Conditions: Rheumatoid Arthritis
Keywords: Rheumatoid Arthritis moderate severe subcutaneous Olokizumab open-label
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2106
Healthy volunteers: no

Brief summary:
The primary objective of this study was to evaluate the long-term safety and tolerability of olokizumab (OKZ) 64 mg administered subcutaneously (SC) once every 2 weeks (q2w) or once every 4 weeks (q4w) in subjects with moderately to severely active rheumatoid arthritis (RA) who previously had completed 24 weeks of double-blind treatment in Study CREDO 1, 2 or 3 (core studies). The long-term efficacy, immunogenicity, the physical function and quality of life of subjects received long-term treatment with OKZ were assessed as well.

Detailed description:
This OLE study (CL04041024) included an 82-week open-label Treatment Period that followed completion of one of the core studies (Study CREDO 1, 2 or 3). The OLE open-label Treatment Period lasted from Visit 1 (OLE Baseline/Week 24) to Visit 10 (End of Treatment (EoT)/Week 106), followed by a 20-week Safety Follow-Up Period from Week 106 to Week 126. The first visit of the OLE study was the same visit as the Week 24 visit in the core studies.

Subjects were randomized to 1 of the 2 OKZ treatment groups in the OLE study based on the treatment received in the core studies. Subjects who had received OKZ (q2w or q4w) in the core study in which they had participated (including subjects who received placebo in Study CREDO 3 and were re-randomized to OKZ at Week 16) received the same OKZ treatment regimen in the OLE study. Subjects who had received placebo (Study CREDO 1 and CREDO 2) or adalimumab (Study CREDO 2) in the core study in which they had participated were randomized in a 1:1 ratio to OKZ 64 mg q2w or OKZ 64 mg q4w regimens in the OLE study.

For the first 12 weeks of the OLE, all subjects were required to remain on a stable dose of background methotrexate (MTX) at 15 to 25 mg/week (or≥10 mg/week if there was documented intolerance to higher doses) with a stable route of administration (oral, SC, or intramuscular (IM)). After 12 weeks (Visit 4 \[Week 36\] of the OLE study), the Investigator might adjust the MTX dosage and route, per local guidelines. Methotrexate might be adjusted only for safety reasons according to Investigator discretion before Visit 4 (Week 36) of the OLE study.

Subjects who had been on rescue disease-modifying anti-rheumatic drugs (DMARDs) during the core studies were asked to continue these medications for the first 12 weeks of the OLE study. The Investigator could adjust these background medications if deemed appropriate after Visit 4 (Week 36) of the OLE study. Background rescue therapy might be adjusted only for safety reasons according to Investigator discretion before Visit 4 (Week 36) of the OLE study.

Throughout the study, concomitant treatment with folic acid ≥ 5 mg per week or equivalent was required for all subjects.

Subjects returned to the study site periodically for safety and response assessments as per the Schedule of Events.

The last dose of open-label study treatment in the OLE study was administered at Week 104 for all subjects. After completion of the 82-week open-label Treatment Period, subjects entered the 20-week Safety Follow-Up Period. During the Safety Follow-Up Period, subjects returned for 3 visits at +4, +8, and +22 weeks after the last dose of study treatment.

Subjects who discontinued the open-label treatment prematurely required to come for the EoT Visit 2 weeks after the last study treatment administration and then return for the 3 Safety Follow-Up Visits +4, +8, and +22 weeks after the last study treatment administration.

Adverse events were assessed throughout the study period and evaluated using the Common Technology Criteria version 4.0 (CTCAE v 4.0).

There were ongoing monitoring of safety events, including laboratory findings by the Sponsor or its designee. In addition, safety parameters were assessed throughout the study by an independent Data Safety Monitoring Board (DSMB).

Arms:
arm 1: Olokizumab 64 mg SC q4w + concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular). arm 2: Olokizumab 64 mg SC q2w + concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular).

Interventions: intervention 1: Olokizumab 64 mg SC q4w intervention 2: Olokizumab 64 mg SC q2w intervention 3: Concomitant treatment
Intervention descriptions: intervention 1: 160 mg/mL sterile solution for SC injection in a 2 mL clear Type I glass vial with target volume of 0.4 mL or in the pre-filled syringe (PFS).PFS is composed of a 1 mL clear Type I glass barrel vial with target volume of 0.4 mL. intervention 2: 160 mg/mL sterile solution for SC injection in a 2 mL clear Type I glass vial with target volume of 0.4 mL or in the pre-filled syringe (PFS). PFS is composed of a 1 mL clear Type I glass barrel vial with target volume of 0.4 mL. intervention 3: Methotrexate 15 to 25 mg/week (or ≥ 10 mg/week if there was documented intolerance to higher doses). (Subject maintained their stable dose and route (oral, SC, or IM) during the core study and for ≥ 12 additional weeks of OLE.)

Folic acid ≥ 5 mg per week or equivalent

Protocol document:
Prot_SAP_000.pdf: 
R-Pharm International 
CL04041024:  Clinical Rheumatoid Arthritis Development for Olokizumab (CREDO) 4 
Olokizumab 
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Clinical Study Protocol 
Protocol Title: 
A Multicenter, Open-Label, Phase III Study of the 
Efficacy and Safety of Olokizumab in Subjects with 
Moderately to Severely Active Rheumatoid Arthritis 
Protocol Number: 
CL04041024:  Clinical Rheumatoid Arthritis 
Development for Olokizumab (CREDO) 4 
Date of Protocol: 
 
 
06 March 2019 
Version of Protocol: 
 
 
Amendment 2 
Product: 
Olokizumab (CDP6038; L04041)  
IND No: 
104933 
EudraCT No: 
2015-005309-35 
Study Phase: 
III 
Sponsor: 
R-Pharm International 
19-1, Berzarina Street, Moscow 
Russian Federation 123154 
 
 
 
 
 
 
Confidentiality Statement 
The confidential information in this document is provided to you as an Investigator or 
consultant for review by you, your staff, and the applicable Institutional Review 
Board/Independent Ethics Committee.  The acceptance of this document constitutes 
agreement that you will not disclose the information contained herein to others without 
written authorization from R-Pharm International. 


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Signatures 
PROTOCOL TITLE: 
A Multicenter, Open-Label, Phase III Study of the Efficacy and 
Safety of Olokizumab in Subjects with Moderately to Severely Active Rheumatoid Arthritis 
PROTOCOL NO: 
CL04041024:  Clinical Rheumatoid Arthritis Development 
for Olokizumab (CREDO) 4 
 
 
--------------------------  
---------------------- 
 
 
--------------- 
Mikhail Samsonov  
Signature 
 
 
 
Date 
Chief Medical Officer 
 
 


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Investigator Signature Page 
PROTOCOL TITLE: 
A Multicenter, Open-label, Phase III Study of the Efficacy and 
Safety of Olokizumab in Subjects with Moderately to Severely Active Rheumatoid Arthritis 
PROTOCOL NO: 
CL04041024:  Clinical Rheumatoid Arthritis Development for 
Olokizumab (CREDO) 4 
This protocol is a confidential communication of R-Pharm International.  I confirm that I 
have read this protocol, I understand it, and I will work according to this protocol.  I will also 
work consistently with the ethical principles that have their origin in the Declaration of 
Helsinki and that are consistent with GCPs and the applicable laws and regulations.  
Acceptance of this document constitutes my agreement that no unpublished information 
contained herein will be published or disclosed without prior written approval from R-Pharm 
International. 
Instructions to the Investigator:  Please SIGN and DATE this signature page.  PRINT your 
name, title, and the name of the site in which the study will be conducted.  Return the signed 
copy to R-Pharm International’s designee. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
Signature of Investigator: 
__________________________ 
 
Date: ________ 
Printed Name:  
 
__________________________ 
Investigator Title: 
 
__________________________ 
Name/Address of Site: 
__________________________ 
 
 
 
 
__________________________ 
 
 
 
 
__________________________ 
 


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EMERGENCY CONTACTS 
24-hour emergency medical contact 
+1 512 652 0191 or  
+1 973 659 6677 or  
+3 318 699 0019 
SAE reporting 
All SAEs should be reported via the EDC 
system by completing the relevant pages of 
the eCRF. 
In the event that the EDC system is not 
functioning, SAEs must be reported to the 
following email address: 
QLS_Olokizumab@iqvia.com 
Abbreviations:  eCRF = electronic case report form; EDC = Electronic Data Capture; SAE = Serious Adverse 
Event. 


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SYNOPSIS 
Name of Sponsor 
R-Pharm International 
Name of Finished 
Product 
Olokizumab 
Name of Active 
Ingredient 
Olokizumab (CDP6038; L04041) 
Title of Study: 
A Multicenter, Open-label, Phase III Study of the Efficacy and Safety of Olokizumab in 
Subjects with Moderately to Severely Active Rheumatoid Arthritis 
Protocol No: 
CL04041024:  Clinical Rheumatoid Arthritis Development for Olokizumab (CREDO) 4 
Investigators: 
A total of approximately 250 Investigators will be involved in the conduct of this study. 
Study sites: 
The study will be conducted at approximately 250 sites across Russia, Belarus, the 
United States (US), Europe, the United Kingdom, Asia, and Latin America. 
Study duration: 
Treatment Period:  82 weeks 
Safety Follow-Up:  20 weeks 
Phase:  III 
Objectives: 
Primary: 
The primary objective of this study is to evaluate the long-term safety and tolerability of olokizumab (OKZ) 
64 mg administered subcutaneously (SC) once every 2 weeks (q2w) or once every 4 weeks (q4w) in subjects 
with moderately to severely active rheumatoid arthritis (RA) who previously completed 24 weeks of 
double-blind treatment in Study CL04041022, CL04041023, or CL04041025 (core studies). 
Secondary: 
 
To evaluate the long-term efficacy of OKZ 
 
To evaluate the long-term immunogenicity of OKZ 
 
To evaluate the physical function and quality of life of subjects receiving long-term treatment with 
OKZ 
Criteria for Evaluation: 
The following endpoints will be assessed to evaluate treatment with OKZ 64 mg administered SC q2w or q4w 
for 106 total weeks for subjects randomized to OKZ in all 3 core studies (CL04041022, CL04041023, and 
CL04041025), and for 82 total weeks for subjects randomized to placebo in the CL04041022 study and to 
placebo or adalimumab in the CL04041023 core study.  In Study CL04041025, subjects randomized to placebo 
will transition to OKZ at Week 16 and complete 8 weeks of double-blind treatment with OKZ; these subjects 
will complete 90 total weeks of treatment with OKZ. 
Safety Endpoints: 
 
The nature, incidence, severity, and outcome of adverse events (AEs), including serious adverse events 
(SAEs) and AEs of special interest (AESIs) 
 
Follow-up- adjusted incidence and event rates (per 100 subject-years of follow-up) for SAEs and 
AESIs 
 
Proportions of subjects with clinically significant laboratory abnormalities 
 
Assessment of changes over time in clinical laboratory parameters, vital sign measurements, and 
physical examination findings 
 
Time from first exposure to OKZ to the first occurrence of any major adverse cardiac event (MACE) 
 
Incidence and titer of antidrug antibodies (ADAs) to OKZ, incidence of neutralizing antibodies, and 


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the time course of antibodies 
Efficacy Endpoints: 
 
Proportion of subjects achieving an American College of Rheumatology 20% (ACR20), American 
College of Rheumatology 50% (ACR50), and American College of Rheumatology 70% (ACR70) 
response who remain on randomized open-label treatment and in the study, assessed at all applicable 
time points 
 
Proportion of subjects with Simplified Disease Activity Index (SDAI) ≤3.3 remission, who remain on 
randomized open-label treatment and in the study, assessed at all applicable time points 
 
Proportion of subjects with Disease Activity Score 28-joint count (DAS28) low disease activity (based 
on DAS28 C-reactive protein [CRP] <3.2), who remain on randomized open-label treatment and in the 
study, assessed at all applicable time points 
 
Change from baseline over time in DAS28 (CRP), assessed at all applicable time points 
 
Change from baseline over time in the measure of physical ability based on Health Assessment 
Questionnaire-Disability Index (HAQ-DI), assessed at all applicable time points 
 
Proportion of subjects with improvement from baseline in HAQ-DI score ≥0.22, who remain on 
randomized open-label treatment and in the study, assessed at all applicable time points 
 
