment, thus up to approximately 44 weeks). A TEAE was defined as an AE that first occurred or worsened in severity after the first dose of the study treatment;
%, percentage of subjects calculated relative to the total number of subjects in the population.
MedDRA, Medical Dictionary for Regulatory Activities (Version 21.1) was used to code AEs.
Abbreviations: ADA, adalimumab; AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; MACE, Major Adverse Cardiac Events;
MedDRA, Medical Dictionary for Regulatory Activities; N, number of subjects; n, number of subjects with events; OKZ, olokizumab; PBO, placebo; q2wk, every 2
weeks; q4wk, every 4 weeks; TEAE, treatment-tmergent adverse event.

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 Table S12. Key serious treatment-emergent adverse events (safety population)
OKZ 64 mg q2wk OKZ 64 mg q4wk ADA 40 mg q2wk Placebo
Number of subjects (%)
N=463 N=477 N=462 N=243
Subjects with at least one key TESAE 22 (4.8) 20 (4.2) 26 (5.6) 12 (4.9)
Serious Infections 6 (1.3) 7 (1.5) 16 (3.5) 4 (1.6)
Pneumonia 1 (0.2) 1 (0.2) 6 (1.3) 0
Sepsis 1 (0.2) 1 (0.2) 2 (0.4) 0
Urosepsis 0 0 2 (0.4) 2 (0.8)
Cellulitis 0 2 (0.4) 0 0
Urinary tract infection 0 0 2 (0.4) 0
Herpes zoster 0 0 1 (0.2) 0
Pulmonary tuberculosis 0 1 (0.2) 0 0
Neoplasms benign, malignant and unspecified (incl. cysts and
3 (0.6) 2 (0.4) 2 (0.4) 3 (1.2)
polyps)
Investigations 3 (0.6) 2 (0.4) 1 (0.2) 2 (0.8)
ALT increased 1 (0.2) 2 (0.4) 1 (0.2) 0
Transaminases increased 2 (0.4) 0 0 1 (0.4)
General disorders and administration site conditions 2 (0.4) 1 (0.2) 1 (0.2) 1 (0.4)

Hepatobiliary disorders* 2 (0.4) 2 (0.4) 0 1 (0.4)

Nervous system disorders 3 (0.6) 0 2 (0.4) 0
Vascular disorders 2 (0.4) 2 (0.4) 1 (0.2) 0

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 OKZ 64 mg q2wk OKZ 64 mg q4wk ADA 40 mg q2wk Placebo
Number of subjects (%)
N=463 N=477 N=462 N=243
Cardiac disorders 0 2 (0.4) 2 (0.4) 0
Respiratory, thoracic and mediastinal disorders 1 (0.2) 0 3 (0.6) 0
Interstitial lung disease 0 0 2 (0.4) 0
Gastrointestinal disorders 1 (0.2) 0 2 (0.4) 0
Musculoskeletal and connective tissue disorders 1 (0.2) 0 2 (0.4) 0
A TEAE Leading to death** 3 (0.6) 2 (0.4) 1 (0.2) 1 (0.4)
Subjects with at least one MACE*** 4 (0.9) 2 (0.4) 2 (0.4) 1 (0.4)

Notes: *One cholecystitis (0.2%) and one cholelytiasis (0.2%) in OKZ q2w; one hepatotoxicity (0.2%) and one hepatic steatosis (0.2%) in OKZ q4w; one
hepatotoxicity (0.4%) in PBO.
**Cerebrovascular accident (stroke) 1(0.2%), infections and infestations (sepsis 1, septic shock 1) 2 (0.4%) in OKZ q2w; infections and infestations (sepsis) 1(0.2%),
cardiac disorders (MI) 1 (0.2%) in OKZ q4w; infections and infestations (sepsis) 1 (0.2%) in ADA and sudden death 1 (0.4%) in PBO.
***One fatal cerebrovascular accident (stroke) (0.2%), one death due to undetermined cause (0.2%), two non-fatal strokes/ TIAs (0.6%) in OKZ q2w; one
cardiovascular death (0.2%) and non-fatal MI (0.2%) in OKZ q4w; two non-fatal strokes/ TIAs (0.4%) in ADA; one cardiovascular death (0.4%) in PBO.
AEs were collected from the signature of the informed consent form until the last visit of the subject in the study (up to 22 weeks after the last dose of study treatment,
thus up to approximately 44 weeks). A TEAE was defined as an AE that first occurred or worsened in severity after the first dose of the study treatment; %, percentage
of subjects calculated relative to the total number of subjects in the population.
Abbrviations: ADA, adalimumab; AE, adverse event; ALT, alanine aminotransferase; MACE, major adverse cardiac events; MI, myocardial infarction; N, number
of subjects; n, number of subjects with events; OKZ, olokizumab; PBO, placebo; q2wk, every 2 weeks; q4wk, every 4 weeks; TEAE, treatment-emergent adverse
event; TESAE, treatment-emergent serious adverse event; TIA, transient ischemic attack.
Definition: MACEs were defined as cardiovascular death, death from undetermined cause, non-fatal myocardial infarction, non-fatal stroke or transient ischemic
attack, hospitalization for unstable angina requiring unplanned revascularization, and coronary revascularization procedures.

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 Table S13. Selected hematology assessments outside of the normal ranges (safety population)
Number of patients, n (%) OKZ 64 mg q2wk OKZ 64 mg q4wk ADA 40 mg q2wk Placebo
N=463 N=477 N=462 N=243
WBC count < 4000/mm3 Nх (%) 463 (100.0) 475 (99.6) 462 (100.0) 243 (100.0)
Baseline
(or < 4 ·109/L) n (%) 3 (0.6) 4 (0.8) 4 (0.9) 5 (2.1)
Nx (%) 427 (92.2) 437 (91.6) 418 (90.5) 213 (87.7)
Wk 12
n (%) 42 (9.1) 36 (7.5) 7 (1.5) 3 (1.2)
Nх (%) 407 (87.9) 411 (86.2) 389 (84.2) 198 (81.5)
Wk 24
n (%) 39 (8.4) 40 (8.4) 7 (1.5) 2 (0.8)
ANC count < 1500/mm3 Nх (%) 463 (100.0) 475 (99.6) 462 (100.0) 243 (100.0)
Baseline
(or < 1.5 ·109/L) n (%) 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.4)
Nх(%) 426 (92.0) 433 (90.8) 416 (90.0) 213 (87.7)
Wk 12
n(%) 16 (3.5) 11 (2.3) 2 (0.4) 1 (0.4)
Nх (%) 406 (87.7) 411 (86.2) 387 (83.8) 198 (81.5)
Wk 24
n (%) 10 (2.2) 13 (2.7) 1 (0.2) 0 (0.0)
ANC count < 1000/mm 3
Nх (%) 463 (100.0) 475 (99.6) 462 (100.0) 243 (100.0)
Baseline
(or < 1.0 ·109/L) n (%) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Nх (%) 426 (92.0) 433 (90.8) 416 (90.0) 213 (87.7)
Wk 12
n (%) 1 (0.2) 0 (0.0) 0 (0.0) 0 (0.0)
Nх (%) 406 (87.7) 411 (86.2) 387 (83.8) 198 (81.5)
Wk 24
n (%) 1 (0.2) 1 (0.2) 0 (0.0) 0 (0.0)
ALC count < 500/mm3 Nх (%) 463 (100.0) 475 (99.6) 462 (100.0) 243 (100.0)
Baseline
(or < 0.5 ·10 /L)
9
n (%) 0 (0.0) 0 (0.0) 2 (0.4) 1 (0.4)
Wk 12 Nх (%) 426 (92.0) 433 (90.8) 416 (90.0) 213 (87.7)

47
Number of patients, n (%) OKZ 64 mg q2wk OKZ 64 mg q4wk ADA 40 mg q2wk Placebo
N=463 N=477 N=462 N=243
n (%) 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.4)
Nх (%) 406 (87.7) 411 (86.2) 387 (83.8) 198 (81.5)
Wk 24
n (%) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Hb ≤80 g/L Nх (%) 463 (100.0) 476 (99.8) 462 (100.0) 243 (100.0)
Baseline
n (%) 1 (0.2) 0 1 (0.2) 0
Nх (%) 428 (92.4) 440 (92.2) 422 (91.3) 215 (88.5)
Wk 12
n (%) 0 0 0 1 (0.4)
Nх (%) 409 (88.3) 411 (86.2) 391 (84.6) 200 (82.3)
Wk 24
n (%) 0 0 0 1(0.4)

Notes: percentage of subjects with non-missing results was calculated relative to the total number of subjects in the population. Percentage of subjects with abnormal
parameters was calculated relative to the number of subjects with non-missing results at a given visit.
Abbreviations: ADA, adalimumab; ALC, absolute lymphocyte count; ANC, absolute neutrophil count; Hb, hemoglobin; N, number of subjects in the arm; Nx(%),
number and percent of the subjects with non-missing results; n(%), number and percent of the subjects with abnormal parameters; OKZ, olokizumab; PBO, placebo;
q2wk, every 2 weeks; q4wk, every 4 weeks; WBC, white blood cells; Wk, week.