Change from baseline over time in the scores for the following patient-reported outcomes (PRO) 
measures, assessed at all applicable time points: 
- 
Short Form-36 (SF-36) Physical Component Summary (PCS) and Mental Component Summary 
(MCS) total scores 
- 
European Quality of Life-5 Dimensions (EQ-5D) 
- 
Work Productivity Survey-Rheumatoid Arthritis (WPS-RA) 
- 
Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-Fatigue) 
 
Change from baseline over time in SDAI and Clinical Disease Activity Index (CDAI), assessed at all 
applicable time points 
 
Proportion of subjects with moderate to good responses for European League Against Rheumatism 
(EULAR) based on DAS28 (CRP), who remain on randomized open-label treatment and in the study, 
assessed at all applicable time points, where a moderate response is defined as either DAS28 (CRP) 
≤5.1 with an improvement from baseline in DAS28 (CRP) >0.6 and ≤1.2, or DAS28 (CRP) >3.2 with 
an improvement from baseline in DAS28 (CRP) >1.2, and a good response is defined as DAS28 
(CRP) ≤3.2 with an improvement from baseline in DAS28 (CRP) >1.2 
 
Change from baseline to all time points in the components of the ACR response criteria 
Immunogenicity: 
 
Evaluating the impact of ADAs to OKZ on subject safety and efficacy 
Methodology: 
This OLE study (CL04041024) includes an 82-week open-label Treatment Period following completion of 1 of 
the core studies (Study CL04041022, CL04041023, or CL04041025) from Visit 1 (OLE Baseline/Week 24) to 
Visit 10 (End of Treatment [EoT]/Week 106), followed by a 20-week Safety Follow-Up Period from Week 106 
to Week 126.  The first visit of the OLE study is the same visit as the Week 24 visit in the core studies. 
An estimated 1880 subjects will receive OKZ: 
1. OKZ 64 mg q4w:  SC injection of OKZ 64 mg q4w + methotrexate (MTX) 
2. OKZ 64 mg q2w:  SC injection of OKZ 64 mg q2w + MTX 
Subjects will be randomized to 1 of the 2 OKZ treatment groups in the OLE study based on the treatment 
received in the core studies.  Subjects who received OKZ (q2w or q4w) in the core study in which they 
participated (including subjects who received placebo in Study CL04041025 and were re-randomized to OKZ 


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at Week 16) will receive the same OKZ treatment regimen in the OLE study.  Subjects who received placebo 
(Study CL04041022 and CL04041023) or adalimumab (Study CL04041023) in the core study in which they 
participated will be randomized in a 1:1 ratio to OKZ 64 mg q2w or OKZ 64 mg q4w regimens in the OLE 
study. 
For the first 12 weeks of the OLE, all subjects will be required to remain on a stable dose of background MTX 
at 15 to 25 mg/week (or ≥10 mg/week if there is documented intolerance to higher doses) with a stable route of 
administration (oral, SC, or intramuscular [IM]).  After 12 weeks (Visit 4 [Week 36] of the OLE study), the 
Investigator may adjust the MTX dosage and route, per local guidelines. Methotrexate may be adjusted only for 
safety reasons according to Investigator discretion before Visit 4 (Week 36) of the OLE study. 
Subjects who are on rescue disease-modifying anti-rheumatic drugs (DMARDs) during the core studies will be 
asked to continue these medications for the first 12 weeks of the OLE study.  The Investigator can adjust these 
background medications if deemed appropriate after Visit 4 (Week 36) of the OLE study. Background rescue 
therapy may be adjusted only for safety reasons according to Investigator discretion before Visit 4 (Week 36) of 
the OLE study. 
Throughout the study, concomitant treatment with folic acid ≥5 mg per week or equivalent is required for all 
subjects. 
Subjects will return to the study site periodically for safety and response assessments as per the Schedule of 
Events. 
The last dose of open-label study treatment in the OLE study will be administered at Week 104 for all subjects.  
After completion of the 82-week open-label Treatment Period, subjects will enter the 20-week Safety 
Follow-Up Period.  During the Safety Follow-Up Period, subjects will return for 3 visits at +4, +8, and 
+22 weeks after the last dose of study treatment. 
Subjects who discontinue the open-label treatment prematurely will be required to come for the EoT Visit 2 
weeks after the last study treatment administration and then return for the 3 Safety Follow-Up Visits +4, +8, 
and +22 weeks after the last study treatment administration. 
Adverse events will be assessed throughout the study period and evaluated using the Common Technology 
Criteria version 4.0 (CTCAE v 4.0). 
There will be ongoing monitoring of safety events, including laboratory findings by the Sponsor or its designee.  
In addition, safety will be assessed throughout the study by an independent Data Safety Monitoring Board 
(DSMB). 
Planned number of subjects: 
Approximately 1880 subjects will be randomly assigned to 1 of 
2 treatment groups (the OKZ 64 mg q4w treatment group or the OKZ 
64 mg q2w treatment group). 
Treatment population: 
Subjects with moderately to severely active RA who previously completed 
24 weeks of double-blind treatment in the core studies. 
Diagnosis and 
main criteria for inclusion: 
1. Subjects willing and able to sign informed consent. 
2. Subject must have completed the 24-week double-blind 
Treatment Period in the core study. 
3. Subject must have maintained their stable dose (and route) of 
MTX 15 to 25 mg/week (or ≥10 mg/week if there is documented 
intolerance to higher doses) during the core study and plan to 
maintain the same dose and route of administration for 
≥12 additional weeks. 
Test product, dose and mode of 
administration: 
Olokizumab is a humanized monoclonal antibody specific for 
interleukin-6 (IL-6). 
Subjects will be assigned to receive OKZ at 64 mg via SC injection either 
q2w or q4w. 


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Statistical Methods: 
Calculation of Sample Size 
It is estimated that 1880 subjects will be enrolled in the OLE study after having completed a core study. 
Analysis Populations 
 
Safety population:  The Safety population will include all subjects who receive at least 1 dose of study 
treatment during the OLE study.  Subjects in the Safety population will be analyzed according to the 
treatment they actually received. 
 
Modified Intent-to-treat (mITT) population:  The mITT population will include all subjects who sign 
an Informed Consent for participation in the OLE study, are randomized in the OLE study, and receive 
at least 1 dose of study treatment in the OLE study.  Subjects will be analyzed according to the study 
treatment group to which they are randomized in the OLE study.  The mITT population will be the 
primary efficacy analysis population. 
 
Per Protocol (PP) population:  The PP population will include all mITT subjects who do not have any 
major protocol violations.  Subjects will be analyzed according to the study treatment group to which 
they are randomized.  The PP population will be used for supportive analyses selected efficacy 
endpoints. 
Safety Analysis 
The main components for the safety analysis will include:   
 
All AEs (and SAEs) will be solicited at every study visit, recorded, and coded according to the most 
recent version of the Medical Dictionary for Regulatory Activities (MedDRA) 
 
Vital signs and physical examination findings 
 
Laboratory parameters 
 
Electrocardiogram (ECG) and other specialized test findings 
Changes from OLE Baseline value in safety parameters will be summarized based on the definition of 
OLE Baseline value as the last available measurement prior to the first OLE dose of study treatment.  
Additionally, changes from Core Baseline will be summarized based on the baseline value from the core study 
(i.e., the last available measurement prior to the first dose of study treatment in the core study).  For subjects 
from Study CL04041025 who initiate OKZ treatment at Week 16 of the core study after having completed 
16 weeks of placebo treatment, changes from the last pre-OKZ value will also be summarized. 
All AEs will be analyzed in terms of descriptive statistics and qualitative analysis.  Adverse events will be 
summarized in terms of incidence during the OLE study, as well as overall during the core studies and the OLE 
study.  Adverse events will be listed for each subject and summarized by system organ class (SOC) and 
preferred term (PT) according to the most recent version of the MedDRA.  In addition, summaries of AEs by 
severity and relationship to study treatment will be presented.  Follow-up-adjusted incidence rates and event 
rates per 100 subject-years of follow-up over the course of the core study and the OLE will be summarized by 
treatment group for SAEs and AESIs.  All safety and tolerability data recorded during the study will be listed 
and summarized by treatment group in both the core study and the OLE, and over time, as appropriate. 
The above collected clinical database will be summarized and presented with particular focus on the following 
safety concerns identified as AESIs based either upon the safety data available to date (refer to the most recent 
version of the Investigator’s Brochure) for OKZ or drug class-related events for a biologic, including 
IL-6 inhibitors: 
 
Infections (particularly serious infections), tuberculosis, opportunistic infections 
 
Malignancies 
- 
The Investigator will be asked to provide relevant medical information/documentation 
(e.g., pathology/histology reports) on all the malignancies cases, whether considered serious 
or not, as these cases will be recorded in the safety database. 
 
Elevation of blood lipids (e.g., hypercholesterolemia, blood cholesterol increased, blood 


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triglycerides increased, hypertriglyceridemia, elevation of low-density lipoprotein [LDL]) 
 
Systemic injection reactions and hypersensitivity reactions, including anaphylaxis 
 
Gastrointestinal perforation 
 
Cardiovascular (CV) events 
 
Neutropenia, thrombocytopenia, leukocytopenia, and pancytopenia 
 
Hepatotoxicity 
- 
The Investigator will be asked to provide relevant medical information/documentation (e.g., 
laboratory test results, including tests for viral hepatitis and, if performed, liver biopsy) on all 
hepatotoxicity cases, whether considered serious or not, as these cases will be recorded in the 
safety database 
 
Injection site reactions 
 
Demyelination in peripheral or central nervous system 
 
Autoimmune disorders 
Cardiovascular Risk Assessment 
The RA population is known to have an increased risk of CV events.  The following approach is proposed to 
fully assess the CV risks associated with OKZ: 
 
Potential MACE will be adjudicated by an independent Cardiovascular Adjudication Committee 
(CVAC) according to a predefined charter.  The charter will define the criteria, data, and source 
documentation required to adjudicate all MACE. 
 
Baseline (of the core study) CV risks including individual risk factors (e.g., tobacco use, presence of 
hypertension, diabetes mellitus, and lipid profile) will be assessed. 
 
Known CV risk factors will be monitored and assessed to detect any trends over long-term exposure. 
Time from first exposure to OKZ treatment (either in the core study or OLE study) to first adjudicated MACE 
event will be summarized using the Kaplan-Meier methodology by treatment group. 
Efficacy Analysis 
Efficacy analyses will be conducted using the mITT population.  Changes from OLE Baseline value in efficacy 
parameters will be summarized based on the definition of OLE Baseline value as the last available 
measurement prior to the first OLE dose of study treatment.  Additionally, changes from Core Baseline will be 
summarized based on the baseline value from the core study (i.e., the last available measurement prior to the 
first dose of study treatment in the core study).  For subjects from Study CL04041025 who initiate OKZ 
treatment at Week 16 of the core study after having completed 16 weeks of placebo treatment, changes from the 
last pre-OKZ value will also be summarized.  There will be no inferential comparisons between treatment 
groups for efficacy assessments.  Descriptive summaries will be provided for each efficacy parameter over time 
by treatment group. 
Assessment of Nonresponders 
Starting at Visit 4 (Week 36) and then at all onsite visits until the end of the open-label Treatment Period, all 
subjects will be assessed for response to treatment, with nonresponders defined as subjects who do not improve 
by at least 20% in swollen and tender joint counts (66-68 joint assessment) from the Core Baseline assessment.  
Investigators will be requested to review carefully the response status at these time points and make appropriate 
actions based on local guidelines regarding management of the subjects, including possible adjustments in 
background therapy or withdrawal from the study. 
Safety Follow-up Assessments 
Given the long half-life of OKZ (approximately 31 days), a 2-step approach to fully capture the safety data after 
subjects discontinue treatment is proposed.  First, this Phase III study requires a full safety assessment at the  
EoT Visit, which will take place 2 weeks after the last dose of study treatment.  For subjects remaining on 
open-label therapy until the last scheduled dose of study treatment, Visit 10 (the EoT Visit) will take place at 
Week 106.  For subjects who discontinue treatment prematurely, the EoT Visit will take place 2 weeks after the 


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last study treatment administration.  Second, subjects will also be followed up for approximately 5 OKZ 
half-lives (i.e., 22 weeks) after the final dose of study treatment.  Specifically, after the EoT Visit, all subjects 
will be scheduled for extended Safety Follow-Up Visits at +4, +8, and +22 weeks after the last dose of study 
treatment.  Subjects will be reminded of study contact information to report potential SAEs and are to inform 
the Investigator if they experience such events during the Safety Follow-Up Period. 


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TABLE OF CONTENTS 
SIGNATURES..........................................................................................................................2 
EMERGENCY CONTACTS ..................................................................................................4 
SYNOPSIS ................................................................................................................................5 
TABLE OF CONTENTS ......................................................................................................11 
1. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................18 
2. 
INTRODUCTION......................................................................................................22 
2.1 
Background ....................................................................................................22 
2.2 
Study Treatment ............................................................................................22 
2.2.1 
Olokizumab .......................................................................................22 
2.2.2 
Nonclinical Development ..................................................................24 
2.2.3 
Summary of Clinical Experience .......................................................25 
2.2.3.1 
Summary of Studies in the Olokizumab 
Clinical Program ..............................................................25 
2.2.3.2 
Summary of Safety Data from Olokizumab 
Studies .............................................................................27 
2.2.3.3 
Summary of Efficacy Data from Olokizumab 
Studies .............................................................................34 
2.2.3.4 
Summary of Pharmacokinetic Data from 
Olokizumab Studies .........................................................36 
2.2.4 
Rationale for Dose Selection .............................................................36 
2.3 
Rationale for the Study ..................................................................................37 
2.4 
Benefit/Risk Assessment ................................................................................38 
3. 
STUDY OBJECTIVES ..............................................................................................40 
3.1 
Primary Objective ..........................................................................................40 
3.2 
Secondary Objectives.....................................................................................40 
4. 
SUMMARY OF STUDY ENDPOINTS ...................................................................41 
4.1 
Safety Endpoints ............................................................................................41 
4.2 
Efficacy Endpoints .........................................................................................41 
4.3 
Immunogenicity..............................................................................................43 
5. 
INVESTIGATIONAL PLAN ...................................................................................44 
5.1 
Summary of Study Design .............................................................................44 


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5.2 
Discussion of Study Design ............................................................................50 
5.2.1 
Cardiovascular Risk Assessment .......................................................51 
5.2.2 
Safety Follow-up Assessments ..........................................................52 
5.3 
Selection of Study Population .......................................................................53 
5.3.1 
Inclusion Criteria ...............................................................................53 
5.3.2 
Exclusion Criteria ..............................................................................53 
5.3.3 
Subject Restrictions ...........................................................................55 
5.3.4 
Premature Subject Withdrawal ..........................................................56 
5.4 
Study Procedures ...........................................................................................56 
5.4.1 
Open-label Treatment Period Visits:  Visit 1 (OLE 
Baseline/Week 24) through Visit 9 (Week 88) .................................58 
5.4.1.1 
Visit 1 (OLE Baseline/Week 24) .....................................58 
5.4.1.2 
Visit 2 (Week 26) ............................................................60 
5.4.1.3 
Visit 3 (Week 28) ............................................................61 
5.4.1.4 
Visit 4 (Week 36) ............................................................62 
5.4.1.5 
Visit 5 (Week 44) ............................................................64 
5.4.1.6 
Visit 6 (Week 52) ............................................................65 
5.4.1.7 
Visit 7 (Week 64) ............................................................66 
5.4.1.8 
Visit 8 (Week 76) ............................................................67 
5.4.1.9 
Visit 9 (Week 88) ............................................................69 
5.4.2 
Visit 10/End of Treatment (2 Weeks After the Last Dose 
of the Study Treatment)/(Week 106) .................................................70 
5.4.3 
Safety Follow-Up:  Visits SFU-1, SFU-2, and SFU-3 ......................72 
5.4.3.1 
Visit SFU-1 (Week 108 or 4 Weeks after the 
Last Dose of the Study Treatment) ..................................72 
5.4.3.2 
Visit SFU-2 (Week 112 or 8 Weeks after the 
Last Dose of the Study Treatment) ..................................72 
5.4.3.3 
Visit SFU-3 (Week 126 or 22 Weeks after the 
Last Dose of the Study Treatment) ..................................73 
5.4.4 
Unscheduled Visit .............................................................................73 
5.5 
Subject Diary ..................................................................................................73 
6. 
STUDY TREATMENTS ...........................................................................................75 
6.1 
Study Treatment Administered ....................................................................75 
6.2 
Identity of Study Treatment .........................................................................75 
6.2.1 
Olokizumab .......................................................................................75 
6.3 
Packaging and Labeling ................................................................................76 
6.4 
Storage ............................................................................................................76 
6.5 
Method of Assigning Subjects to Treatment Group ...................................77 
6.6 
Study Treatment Accountability ..................................................................77 
6.7 
Treatment Compliance ..................................................................................77 
6.8 
Preparation and Administration of Study Treatment ................................78 
6.9 
Selection and Timing of Dose for Each Subject ..........................................81 
6.10 
Dose Adjustments...........................................................................................81 


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6.11 
Discontinuation of Study Treatment ............................................................81 
6.11.1 
Temporary Discontinuation of Study Treatment ...............................81 
6.11.2 
Permanent Discontinuation of Study Treatment ...............................82 
6.12 
Blinding ...........................................................................................................84 
6.13 
Prior and Concomitant Treatments .............................................................84 
6.13.1 
Olokizumab Potential Impact on Cytochrome P and 
Transporter Pathways ........................................................................86 
6.13.2 
Allowed Medications .........................................................................87 
6.13.3 
Modification of Background Therapy ...............................................88 
6.14 
Medical Treatment for Subjects after End of Treatment 
Period ..............................................................................................................89 
7. 
EFFICACY, SAFETY, PHARMACOKINETIC, AND HEALTH 
OUTCOME ASSESSMENTS ...................................................................................90 
7.1 
Efficacy Assessments .....................................................................................90 
7.1.1 
American College of Rheumatology 20%/50%/70% 
Response Criteria ...............................................................................90 
7.1.2 
66-68 Joint Assessment .....................................................................90 
7.1.3 
Patient Global Assessment of Disease Activity (Visual 
Analog Scale) ....................................................................................91 
7.1.4 
Patient Assessment of Pain (Visual Analog Scale) ...........................91 
7.1.5 
Physician Global Assessment (Visual Analog Scale) .......................91 
7.1.6 
Disease Activity Score 28-Joint Count (C-Reactive 
Protein) ..............................................................................................91 
7.1.7 
Disease Activity Score 28-Joint Count (Erythrocyte 
Sedimentation Rate) ..........................................................................92 
7.1.8 
Simplified Disease Activity Index .....................................................92 
7.1.9 
Clinical Disease Activity Index .........................................................92 
7.1.10 
Health Assessments and Patient-Reported Outcomes .......................93 
7.1.10.1 
Health Assessment Questionnaire – Disability 
Index ................................................................................93 
7.1.10.2 
Short Form-36 .................................................................93 
7.1.10.3 
European Quality of Life – 5 Dimensions .......................94 
7.1.10.4 
Work Productivity Survey – Rheumatoid 
Arthritis ............................................................................95 
7.1.10.5 
Functional Assessment of Chronic Illness 
Therapy – Fatigue Scale ..................................................95 
7.2 
Pharmacokinetics ...........................................................................................95 
7.3 
Immunogenicity..............................................................................................96 
7.4 
Safety ...............................................................................................................96 
7.4.1 
Adverse Events ..................................................................................97 
7.4.1.1 
Eliciting Adverse Event Information ...............................99 
7.4.2 
Serious Adverse Events .....................................................................99 


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7.4.2.1 
Lack of Efficacy or Worsening of 
Rheumatoid Arthritis .....................................................101 
7.4.2.2 
Overdose ........................................................................101 
7.4.2.3 
Reporting and Follow-up Requirements for 
Pregnancies ....................................................................102 
7.4.3 
Adverse Events of Special Interest ..................................................103 
7.4.3.1 
Infections .......................................................................104 
7.4.3.2 
Systemic Injection Reactions, Including 
Anaphylaxis ...................................................................104 
7.4.3.3 
Gastrointestinal Perforation ...........................................105 
7.4.3.4 
Hepatotoxicity ...............................................................106 
7.4.3.5 
Injection Site Reactions .................................................107 
7.4.4 
Study Committees ...........................................................................108 
7.4.4.1 
Data Safety Monitoring Board ......................................108 
7.4.4.2 
Cardiovascular Adjudication Committee ......................108 
7.4.5 
Reporting of Adverse Events ...........................................................109 
7.4.5.1 
Patient-Reported Outcome Data ....................................110 
7.4.5.2 
Reporting of Serious Adverse Events ............................110 
7.4.5.3 
Reporting of Serious Adverse Events to 
Regulatory Authorities and Investigators ......................111 
7.4.5.4 
Follow-up of Adverse Events ........................................111 
7.4.5.5 
Follow-up of Serious Adverse Events by the 
Investigator ....................................................................112 
7.4.6 
Clinical Laboratory Evaluations ......................................................112 
7.4.6.1 
Laboratory Parameters ...................................................112 
7.4.6.2 
Mandatory Retesting of Laboratory 
Abnormalities ................................................................114 
7.4.7 
Vital Signs, Physical Findings, and Other Safety 
Assessments .....................................................................................114 
7.4.7.1 
Physical Examination ....................................................114 
7.4.7.2 
Vital Signs .....................................................................115 
7.4.7.3 
Body Weight and Height ...............................................115 
7.4.7.4 
Cardiovascular Risk Assessment ...................................116 
7.4.7.5 
Electrocardiogram .........................................................116 
7.4.7.6 
Evaluation of Chest X-ray .............................................116 
7.4.8 
Safety Monitoring ............................................................................116 
7.4.9 
Tuberculosis Risk Questionnaire .....................................................117 
7.4.10 
Management of Tuberculosis ..........................................................117 
7.5 
Appropriateness of Measurements .............................................................118 
8. 
QUALITY CONTROL AND QUALITY ASSURANCE .....................................119 
8.1 
Monitoring ....................................................................................................119 
8.2 
Quality Assurance Audit .............................................................................122 


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9. 
STATISTICS ............................................................................................................123 
9.1 
Determination of Sample Size .....................................................................123 
9.2 
Data to be Analyzed .....................................................................................123 
9.3 
Analysis Populations ....................................................................................123 
9.4 
Statistical Methods .......................................................................................124 
9.4.1 
Definition of Baseline ......................................................................125 
9.4.2 
Disposition of Study Subjects .........................................................126 
9.4.3 
Demography and Baseline Characteristics ......................................126 
9.4.4 
Prior and Concomitant Medications ................................................126 
9.4.5 
Exposure and Compliance ...............................................................127 
9.4.6 
Safety Analyses ...............................................................................127 
9.4.6.1 
Adverse Events ..............................................................128 
9.4.6.2 
Other Safety Analyses ...................................................132 
9.4.7 
Analysis of Efficacy Endpoints .......................................................133 
9.4.8 
Handling of Missing Data ...............................................................134 
9.4.9 
Pharmacokinetic/Pharmacodynamic Correlations ...........................134 
9.4.10 
Immunogenicity ...............................................................................134 
9.5 
Subgroup Analysis .......................................................................................135 
9.6 
Safety Monitoring Committees ...................................................................135 
9.7 
Interim Analysis ...........................................................................................135 
10. 
ETHICS ....................................................................................................................136 
10.1 
Institutional Review Board/Independent Ethics Committee ...................136 
10.2 
Ethical Conduct of the Study ......................................................................136 
10.3 
Subject Information and Informed Consent .............................................137 
10.4 
Subject Data Protection ...............................................................................137 
11. 
STUDY ADMINISTRATION ................................................................................138 
11.1 
Administrative Structure ............................................................................138 
11.2 
Study and Study Site Closure .....................................................................138 
11.3 
Study Discontinuation .................................................................................138 
11.4 
Data Handling and Record Keeping ..........................................................139 
11.5 
Direct Access to Source Data/Documents ..................................................139 
11.6 
Investigator Information .............................................................................140 
11.6.1 
Investigator Obligations ..................................................................140 
11.6.2 
Protocol Signatures ..........................................................................141 
11.6.3 
Publication Policy ............................................................................141 
11.7 
Financing and Insurance .............................................................................141 
12. 
REFERENCES .........................................................................................................142 
13. 
APPENDICES ..........................................................................................................144 
13.1 
Appendix 1:  Methotrexate Dose Reduction Guidelines ..........................145 