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 Table S14. Selected chemistry assessments outside of the normal ranges (safety population)
OKZ 64 mg q2wk OKZ 64 mg q4wk ADA 40 mg q2wk Placebo
Number of
N=463 N=477 N=462 N=243
Nx 463 (100.0) 477 (100.0) 462 (100.0) 243 (100.0)
ALT >1x ULN to ≤ 3x ULN 43 (9.3) 58 (12.2) 37 (8.0) 21 (8.6)
ALT, n (%) BL
> 3x ULN to ≤ 5x ULN 1 (0.2) 0 (0.0) 2 (0.4) 1 (0.4)
> 5x ULN 1 (0.2) 0 (0.0) 0 (0.0) 0 (0.0)
Nx 463 (100.0) 477 (100.0) 461 (99.8) 243 (100.0)
ALT, n (%) ALT >1x ULN to ≤ 3x ULN 247 (53.3) 250 (52.4) 153 (33.2) 75 (30.9)
post-BL worst case > 3x ULN to ≤ 5x ULN 34 (7.3) 30 (6.3) 11 (2.4) 2 (0.8)
> 5x ULN 8 (1.7) 10 (2.1) 3 (0.7) 3 (1.2)
Nx 463 (100.0) 477 (100.0) 462 (100.0) 243 (100.0)
Total bilirubin, n (%) BL > 2x ULN 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
> 3x ULN 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Total bilirubin, n (%) Nx 463 (100.0) 477 (100.0) 461 (99.8) 243 (100.0)
post-BL worst case > 2x ULN 4 (0.9) 4 (0.8) 0 (0.0) 1 (0.4)
Nx 459 (99.1) 473 (99.2) 458 (99.1) 237 (97.5)
Cholesterol, n (%) BL
High 174 (37.9) 177 (37.4) 191 (41.7) 92 (38.8)
Cholesterol, n (%) Post-BL Nx 459 (99.1) 474 (99.4) 459 (99.4) 243 (100.0)
High 346 (75.4) 357 (75.3) 295 (64.3) 129 (53.1)
Wk 12, n (%) 126 ( 29.2) 126 ( 28.8) 64 ( 15.2) 17 ( 8.1)
Cholesterol shifts from normal
Mean change, mmol/L, (SD) 1.31 (0.66) 1.40 (0.87) 0.90 (0.56) 0.67 (0.50)
to high
Wk 24, n (%) 122 ( 30.3) 109 ( 26.6) 66 ( 16.8) 21 ( 10.6)

49
 OKZ 64 mg q2wk OKZ 64 mg q4wk ADA 40 mg q2wk Placebo
Number of
N=463 N=477 N=462 N=243
Mean change, mmol/L, (SD) 1.39 (0.73) 1.32 (0.69) 0.98 (0.57) 0.81 (0.74)
Nx 459 ( 99.1) 473 ( 99.2) 458 ( 99.1) 237 ( 97.5)
LDL Cholesterol, n (%) BL
High 101 ( 22.0) 119 ( 25.2) 113 ( 24.7) 50 ( 21.1)

LDL Cholesterol, n (%) Post- Nx 459 ( 99.1) 474 ( 99.4) 459 ( 99.4) 243 (100.0)
BL High 259 ( 56.4) 272 ( 57.4) 200 ( 43.6) 81 ( 33.3)
Wk 12, n (%) 97 ( 22.6) 99 ( 22.7) 46 ( 11.0) 13 ( 6.2)
LDL Cholesterol shifts from Mean change, mmol/L, (SD) 1.06 (0.58) 1.15 (0.85) 0.88 (0.49) 0.60 (0.26)
normal to high Wk 24, n (%) 96 ( 23.9) 87 ( 21.3) 51 ( 13.0) 19 ( 9.6)
Mean change, mmol/L,(SD) 1.18 (0.60) 1.08 (0.53) 0.91 (0.50) 0.77 (0.61)
Notes: there were no subjects with concomitant elevations of ALT or AST ≥3xULN and bilirubin ≥2xULN. Percentage of subjects with non-missing results (Nx) was
calculated relative to the total number of subjects in the population. All other percentages of subjects were calculated relative to the number of subjects with non-missing
results at a given visit.
Abbreviations: ADA, adalimumab; ALT, alanine aminotransferase; BL, baseline; LDL, low density lipoproteins; N, number of subjects in the population; Nx, number
of the subjects with non-missing results; n(%), number and percent of the subjects with abnormal parameters; OKZ, olokizumab; PBO, placebo; q2wk, every 2 weeks;
q4wk, every 4 weeks; SD, standard deviation; ULN, upper limit of normal; Wk, week.

50
 Contributorship

CJSC R-Pharm was involved in the study design, collection, analysis, interpretation of data, and
validation of information provided in the manuscript. EN, MS, SF, and EK were involved in study
conceptualization and data analysis. All authors had unrestricted access to the study data, contributed
to the interpretation of the results and participated in the development of this manuscript. The authors
did not receive honoraria related to the development of this manuscript. All authors were responsible
for all the content and editorial decisions. The authors meet the authorship criteria recommended by
the International Committee of Medical Journal Editors (ICMJE).

Medical writing assistance, under the direction of the authors, and editorial support, including
development of the first draft, were provided by Sofia Kuzkina according to CONSORT 2010
Statement: updated guidelines for reporting parallel-group randomized trials
(https://www.bmj.com/content/340/bmj.c332) and Good Publication Practice guidelines.

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