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13.2 
Appendix 2:  Tuberculosis Risk Questionnaire ........................................147 
13.3 
Appendix 3:  Clinical Criteria for Diagnosing Anaphylaxis ....................150 
13.4 
Appendix 4:  Recommendations for Management of Latent 
Tuberculosis Infection .................................................................................151 
13.5 
Appendix 5:  Protocol Amendment 2 Summary of Changes ...................152 
 


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LIST OF TABLES 
Table 1 
CL04041024 (CREDO 4) Schedule of Events (Open-Label 
Treatment Period and Safety Follow-Up Period) ............................................46 
Table 2 
Components and Composition of OKZ (CDP6038; L04041) Drug 
Product .............................................................................................................76 
Table 3 
Prohibited Medications ....................................................................................85 
Table 4 
CTCAE Grades and Corresponding AE Severity ............................................98 
Table 5 
List of Endemic TB Countries (Incidence >50/100,000)...............................148 
 
 
LIST OF FIGURES 
Figure 1 
CL04041024 (CREDO 4) Study Schematic ....................................................45 
 


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1. LIST OF ABBREVIATIONS AND DEFINITIONS OF 
TERMS 
Abbreviation 
Definition 
ACR 
American College of Rheumatology 
ACR20 
American College of Rheumatology 20% response criteria 
ACR50 
American College of Rheumatology 50% response criteria 
ACR70 
American College of Rheumatology 70% response criteria 
ADA 
antidrug antibody 
ADL 
activities of daily living 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANA 
antinuclear antibodies 
ApoB 
apolipoprotein B 
ApoA1 
apolipoprotein A1 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ATC 
Anatomic Therapeutic Class 
bDMARD 
biologic disease-modifying anti-rheumatic drug 
BNP 
brain natriuretic peptide 
BP 
blood pressure 
CDAI 
Clinical Disease Activity Index 
CDC 
Centers for Disease Control and Prevention 
cDMARD 
conventional disease-modifying anti-rheumatic drug 
CDR 
complementarity determining region 
CMF 
cumulative mean function 
CRP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
cardiovascular 
CVAC 
Cardiovascular Adjudication Committee 
CYP 
cytochrome P 
DAS28 
Disease Activity Score 28-joint Count 
DMARD 
disease-modifying anti-rheumatic drug 
dsDNA 
double-stranded DNA 


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Abbreviation 
Definition 
DSMB 
Data Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
Electronic Data Capture 
EQ-5D 
European Quality of Life-5 Dimensions 
EQ-5D VAS 
European Quality of Life-5 Dimensions Visual Analog Scale 
ESR 
erythrocyte sedimentation rate 
EoT 
End of Treatment 
ER 
event rate 
EudraCT 
European Clinical Trials Database 
EULAR 
European League Against Rheumatism 
FACIT-Fatigue 
Functional Assessment of Chronic Illness Therapy – Fatigue Scale 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
gp80 
interleukin-6 receptor alpha chain 
gp130 
interleukin-6 receptor signal-transducing subunit 
HAQ-DI 
Health Assessment Questionnaire - Disability Index 
HbA1c 
glycosylated hemoglobin 
HDL 
high-density lipoprotein 
HIV 
human immunodeficiency virus 
IA 
intra-articular 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IGRA 
interferon-gamma release assay 
IL-6 
interleukin-6 
IL-6R 
interleukin-6 receptor 
IM 
intramuscular 
INR 
international normalized ratio 
IP 
interphalangeal(s) 
IR 
incidence rate 
IRB 
Institutional Review Board 


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Abbreviation 
Definition 
ISS 
Integrated Summary of Safety 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IV 
intravenous(ly) 
IWRS 
Interactive Web Response System 
LDL 
low-density lipoprotein 
LFT 
liver function test 
LS 
least squares 
mAb 
monoclonal antibody 
MACE 
major adverse cardiac event 
MCP 
metacarpophalangeal 
MCS 
Mental Component Summary 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MTP 
metatarsophalangeals 
MTX 
methotrexate 
n 
number of available values 
NOAEL 
no observed adverse effect level 
NSAID 
non-steroidal anti-inflammatory drugs 
NT-proBNP 
N-terminal pro-hormone of brain natriuretic peptide 
OKZ 
olokizumab 
OLE 
open-label extension 
PCS 
Physical Component Summary 
PD 
pharmacodynamic(s) 
PEF 
peak expiratory flow 
PFS 
pre-filled syringe(s) 
PIP 
proximal interphalangeals 
PK 
pharmacokinetic(s) 
PP 
Per Protocol 
PRO 
patient-reported outcome 
PT 
preferred term 
q2w 
once every 2 weeks 
q4w 
once every 4 weeks 
QALY 
quality-adjusted life years 


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Abbreviation 
Definition 
RA 
rheumatoid arthritis 
RBC 
red blood count 
SAA 
serum amyloid A 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous(ly) 
SDAI 
Simplified Disease Activity Index 
SF-36 
Short Form-36 
SJC 
swollen joint count 
SOC 
system organ class 
SOP 
standard operating procedures 
SUSAR 
suspected unexpected serious adverse reaction 
SY 
subject-years 
TB 
tuberculosis 
TEAE 
treatment-emergent adverse event 
TJC 
tender joint count 
TNF-α 
tumor necrosis factor-α 
TNFi 
tumor necrosis factor-α inhibitor 
ULN 
upper limit of normal 
UK 
United Kingdom 
US 
United States 
VAS 
Visual Analog Scale 
WBC 
white blood count 
WHO 
World Health Organization 
WHO DDE 
World Health Organization Drug Dictionary Enhanced 
WPS-RA 
Work Productivity Survey – Rheumatoid Arthritis 


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2. INTRODUCTION 
2.1 
Background 
Rheumatoid arthritis (RA) is a chronic immune/inflammatory disease characterized by 
persistent synovitis, with synovial cell proliferation and destructive changes in bone and 
cartilage of multiple joints.  Untreated, RA can lead to destruction, deformation, and 
dysfunction of affected joints, which may result in significant morbidity, and accelerated 
mortality (Jacobsson et al, 2007).  Moderately to severely active RA is often treated with 
disease-modifying anti-rheumatic drugs (DMARDs), with methotrexate (MTX) being the 
most commonly used conventional DMARD (cDMARD).  For patients with an inadequate 
response to cDMARDs, biologic agents (i.e., biologic DMARDs [bDMARDs]) are the next 
step, and include, but are not limited to, tumor necrosis factor-α (TNF-α) inhibitors (TNFi), 
interleukin-6 (IL-6) receptor (IL-6R) antagonists, and T-cell co-stimulation modulators.  
Among these, TNFi, especially in combination with MTX, are used most often 
(Smolen et al, 2014).  Despite early treatment with cDMARD and/or bDMARD therapy, 
approximately 30% to 40% of patients with established RA fail to respond and 50% to 60% 
of patients fail to achieve a major clinical American College of Rheumatology (ACR) 
response or good European League Against Rheumatism (EULAR) response 
(Marchesoni et al, 2009; Rubbert-Roth and Finckh, 2009; Cohen et al, 2008).  Even among 
responders, the majority do not achieve remission.  Thus, there continues to be an unmet 
medical need for new therapeutic approaches in the RA patient population. 
One such therapeutic approach is to target IL-6 directly instead of indirectly via a receptor 
antagonist.  Interleukin-6 is a pleiotropic, pro-inflammatory cytokine produced by a variety 
of cell types including lymphocytes, monocytes, and fibroblasts.  It is involved in multiple 
immunologic processes such as T-cell activation, B-cell proliferation, initiation of 
acute-phase response, stimulation of hematopoietic precursor cell growth, differentiation and 
trafficking, as well as osteoclast differentiation, which subsequently contributes to joint 
destruction.  Due to the key role played by IL-6 in several RA mechanisms, targeting IL-6 is 
considered an attractive therapeutic option. 
2.2 
Study Treatment 
2.2.1 
Olokizumab 
Olokizumab (OKZ; CDP6038; L04041) is being developed by R-Pharm International for the 
treatment of moderately to severely active RA.  Olokizumab was previously developed by 
UCB Pharma SA, and was transferred to R-Pharm International for further global 
development. 


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Olokizumab is a humanized (complementarity determining region [CDR]-grafted) 
monoclonal antibody (mAb) of immunoglobulin (Ig) G4/kappa isotype, developed as an 
antagonist of IL-6 that is anticipated to have utility in a wide range of 
autoimmune/inflammatory conditions. 
Interleukin-6 is a multifunctional cytokine that has been shown to play a central role in 
immune regulation, inflammation, hemopoiesis, and oncogenesis, and has been linked to a 
wide range of human diseases.  It is a glycoprotein of 184 amino acids that is produced by a 
wide range of cell types including monocytes/macrophages, fibroblasts, epidermal 
keratinocytes, vascular endothelial cells, renal mesangial cells, glial cells, chondrocytes, 
T and B cells, and some tumor cells.  Stimuli of IL-6 production include TNF-α, 
lipopolysaccharides, and viral infections; inhibitors of IL-6 production include 
glucocorticoids.  Within the context of an immune and inflammatory response, IL-6 has been 
shown to exert a wide range of effects, such as those described below: 
 
Induction of antibody production by B cells 
 
Important role in the generation of a subpopulation of T-helper cells, Th17 cells, 
which may play an important pathogenic role in a number of autoimmune diseases 
 
Key driver of the acute phase response (the increased production, mainly by the liver, 
of soluble factors, such as C-reactive protein [CRP] and serum amyloid A [SAA], 
during inflammation) 
In developing an antagonist mAb to IL-6, potential therapeutic strategies include inhibition 
of nonsignaling IL-6R receptor alpha chain (gp80), which gives the IL-6 family members 
their specificity, and the IL-6R signal-transducing subunit (gp130).  The identification of the 
optimum epitope to target on IL-6 (binding IL-6 in a region that is predicted to be involved 
with gp80 or gp130) was conducted using antibodies with similar affinities, but different 
binding axes, as determined by surface plasmon resonance (BIAcore).  Antibodies directed 
against mouse or human IL-6 that targeted the gp130 axis were more potent than those that 
targeted the gp80 axis in inhibiting IL-6-dependent phosphorylation of signal transducer and 
activator of transcription 3 in in vitro cell-based assays and in inhibiting the secretion of the 
acute phase protein SAA in vivo.  Olokizumab binds to a region of IL-6 involved with 
gp130 binding.  The epitope recognized by OKZ was initially established by BIAcore and 
confirmed by nuclear magnetic resonance studies.  Olokizumab has been shown to have a 
high affinity for human IL-6 as determined using BIAcore analysis.  In vitro whole blood and 
cell line assays as well as animal studies have shown that OKZ potently neutralizes 
IL-6-mediated effects in vitro and in vivo, respectively.  Data suggest that OKZ neither 
significantly binds to nor affects the function of other IL-6 family members, nor does it 
appear to activate the IL-6 signaling pathway under a range of conditions tested. 


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Currently, patients with moderately to severely active RA are often treated with cDMARDs, 
with MTX being the most commonly used.  For patients with an inadequate response to 
cDMARDs, biologic agents that inhibit TNF-, especially in combination with MTX, are 
indicated (Smolen et al, 2014).  Nonetheless, a substantial proportion of patients receiving 
biologics (i.e., approximately 40% to 50% of those receiving TNFi therapy) have inadequate 
response to such treatment (Marchesoni et al, 2009; Rubbert-Roth and Finckh, 2009; 
Cohen et al, 2008).  Thus, there is an unmet need for new therapeutic approaches utilizing 
alternative modes of action in this patient population. 
Olokizumab is being developed to address the unmet needs of patients with these severe, 
progressive, and debilitating disorders through a different therapeutic approach, utilizing an 
alternative mode of action.  Within the class of therapeutic antibodies targeting the 
IL-6 pathway, OKZ is anticipated to be more potent because of its high affinity for IL-6 and 
its axis of intervention (inhibiting the interaction between IL-6 and gp130).  Also, since OKZ 
is of the Ig G4 isotype, it would not be expected to mediate significant levels of 
antibody-mediated complement fixation or cell-mediated cytotoxicity. 
Olokizumab is being developed for the treatment of RA to reduce signs and symptoms of 
disease and improve physical functioning.  The proposed indication for OKZ is to be used in 
combination with MTX for the treatment of moderately to severely active RA in adult 
patients who have been inadequately controlled by MTX treatment or previous TNFi 
treatment. 
Refer to the most recent version of the Investigator’s Brochure for additional information on 
OKZ, including: 
 
In vitro activity 
 
Nonclinical pharmacokinetics (PK) and product metabolism 
 
Nonclinical pharmacology and toxicology 
 
Pharmacokinetics, efficacy, and safety profile in clinical studies 
2.2.2 
Nonclinical Development 
Nonclinical studies have shown that inhibition of IL-6 signaling does not result in any 
life-threatening effects either in animal models or formal toxicology studies.  There is no 
evidence from in vitro and in vivo nonclinical data to suggest that there is a risk of OKZ 
inducing an uncontrolled biological cascade.  All nonclinical data generated to date are 
consistent with OKZ functioning as an effective antagonist of the IL-6 pathway.  Cellular 
in vitro assay data suggest that OKZ neutralizes the biological effects of IL-6 in both humans 


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and cynomolgus monkeys with similar potency.  Therefore, the cynomolgus monkey is 
considered an appropriate species to evaluate the potential toxicity of OKZ.  Due to the lack 
of activity of OKZ on IL-6 in rats and mice, the toxicology program was restricted to using a 
single non-rodent species, the cynomolgus monkey. 
Olokizumab is well tolerated in the cynomolgus monkey, with a no observed adverse effect 
level (NOAEL) of 200 mg/kg/week and 50 mg/kg/week after intravenous (IV) and 
subcutaneous (SC) administration, respectively. 
In a study aimed at assessing the effects of OKZ on prenatal and postnatal development in 
the cynomolgus monkey, the treatment was well tolerated during the pregnancy and had no 
abortifacient effect.  However, some OKZ-treated females experienced dystocia and 
placental retention, sometimes associated with significant urogenital bleeding, which resulted 
in some deaths.  Given similar human and cynomolgus monkey physiology and the risk of 
dystocia and hemorrhage at parturition, inhibition of IL-6 signaling during pregnancy is not 
recommended. 
Taken together, the currently completed nonclinical studies support continued clinical 
development for marketing approval of OKZ. 
2.2.3 
Summary of Clinical Experience 
Nonclinical data were deemed sufficient to support clinical development of OKZ in humans 
for the treatment of moderately to severely active RA (lead indication), other auto-immune 
inflammatory diseases, and oncological diseases with IL-6 pathophysiology. 
The safety, efficacy, and PK of OKZ have been investigated in 3 Phase I clinical studies 
(RA0001, RA0010, and RA0074) and 2 Phase II clinical studies (RA0056 and RA0083).  
The safety and efficacy of OKZ were also studied in long-term open-label extension (OLE) 
studies for both Phase II studies (RA0057 and RA0089). 
The information in this section of the protocol regarding clinical studies with OKZ is current 
as of 29 January 2016 (for updated information on results of clinical studies, refer to the most 
recent version of the Investigator’s Brochure). 
2.2.3.1 
Summary of Studies in the Olokizumab Clinical Program 
Study RA0001 
Study RA0001 was a Phase I, randomized, double-blind, placebo-controlled, dose-escalating, 
first-in-human study that investigated the safety and tolerability, PK, and 
pharmacodynamics (PD) of IV OKZ in 67 healthy Caucasian male subjects (33 on active 
drug and 34 on placebo) with a 99-day follow-up. 


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Study RA0010 
Study RA0010 was a Phase I/IIa study to characterize the PK/PD relationship between 
systemic OKZ exposure and CRP suppression, following single-dose IV and SC OKZ 
administration to subjects with RA and to evaluate the safety and tolerability of single doses 
of OKZ in RA subjects over a therapeutic dose range (as defined by CRP suppression). 
Study RA0074 
Study RA0074 was a Phase I study in healthy Japanese subjects undertaken to evaluate the 
PK, PD, safety, and tolerability of SC OKZ prior to undertaking clinical studies in Japanese 
subjects with RA. 
Studies RA0056 and RA0057 
Study RA0056 was a Phase II, multicenter, randomized, double-blind, placebo- and 
active-controlled study of OKZ in 221 subjects in the United States (US) and Europe with 
active RA who had previously failed TNFi therapy, administered SC at various doses and 
frequencies to evaluate the efficacy relative to placebo.  Eligible subjects were randomized to 
1 of 9 treatment groups:  OKZ 60 mg SC once every 2 weeks (q2w), OKZ 60 mg SC once 
every 4 weeks (q4w), OKZ 120 mg SC q2w, OKZ 120 mg SC q4w, OKZ 240 mg SC q2w, 
OKZ 240 mg SC q4w, placebo SC q2w, placebo SC q4w, and tocilizumab 8 mg/kg IV q4w. 
Study RA0057 was the long-term OLE study of RA0056, which was open for enrollment of 
subjects who had completed the Week 12 visit of Study RA0056.  A total of 190 subjects in 
Study RA0057 received SC injections of OKZ 120 mg q2w throughout the study, regardless 
of their treatment assignment in RA0056. 
Studies RA0083 and RA0089 
Study RA0083 was a Phase II, multicenter, randomized, double-blind, placebo-controlled, 
dose-ranging study of OKZ in 119 Asian subjects with moderately to severely active RA who 
had previously failed TNFi therapy and were on a stable dose of MTX.  Eligible subjects 
were randomized to 1 of 6 treatment groups:  OKZ 60 mg q2w, 60 mg q4w, 120 mg q2w, 
120 mg q4w, 240 mg q4w, or placebo q2w, all administered SC. 
Study RA0089 was the long-term OLE study of RA0083, which was open for enrollment of 
subjects who had completed the Week 12 visit of Study RA0083.  A total of 103 subjects in 
Study RA0089 received SC injections of OKZ 120 mg q2w throughout the study, regardless 
of their treatment assignment in Study RA0083. 


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2.2.3.2 
Summary of Safety Data from Olokizumab Studies 
Study RA0001 
There were no deaths or serious adverse events (SAEs) reported during the study and no 
subject discontinued the study as a result of an adverse event (AE).  The overall incidence of 
treatment-emergent adverse events (TEAEs) was slightly higher in the placebo group overall 
(18 subjects [52.9%]; 35 events) than in the OKZ treatment groups overall (11 subjects 
[33.3%]; 26 events).  No increase in the incidence of TEAEs was observed with increasing 
dose of OKZ. 
The most commonly reported TEAEs were in the system organ classes (SOCs) of 
gastrointestinal (GI) disorders, general disorders, and infections and infestations.  The 
incidence of GI disorders was similar in both the OKZ group overall (12.1%) and the placebo 
group overall (11.8%); however, at the preferred term (PT) level, abdominal distension 
(1 subject [3.0%]), abdominal pain (1 subject [3.0%]), and vomiting (2 subjects [6.1%]) were 
only seen in the OKZ group.  The most frequently reported TEAEs (occurring in ≥3% of 
subjects in any treatment group) by PT were influenza-like illness (11.8% placebo, 
6.1% OKZ), headache (11.8% placebo, 3.0% OKZ), nasopharyngitis (8.8% placebo, 
3.0% OKZ), rhinitis (8.8% placebo, 0.0% OKZ), diarrhea (5.9% placebo, 3.0% OKZ), and 
vomiting (0.0% placebo, 6.1% OKZ). 
For the majority of hematology and clinical chemistry parameters there were no clinically 
significant differences in mean actual values between the placebo group and OKZ treatment 
groups, and no clinically significant fluctuations in mean actual values over time. 
Study RA0010 
There were no deaths during Study RA0010.  Two subjects (1 subject in the placebo 
IV + MTX group and 1 subject in the OKZ 1 mg/kg SC + MTX group) experienced SAEs:  
Bowen’s disease and worsening of RA, respectively.  Neither event was considered by the 
Investigator to be related to the study treatment.  One subject in the placebo + MTX overall 
group withdrew from the study as a result of exacerbation of their RA.  All subjects (100%) 
in the placebo + MTX overall group and 96.7% of subjects in the OKZ + MTX overall group 
experienced at least 1 TEAE.  The incidence of TEAEs did not increase with increasing dose 
of OKZ + MTX administered; although, a slightly higher number of AEs were experienced 
by subjects in the OKZ (1 mg/kg and 3 mg/kg) + MTX SC treatment groups 
(16 subjects [94.12%]; 101 events) compared with the OKZ (0.1 mg/kg and 1 mg/kg) + MTX 
IV treatment groups (13 subjects [100%]; 54 events). 


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Study RA0074 
In Study RA0074, there were no deaths, SAEs, severe AEs, or AEs that led to 
discontinuation.  The incidence of TEAEs was higher in the OKZ groups compared with the 
placebo group.  In the placebo group, 50% of subjects (2 of 4) had TEAEs (6 events), 
compared with 75% of subjects (3 of 4) in the OKZ 3 mg/kg treatment group (11 events), and 
100% of subjects (4 of 4) in each of the OKZ 0.3 mg/kg (16 events), OKZ 1 mg/kg 
(25 events), and OKZ 6 mg/kg (24 events) treatment groups.  The incidence of TEAEs did 
not appear to be related to the dose of OKZ administered. 
The most commonly reported TEAEs were within the SOCs of general disorders and 
administration site conditions; investigations; GI disorders; infections and infestations; 
respiratory, thoracic and mediastinal disorders; and skin and SC tissue disorders.  Events 
occurring in >20% of subjects in the OKZ overall group, by PT, included injection site 
hematoma (31.3%), abdominal pain (25.0%), and alanine aminotransferase (ALT) increased 
(25.0%).  The overall incidence of TEAEs in the OKZ-treated groups was higher than in the 
placebo-treated group, but given the small number of subjects in each treatment group, it is 
not possible to make any meaningful conclusions. 
In Studies RA0001, RA0010, and RA0074, OKZ was tolerated at doses of up to 3 mg/kg SC 
(all studies), 6 mg/kg SC (Study RA0074 only), and 10 mg/kg IV (Study RA0001 only).  
There were no deaths in any of these studies and only 2 SAEs in Study RA0010.  One subject 
in Study RA0010 discontinued the study early due to an AE (exacerbation of RA symptoms), 
but no subjects withdrew from Study RA0001 or Study RA0074 due to TEAEs. 
Study RA0056 
In Study RA0056, OKZ was well tolerated at doses of up to 240 mg q2w.  Serious AEs were 
reported by 6 subjects in the OKZ groups and 3 subjects in the placebo groups.  A total of 
11 subjects in the OKZ and placebo groups discontinued due to TEAEs (10 subjects in the 
OKZ group and 1 subject in the placebo group).  Overall, 10 subjects in the OKZ groups 
reported 13 TEAEs leading to discontinuation, with the most subjects discontinuing due to 
TEAEs in the OKZ 60 mg q4w group (5 subjects [22.7%] compared with 2 subjects [10%] in 
the OKZ 60 mg q2w group, 1 subject [4.5%] in the OKZ 120 mg q2w group, and 2 subjects 
[8.7%] in the OKZ 240 mg q2w group).  One subject (4.5%) in the placebo q2w group also 
discontinued due to TEAEs.  No TEAE PT leading to discontinuation was reported by more 
than 1 subject in any treatment group. 
Treatment-emergent AEs were reported by 17 subjects (77.3%) in the placebo q4w group, 
19 subjects (86.4%) in the placebo q2w group, 18 subjects (81.8%) in the OKZ 60 mg 
q4w group, 14 subjects (70.0%) in the OKZ 60 mg q2w group, 20 subjects (87.0%) in the 


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OKZ 120 mg q4w group, 14 subjects (63.6%) in the OKZ 120 mg q2w group, and 
19 subjects each in the OKZ 240 mg q4w (86.4%) and OKZ 240 mg q2w (82.6%) groups.  
The majority of these TEAEs were reported during the Treatment Period. 
The most commonly reported TEAEs (>10% of subjects in any treatment group) in the 
OKZ q4w, OKZ q2w, and placebo groups were in the SOCs of GI disorders, general 
disorders and administration site conditions, infections and infestations, investigations, and 
nervous system disorders. 
The TEAEs that occurred with the greatest incidence (i.e., occurring in ≥10% of subjects) in 
any OKZ treatment group included:  diarrhea, injection site reaction, injection site pruritus, 
nasopharyngitis, upper respiratory tract infection, urinary tract infection, ALT increased, 
aspartate aminotransferase (AST) increased, and liver function test (LFT) abnormal. 
When considering TEAEs by grade according to the Common Terminology Criteria for 
Adverse Events (CTCAE), the majority of subjects in all treatment groups (≥59.1%) had 
CTCAE Grade 1 TEAEs.  The CTCAE Grade 3 TEAEs included head injury, anemia, chest 
pain, basal cell carcinoma, injection site reaction, contusion, abscess limb, laceration, 
musculoskeletal pain, mania, breast discharge, breast swelling, erythema, pruritus, 
osteoarthritis, ligament sprain, back pain, cellulitis, and spinal cord compression.  No 
CTCAE Grade 3 TEAE was reported by more than 1 subject.  Of the CTCAE 
Grade 3 TEAEs, all were reported during the Treatment Period, with the exception of 
1 subject in the OKZ 60 mg q4w (4.5%) group who reported CTCAE Grade 3 TEAEs during 
the Safety Follow-Up Period.  No CTCAE Grade 4 or 5 TEAEs were observed in any 
treatment group.  There were no deaths reported in Study RA0056.  Overall, 6 subjects in the 
OKZ groups reported 7 SAEs (3 subjects [15.0%] reporting 3 events in the OKZ 60 mg q2w 
group [chest pain, basal cell carcinoma, and mania], 1 subject [4.5%] reporting 1 event in the 
OKZ 60 mg q4w group [LFT abnormal], and 2 subjects [9.1%] reporting 3 events in the 
OKZ 240 mg q4w group [pneumonia, perineal abscess, and back pain]).  No subjects in the 
OKZ 120 mg q2w or q4w groups or in the OKZ 240 mg q2w group experienced SAEs.  A 
total of 3 subjects in the placebo treatment groups reported 3 SAEs (2 subjects [9.1%] 
reporting 2 events in the placebo q2w group and 1 subject [4.5%] reporting 1 event in the 
placebo q4w group). 
Of the SAEs reported in the OKZ groups, only LFT abnormal (1 subject [4.5%] in the OKZ 
60 mg q4w group) was judged to be related to the study treatment by the Investigator.  
Additionally, only the SAEs of LFT abnormal (1 subject [4.5%] in the OKZ 60 mg q4w 
group), and chest pain (1 subject [5.0%] in the OKZ 60 mg q2w group), led to 
discontinuation from the study.  All of the SAEs were reported as recovered/resolved with 
the exception of anemia (1 subject [4.5%] in the placebo q4w group). 


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Study RA0057 
Overall, 33 subjects reported 321 TEAEs leading to discontinuation during the study.  The 
most common TEAE PT leading to discontinuation was upper respiratory tract infection 
(8 subjects [4.2%]). 
Three additional subjects experienced TEAEs leading to permanent discontinuation of OKZ 
(bladder cancer, palmar pustular dermatitis, and cholecystitis chronic).  These subjects were 
not represented within the patient data sets or tables as this additional information was based 
on source documentation received from the respective study sites after the clinical database 
had been locked. 
Treatment-emergent AEs were reported by 178 subjects (93.7%).  The most commonly 
reported TEAEs (>10% of subjects) were in the SOCs of infections and infestations; 
musculoskeletal and connective tissue disorders; GI disorders; investigations; general 
disorders and administration site conditions; respiratory, thoracic and mediastinal disorders; 
skin and SC tissue disorders; injury, poisoning and procedural complications; nervous system 
disorders; metabolism and nutrition disorders; and vascular disorders. 
When considering TEAEs by CTCAE grade, the majority of subjects had CTCAE 
Grade 1 (85.8%) and/or Grade 2 (56.3%) TEAEs.  At the SOC level, infections and 
infestations was the TEAE that occurred most frequently (68.4% of subjects), with a 
maximum intensity of mild (102 subjects [53.7%]; 239 events), moderate (58 subjects 
[30.5%]; 103 events), and severe (14 subjects [7.4%]; 17 events).  At the PT level, CTCAE 
Grade 3 TEAEs that occurred in ≥2 subjects included cellulitis, pneumonia, staphylococcal 
infection, urinary tract infection, back pain, RA, pulmonary embolism, and chest pain.  No 
CTCAE Grade 3 TEAE was reported by more than 3 subjects for any PT.  A total of 
93 subjects (48.9%) reported TEAEs (281 events) that were judged as related to the study 
treatment by the Investigator.  The TEAE most frequently assessed as being drug-related by 
the Investigator was injection site reaction SOC (21 subjects [11.1%]; 29 events). 
There were 2 deaths reported in Study RA0057.  The first subject experienced the 
treatment-emergent SAE of a road traffic accident, reported as severe and considered not 
related to the study treatment.  The second subject had multiple co-morbidities and 
experienced necrotizing fasciitis, acute renal failure, multi-system organ failure, and sepsis 
after approximately 9 months of exposure to OKZ.  Two months prior to death, OKZ was 
discontinued as the subject was lost to follow-up.  The Investigator and Sponsor judged that 
necrotizing fasciitis and sepsis were related to the study treatment, and that acute renal failure 
and multi-system organ failure were not related to the study treatment. 


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A total of 50 subjects (26.3%) reported 83 treatment-emergent SAEs.  The highest incidence 
of events was observed for the SOC of infections and infestations (19 subjects [10.0%]; 
24 events).  At the PT level, chest pain occurred with the highest frequency (4 subjects 
[2.1%]; 4 events). 
Of the SAEs reported, diverticulitis (2 subjects), diverticular perforation, pneumonia, bladder 
cancer, furuncle, necrotizing fasciitis, sepsis, B-cell lymphoma, elevated lactate 
dehydrogenase, elevated liver enzymes, and cellulitis (1 subject each) were judged to be 
related to the study treatment by both the Investigator and Sponsor. 
One SAE (maculopapular rash) was judged related to the study treatment by the Investigator, 
but not related by the Sponsor.  One SAE (staphylococcal infection) was judged not related 
to the study treatment by the Investigator, but related by the Sponsor. 
The remaining SAEs were judged not related to the study treatment by both the Investigator 
and Sponsor. 
Study RA0083 
Safety findings in Study RA0083 were consistent with the safety profile expected with this 
class of drug.  Serious AEs were reported by 2 subjects (6.9%) in the placebo group and 
2 subjects each in the OKZ treatment groups.  Overall, 2 subjects in the placebo group, and 
5 subjects in the OKZ treatment groups reported a total of 9 TEAEs leading to 
discontinuation.  Discontinuations due to TEAEs were reported by very few subjects in any 
4-week cumulative dose group:  2 subjects each in the placebo, OKZ 60 mg, and OKZ 
240 mg groups and 1 subject in the OKZ 120 mg group.  Of the 7 subjects overall who 
discontinued due to TEAEs, a similar number of subjects discontinued during the Treatment 
Period (3 subjects overall) and the Safety Follow-Up Period (4 subjects overall).  With the 
exception of 2 subjects in the placebo group who discontinued due to RA exacerbation, no 
TEAE PT leading to discontinuation was reported by more than 1 subject in any treatment 
group. 
Treatment-emergent AEs were reported at similar incidences across the OKZ 4-week 
cumulative dose groups and the placebo group. 
The most commonly reported TEAEs (>10% in any treatment group) were in the SOCs of 
infections and infestations, GI disorders, general disorders and administration site conditions, 
hepatobiliary disorders, nervous system disorders, and skin and SC disorders.  
Nasopharyngitis, headache, and rash occurred with the greatest incidence in the all OKZ 
group.  The incidence of diarrhea was higher in the placebo group than the all OKZ group.  


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The incidence of TEAEs of hepatic function abnormal and nasopharyngitis increased with 
higher cumulative doses of OKZ. 
When considering TEAEs by CTCAE grade, there were no Grade 4 or 5 TEAEs. 
The majority of subjects across all 4-week cumulative dose groups (≥56.3%) had CTCAE 
Grade 1 TEAEs.  Three subjects reported Grade 3 TEAEs:  1 subject in the OKZ 120 mg 
4-week cumulative dose group reported face edema and 2 subjects in the placebo group 
reported exacerbation of RA. 
Treatment-emergent AEs considered related to the study treatment by the Investigator were 
reported at a higher incidence across the OKZ 4-week cumulative dose groups compared 
with the placebo group.  The overall incidence of drug-related TEAEs was highest in the 
OKZ 60 mg 4-week cumulative dose group.  The most commonly reported individual 
drug-related TEAEs were nasopharyngitis, stomatitis, injection site erythema, rash, and 
headache.  The incidences of drug-related TEAEs of injection site erythema, injection site 
swelling, and nasopharyngitis were highest in the OKZ 240 mg 4-week cumulative dose 
group.  There were no deaths reported in any treatment group during Study RA0083.  Serious 
TEAEs were reported by 2 subjects (6.9%) in the placebo group (RA in both subjects; both 
events led to study discontinuation and were considered resolved after 44 days) and 1 subject 
each (3.1% and 3.8%) in the OKZ 60 and 240 mg 4-week cumulative dose groups (cellulitis 
and pneumonia, respectively).  No SAEs were reported by subjects in the OKZ 120 mg 
4-week cumulative dose group.  Both the cellulitis and pneumonia SAEs in subjects 
receiving OKZ were reported as moderate in intensity and not related to the study treatment.  
The cellulitis event led to study discontinuation and resolved after 11 days.  The pneumonia 
event required hospitalization, but the subject continued in the study and the event resolved 
after 57 days. 
Study RA0089 
Overall, 7 subjects (6.8%) reported 33 TEAEs leading to discontinuation during the study.  
The mostly commonly reported TEAEs leading to discontinuation were in the SOC of 
infections and infestations (5 subjects [4.9%]). 
Treatment-emergent AEs were reported by 90 subjects (87.4%).  The most commonly 
reported TEAEs (>10% of subjects) were in the SOCs of infections and infestations; GI 
disorders; general disorders and administration site condition; skin and SC tissue disorders; 
investigations; injury, poisoning and procedural complications; respiratory, thoracic and 
mediastinal disorders; musculoskeletal and connective tissue disorders; nervous system 
disorders; eye disorders; metabolism and nutrition disorders; and vascular disorders. 


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When considering TEAEs by CTCAE grade, the majority of subjects (89 subjects [86.4%]; 
571 events) had CTCAE Grade 1 TEAEs.  At the SOC level, infections and infestations 
occurred most frequently (65.0% of subjects) with a maximum intensity of mild (62 subjects 
[60.2%]; 135 events), moderate (9 subjects [8.7%]; 16 events), or severe (4 subjects [3.9%]; 
4 events). 
A total of 73 subjects (70.9%) reported TEAEs that were judged to be related to the study 
treatment by the Investigator.  Within the SOC of infections and infestations, 44 subjects 
(42.7%) reported 89 TEAEs that were judged to be related to the study treatment by the 
Investigator. 
There were no deaths reported in Study RA0089. 
A total of 14 subjects (13.6%) reported 20 SAEs.  The highest incidence of events was 
observed for the infections and infestations SOC (7 subjects [6.8%]).  At the PT level, 
cellulitis occurred with the highest frequency (2 subjects [1.9%]; 2 events).  No other PT was 
reported more than once. 
Of the SAEs reported, cellulitis (2 subjects), gastroenteritis, pleurisy, pneumonia, elevated 
liver enzymes, pulmonary tuberculosis (TB), interstitial lung disease, and epiglottitis 
(1 subject each) were judged to be related to the study treatment by both the Investigator and 
Sponsor. 
One SAE (infectious pleural effusion) was judged to be related to the study treatment by the 
Investigator, but not related by the Sponsor. 
There was 1 subject who reported an SAE of pulmonary TB that was considered by the 
Investigator to be related to OKZ.  The subject had no history of active or latent TB, chronic 
productive cough, persistent fever, persistent asthenia, human immunodeficiency virus (HIV) 
infection, or organ transplants.  Chest imaging revealed increased infiltration of bilateral lung 
fields, borderline heart size, and calcified lesion over the left aspect of the upper 
mediastinum.  Chest X-ray and bronchial culture were positive for TB, and the diagnosis was 
confirmed by acid fast bacillus stain.  The subject was treated with 250 mg tranexamic acid 
4 times per day/capsule, rifampin 5 tablets daily, and ethambutol 800 mg daily for TB.  There 
was no action taken with OKZ due to the event, as the event was confirmed during the 
follow-up period of the study, after the last dose of study treatment had been administered.  
The subject completed the entire anti-TB treatment course, and the event resolved.  The 
Investigator and the Sponsor assessed the event to be related to OKZ. 


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2.2.3.3 
Summary of Efficacy Data from Olokizumab Studies 
Study RA0010 
Preliminary efficacy data in terms of the Disease Activity Score 28-joint Count 
(DAS28) (CRP) were obtained in Study RA0010.  An indication of the efficacy of OKZ was 
obtained in the subpopulation of subjects with a baseline DAS28 (CRP) of >3.2 (i.e., those 
with moderate to high disease activity).  Although the number of subjects falling into this 
moderate to high category was small, improvements in DAS28 (CRP) were seen following 
OKZ + MTX administration, especially in the OKZ 1 mg/kg SC + MTX group. 
Study RA0056 
In Study RA0056, a greater improvement in least squares (LS) mean DAS28 (CRP) from 
baseline at Week 12 was observed across all OKZ treatment groups compared with the 
placebo groups, with the greatest improvement observed in the OKZ 240 mg q2w group.  
The overall dose-response trend (across the q4w and q2w dosing frequencies) was 
statistically significant (p<0.0001).  Comparisons of dosing frequency (q2w versus q4w) and 
dose-by-dose frequency interactions (q2w trend versus q4w trend) were not statistically 
significant.  The secondary efficacy variables were ACR 20% (ACR20), 50% (ACR50), and 
70% (ACR70) response criteria at Week 12 for the OKZ and placebo treatment groups.  The 
ACR20 and ACR50 estimated response rates at Week 12 were higher in all OKZ treatment 
groups compared with the placebo groups.  Very few subjects in any treatment group were 
ACR70 responders; however, those subjects that were ACR70 responders were all in the 
OKZ treatment groups. 
Study RA0083 
In Study RA0083, a greater improvement in LS mean change from baseline in DAS28 (CRP) 
at Week 12 was observed across all OKZ 4-week cumulative dose groups compared with the 
placebo group, with the greatest improvement observed in the OKZ 240 mg 4-week 
cumulative dose group.  The overall dose-response trend (for the 4-week cumulative dose) 
was statistically significant (p<0.0001), as were the differences between each treatment 
group versus placebo (p<0.0001 for each treatment group).  The comparisons of dosing 
frequency (OKZ 120 mg group [60 mg q2w versus 120 mg q4w] and OKZ 240 mg [120 mg 
q2w versus 240 mg q4w]), dosing frequency effect (q4w versus q2w dose frequency), and 
dose frequency interactions (individual doses by dose frequency interaction) were not 
statistically significant.  The ACR20 and ACR50 estimated response rates at Week 12 were 
higher in all OKZ 4-week cumulative dose groups compared with the placebo group.  The 
overall dose-response trend at Week 12 was statistically significant, as were all treatment 


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group comparisons versus placebo.  Very few subjects were ACR70 responders; however, 
14 of the 15 subjects that were ACR70 responders were in OKZ treatment groups. 
 Study RA0057 
Study RA0057 was designed to collect safety data and had no primary efficacy endpoints; 
however, some trends could be identified.  All treatment groups described in 
Study RA0057 belong to Study RA0056, from which the subjects were transferred to a single 
treatment group of 120 mg q2w in Study RA0057.  The change in DAS28 (CRP) was 
summarized at Weeks 12, 24, and 48 relative to baseline (Week 0) in Study RA0056 and 
baseline in Study RA0057.  Relative to the Study RA0057 baseline, all treatment groups 
(except OKZ 60 mg q4w group at Week 12) showed a further decrease in DAS28 (CRP) at 
Weeks 12, 24, and 48.  Subjects switching from the placebo group in Study RA0056 to 
treatment with OKZ 120 mg q2w in Study RA0057 showed a marked improvement in 
DAS28 (CRP), similar to the improvement shown by subjects in the OKZ groups in the 
parent RA0056 study.  The ACR20, ACR50, and ACR70 response criteria were summarized 
at Weeks 0, 12, 24, and 48.  Relative to the Study RA0056 baseline, a clinically relevant 
proportion of subjects achieved ACR20 at Week 24 across all the treatment groups, ranging 
from 30.0% of subjects in the OKZ 240 mg q4w group to 66.7% of subjects in the OKZ 
240 mg q2w group.  Fewer subjects achieved ACR50 at Week 24, ranging from 11.8% to 
43.8% of subjects.  Very few subjects achieved ACR70 at Week 24, ranging from 0% to 25% 
of subjects. 
Study RA0089 
All treatment groups described in Study RA0089 belong to Study RA0083, from which the 
subjects were transferred to a single treatment group of 120 mg q2w in Study RA0089.  The 
baseline values in Study RA0089 corresponded to the baseline values from Study RA0083, 
and the Week 0 values in Study RA0089 corresponded to the Week 12 values from 
Study RA0083.  The change in DAS28 (CRP) was summarized at Weeks 12, 24, and 
48 relative to baseline (Week 0) in Study RA0083 and baseline in Study RA0089.  Relative 
to the Study RA0089 baseline, all treatment groups showed a notable decrease in 
DAS28 (CRP) at Weeks 12, 24, and 48.  Subjects assigned to placebo in 
Study RA0083 showed marked improvements in all parameters of disease activity after they 
began therapy with OKZ in Study RA0089, with an improvement in DAS28 (CRP) similar to 
the improvement shown by subjects in the OKZ groups in the parent RA0083 study.  The 
ACR20, ACR50, and ACR70 response criteria were summarized at Weeks 0, 12, 24, and 48.  
Relative to the Study RA0083 baseline, a clinically relevant proportion of subjects achieved 
ACR20 at Week 24 across all the treatment groups, ranging from 46.7% of subjects in the 
OKZ 120 mg q4w treatment group to 81.8% in OKZ 240 mg q4w treatment group.  Fewer 


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subjects achieved ACR50 at Week 24, ranging from 40.0% to 63.6% of subjects.  Only a 
small proportion of subjects achieved ACR70 at Week 24, ranging from 10.0% to 54.5% of 
subjects. 
2.2.3.4 
Summary of Pharmacokinetic Data from Olokizumab Studies 
Studies RA0001, RA0010, and RA0056 
Single dose PK of OKZ were studied in Studies RA0001 (healthy non-Asian), 
RA0074 (healthy Japanese), and RA0010 (subjects with RA).  Sparse sampling following 
repeated administration of OKZ was performed in non-Asian and Asian subjects with RA in 
Studies RA0056 and RA0083, respectively.  Exposure to OKZ following single dose 
administration appeared to be similar in non-Asian and Asian volunteers.  Following SC 
administration, maximum plasma concentrations were generally reached between 
approximately 4 days (in Study RA0074, 6 mg/kg SC) and 14 days (in Study RA0001, 
1 mg/kg SC).  Over the 0.3 to 6 mg/kg SC dose range evaluated in Studies RA0001 and 
RA0074, the median terminal half-life ranged from 30.1 to 39.6 days.  The PK profile of 
OKZ in Study RA0010 (non-Asian RA volunteers) was similar to that seen in healthy 
volunteers in Study RA0001 for the same doses.  The maximum concentration of OKZ 
following SC administration was achieved within a median of 7 to 13 days following 
3 mg/kg and 1 mg/kg dosing, respectively.  The estimate of terminal half-life across doses 
and routes of administration was 31 days (median range:  12 to 63 days). 
Pharmacokinetic bioavailability of OKZ via SC administration was estimated to be 63% 
across the 3 studies evaluated (Studies RA0001, RA0010, and RA0056).  Population PK 
analysis utilizing sparse plasma concentration versus time data collected in RA0056 along 
with intense PK data collected in Studies RA0001 and RA0010 indicated similar PK 
characteristics of OKZ in subjects with moderately to severely active RA and in healthy 
subjects.  Body weight was found to be the only “statistically significant” covariate on 
volume of distribution. 
2.2.4 
Rationale for Dose Selection 
The dose regimens of OKZ to be evaluated in this Phase III study are 64 mg q2w and 
64 mg q4w.  These are the same doses investigated in the 3 core studies (CL04041022, 
CL04041023, and CL04041025).  The rationale for selecting these dose regimens is provided 
below. 
In the Phase II studies, RA0056 and RA0083, the primary efficacy variable was met in all 
OKZ treatment groups, demonstrating improvement compared with placebo groups and a 
statistically significant overall dose-response trend as evidenced by the change from baseline 
in DAS28 (CRP).  Study RA0001 demonstrated that OKZ was pharmacologically active at 


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all doses tested.  This finding was supported by the PD and clinical findings of the 
subsequent Phase I/IIa study, RA0010, conducted in subjects with mild to moderate RA.  The 
data from these studies highlight the potency of OKZ as well as the existence of 
dose-response dependence, shown by the results of the concentration effect relationship 
evaluation for efficacy outcomes.  The relatively flat concentration-effect relationship for 
safety outcomes and the dose-dependent occurrence of injection site reactions for the 
OKZ 240 mg dose regimen, in contrast to the modest efficacy gains versus the 120 mg dose 
regimens, led to the exclusion of the 240 mg dose regimen from further evaluation in the 
Phase III program.  This decision was further supported by the inconvenience of 
administering 2 injections of 120 mg OKZ in order to achieve the 240 mg dose level even 
with the new 160 mg/mL formulation. 
In a thorough dose-response analysis using the combined database from the 2 Phase II 
studies, it was confirmed that a plateau of efficacy was reached at a cumulative monthly dose 
of 120 mg.  The 60 mg monthly dose seemed to have slightly lower efficacy in the modeling 
analysis; however, in both Phase II studies that were conducted in relatively difficult to treat 
population of subjects resistant to 1 or more TNFi biologics, the 60 mg monthly treatment 
groups showed statistically significant efficacy.  While there was not a detectable increase in 
safety events observed with doses above 120 mg monthly, there also did not seem to be a 
substantial gain in efficacy with higher doses.  Thus, the 120 mg monthly dose, administered 
as either 60 mg q2w or 120 mg q4w, seemed to be associated with optimal efficacy/safety 
ratio.  The lower 60 mg monthly dose was also efficacious with a potential for a safety 
advantage, especially over the long-term treatment. 
Due to an increase in the concentration of the formulation subsequent to Phase II, it should 
be noted that the lowest volume that can be used in Phase III (0.4 mL) results in a nominal 
dose of 64 mg rather than 60 mg. 
Consequently, using the primary efficacy outcomes from individual Phase II studies, and 
additional dose-response analysis performed on a combined database derived from these 
studies, 2 OKZ dose regimens were selected for further investigation:  64 mg SC q2w and 
64 mg SC q4w since the totality of the data strongly suggested that both of these dose 
regimens could potentially be successful in a large Phase III program. 
2.3 
Rationale for the Study 
The multicenter, open-label design used in this study is consistent with the precedent set for 
Phase III OLE trials of other biologics and is in accordance with health authority guidelines. 
The goal of this Phase III study is to evaluate the long-term safety, tolerability, and efficacy 
of OKZ in subjects with moderately to severely active RA who previously completed 


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24 weeks of double-blind treatment with OKZ in the core studies.  Olokizumab is expected to 
reduce the disease activity and induce an improvement in physical function.  The study is 
expected to provide long-term safety information in a large group of subjects treated with 
OKZ for up to 106 weeks. 
All subjects in this study will receive the first dose of OKZ at Week 24.  For subjects 
transitioning from the adalimumab treatment group (core study CL04041023), there will be 
no additional time added for wash out of adalimumab other than the 2 weeks between the last 
dose of adalimumab in the core study (Week 22) and first dose of OKZ in the OLE study 
(Visit 1 [Week 24]).  Similar approaches have been implemented in a number of other 
clinical studies involving adalimumab and other biologics or kinase inhibitors, and such a 
switch from one biologic to another is commonly observed in clinical practice without 
significant safety concerns (Bykerk et al, 2012; Furst et al, 2007; Schiff et al, 2009; 
Wollenhaupt et al, 2014).  Despite this, the possibility for an increased risk of AEs, including 
infections, cannot be excluded (Humira® [adalimumab] Prescribing Information).  This 
potential risk will be mitigated by closely monitoring all subjects throughout the OLE study. 
It is possible that subjects assigned to the adalimumab treatment group in core study 
CL04041023 might achieve remission or a decrease in disease activity while being treated 
with adalimumab and switching to another biological treatment may lead to undesirable 
results for such subjects.  However, it will not be known at the completion of the 24-week 
double-blind Treatment Period whether a subject was assigned to the adalimumab treatment 
group.  Therefore, following a subject’s completion of the core study and prior to enrollment 
in the OLE study, the Investigator and subject will decide jointly whether the subject will 
continue with the open-label administration of OKZ in this OLE study or exit the study. 
2.4 
Benefit/Risk Assessment 
Olokizumab has undergone extensive nonclinical testing, and 7 clinical studies have been 
completed.  In the difficult-to-treat population of RA patients who previously failed TNFi 
therapy, OKZ has demonstrated efficacy in 2 Phase II studies (Study RA0056 [extended with 
Study RA0057] in 221 subjects and Study RA0083 [extended with Study RA0089] in 
119 Asian subjects) using the doses of OKZ that are proposed for this Phase III study; at 
higher doses, the safety profile was similar.  Bioavailability of OKZ via SC administration 
was estimated to be 63% across 3 studies evaluated (Studies RA0056, RA0001, and 
RA0010). 
The clinical program to date suggests that OKZ is effective in reducing disease symptoms in 
subjects with RA, and that OKZ is generally well tolerated (for further efficacy and safety 
information, refer to the most recent version of the Investigator’s Brochure).  The safety 
profile of OKZ is consistent with the known effects of IL-6 blockers.  Overall, the 


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benefit/risk profile for subjects in the proposed study is favorable.  The study will provide 
valuable information on the efficacy, safety, and tolerability of OKZ in subjects with RA, 
which may subsequently help to address the unmet medical needs for this patient population. 
The design of this study contains adequate measures to mitigate risk factors and adequate 
safety monitoring to protect the subjects.  All subjects will be eligible for modification of 
background therapy (i.e., MTX for all subjects, sulfasalazine and/or hydroxychloroquine for 
subjects assigned rescue medication in the core studies, and oral corticosteroids [if 
applicable]), administration of parenteral corticosteroids, and modification of non-steroidal 
anti-inflammatory drugs (NSAIDs) after 12 weeks of open-label treatment (see 
Section 6.13.3), according to Investigator discretion and local practice.  In addition, all 
subjects will be assessed at Visit 4 (Week 36) and then at all onsite visits until the end of the 
study treatment administration for response to treatment, with nonresponders defined as 
subjects who do not improve by at least 20% in swollen and tender joint counts (66-68 joint 
assessment) from the Core Baseline assessment.  Investigators will be requested to review 
carefully the response status at these time points and make appropriate actions based on local 
guidelines regarding management of the subjects, including possible adjustments in 
background therapy or withdrawal from the study. 
In the context of the progressive, severe, and debilitating nature of RA, the balance between 
risks that have been identified from cumulative safety data for OKZ and the anticipated 
efficacy/benefit remains favorable. 
 


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3. STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is to evaluate the long-term safety and tolerability of 
OKZ 64 mg administered SC q2w or q4w in subjects with moderately to severely active RA 
who previously completed 24 weeks of double-blind treatment in the core studies. 
3.2 
Secondary Objectives 
The secondary objectives of this study are as follows: 
 
To evaluate the long-term efficacy of OKZ 
 
To evaluate the long-term immunogenicity of OKZ 
 
To evaluate the physical function and quality of life of subjects receiving long-term 
treatment with OKZ 


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4. SUMMARY OF STUDY ENDPOINTS 
The following safety, efficacy, and immunogenicity endpoints will be assessed to evaluate 
long-term treatment with OKZ 64 mg q2w or OKZ 64 mg q4w. 
4.1 
Safety Endpoints 
The following safety endpoints will be evaluated: 
 
Nature, incidence, severity, and outcome of AEs, including SAEs and AEs of special 
interest (AESIs) 
 
Follow-up-adjusted incidence rates (IR) and event rates (ER) (per 100 subject-years 
[SY] of follow-up) for SAEs and AESIs 
 
Proportions of subjects with clinically significant laboratory abnormalities 
 
Assessment of changes over time in clinical laboratory parameters, vital sign 
measurements, and physical examination findings 
 
Time from first exposure to OKZ to the first occurrence of any major adverse cardiac 
event (MACE) 
 
Incidence and titer of antidrug antibodies (ADAs) to OKZ, incidence of neutralizing 
antibodies, and the time course of antibodies 
4.2 
Efficacy Endpoints 
For the efficacy endpoints, comparison will be made with Core Baseline values (i.e., Week 0 
baseline values in the core study) and OLE Baseline values (i.e., Week 24 baseline values in 
the OLE study) for most parameters, as defined in Section 9.4.1.  For subjects from 
Study CL04041025 who initiate OKZ treatment at Week 16 of the core study after having 
completed 16 weeks of placebo treatment, changes from the last pre-OKZ value will also be 
summarized. 
The following efficacy endpoints will be evaluated: 
 
Proportion of subjects achieving an ACR20, ACR50, and ACR70 response who 
remain on randomized open-label treatment and in the study, assessed at all applicable 
time points 
 
Proportion of subjects with Simplified Disease Activity Index (SDAI) ≤3.3 remission, 
who remain on randomized open-label treatment and in the study, assessed at all 
applicable time points 


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 
Proportion of subjects with Disease Activity Score 28-joint count (DAS28) low 
disease activity (based on DAS28 C-reactive protein [CRP] <3.2), who remain on 
randomized open-label treatment and in the study, assessed at all applicable time 
points 
 
Change from baseline over time in DAS28 (CRP), assessed at all applicable time 
points 
 
Change from baseline over time in the measure of physical ability based on Health 
Assessment Questionnaire-Disability Index (HAQ-DI), assessed at all applicable time 
points 
 
Proportion of subjects with improvement from baseline in HAQ-DI score ≥0.22, who 
remain on randomized open-label treatment and in the study, assessed at all applicable 
time points 
 
Change from baseline over time in the scores for the following patient-reported 
outcomes (PRO) measures, assessed at all applicable time points: 
 Short Form-36 (SF-36) Physical Component Summary (PCS) and Mental Component 
Summary (MCS) total scores 
 European Quality of Life-5 Dimensions (EQ-5D) 
 Work Productivity Survey-Rheumatoid Arthritis (WPS-RA) 
 Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-Fatigue) 
 
Change from baseline over time in SDAI and Clinical Disease Activity Index (CDAI), 
assessed at all applicable time points 
 
Proportion of subjects with moderate to good responses for EULAR based on DAS28 
(CRP), who remain on randomized open-label treatment and in the study, assessed at 
all applicable time points, where a moderate response is defined as either DAS28 
(CRP) ≤5.1 with an improvement from baseline in DAS28 (CRP) >0.6 and ≤1.2, or 
DAS28 (CRP) >3.2 with an improvement from baseline in DAS28 (CRP) >1.2, and a 
good response is defined as DAS28 (CRP) ≤3.2 with an improvement from baseline in 
DAS28 (CRP) >1.2 
 
Change from baseline to all time points in the components of the ACR response 
criteria 


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4.3 
Immunogenicity 
The following immunogenicity endpoint will be evaluated: 
 
Impact of ADAs to OKZ on subject safety and efficacy 


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5. INVESTIGATIONAL PLAN 
5.1 
Summary of Study Design 
This is a multicenter, open-label, Phase III study that will evaluate the efficacy and safety of 
OKZ in subjects with moderately to severely active RA who previously completed 24 weeks 
of double-blind treatment in Study CL04041022, CL04041023, or CL04041025. 
This study will be conducted at approximately 250 global sites across Russia, Belarus, 
the US, Europe, the United Kingdom (UK), Asia, and Latin America.  It is estimated that 
approximately 1880 subjects will be enrolled. 
Subjects will be assessed for eligibility to enter the study at Visit 1 (which is the same visit as 
the Week 24 visit of the core studies), and eligible subjects will be assigned to 1 of 2 dosing 
frequencies (q2w or q4w) of 64 mg OKZ as described in Section 5.2. 
The study will consist of an 82-week open-label Treatment Period, with the last dose of OKZ 
being administered at Week 104.  After completion of the open-label Treatment Period, 
subjects will come to Visit 10 (End of Treatment [EoT]/Week 106) 2 weeks after the last 
dose of OKZ for scheduled safety and efficacy assessments.  After Visit 10 (EoT/Week 106), 
subjects will be scheduled for Safety Follow-Up Visits SFU-1 (Week 108), SFU-2 
(Week 112), and SFU-3 (Week 126) to perform adequate safety assessments. 
The total amount of time to complete the OLE study will be approximately 102 weeks 
(inclusive of the open-label Treatment Period and the Safety Follow-Up Period).  The total 
amount of time to complete both the core study and the OLE study will be approximately 
130 weeks (2.5 years) (inclusive of the Screening, double-blind Treatment Period, open-label 
Treatment Period, and Safety Follow-Up Period). 
Subjects who discontinue treatment prematurely will be required to come to Visit 10 
(EoT/Week 106) 2 weeks after the last dose of study treatment for scheduled efficacy and 
safety assessments.  These subjects will subsequently be followed for an additional 20 weeks 
(i.e., 22 weeks after the final dose of study treatment) during a Safety Follow-Up Period. 
A schematic of the study design is presented in Figure 1.  The Schedule of Events to be 
conducted during the 82-week open-label Treatment Period (Week 24 through Week 106) 
and the Safety Follow-Up Period (Week 106 through Week 126) is presented in Table 1.


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Figure 1 
CL04041024 (CREDO 4) Study Schematic 
 
 
 
 
 
 
 
 
 
 
 
Week 0 
Week 24 
Week 104 
Week 106 
Week 108 
Week 112 
Week 126
Core Baseline 
OLE Baseline 
Last Dose 
EoT 
Safety 
Safety 
Safety 
 
Follow-Up 
Follow-Up 
Follow-Up  
Abbreviations:  EoT = End of Treatment; MTX = methotrexate; N = total number of subjects; OKZ = olokizumab; OLE = open-label extension; q2w = once 
every 2 weeks; q4w = once every 4 weeks; R = randomization; SC = subcutaneous(ly). 
OKZ 64 mg SC q4w + MTX 
Open-label Treatment Period 
Weeks 24 to 106 
OKZ 64 mg SC q2w + MTX 
Subjects who 
have completed 
24 weeks of 
treatment in the 
core studies 
(N=1880) 
Safety Follow-Up Period 
Weeks 106 to 126 
Double-blind 
Treatment Period 
Weeks 0 to 24 
Enter Safety  
Follow-Up 
R 


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Table 1 
CL04041024 (CREDO 4) Schedule of Events (Open-Label Treatment Period and Safety Follow-Up Period) 
Assessments 
OLE 
Baseline 
Open-Label Treatment Period 
EoT 
Safety Follow-Up Period 
Visit 
1a 
2 
3 
4 
5 
6 
7 
8 
9 
10 
SFU-1 
SFU-2 
SFU-3 
Week 
24 
26 
28 
36 
44 
52 
64 
76 
88 
106 (+2b) 108 (+4b) 112 (+8b) 126 (+22b) 
Visit Window (days) 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±7 
±7 
±7 
Obtain informed consent 

 
 
 
 
 
 
 
 
 
 
 
Determine eligibility for OLE 


 
 
 
 
 
 
 

 
 
 
Height 













Weight 

 
 
 





Physical examination 
c
 
c 
 

c


c
Vital signsd 
 
 



 
 
 
Contraceptive history/status 







Concomitant and prior medications/non-drug 
therapy 







Randomization 
 

 
 
 
 
 
 
 
 
 
 
 
Training for study treatment administratione 
 
 
 
 
 
 
 
 
 
 
 
 
Study treatment allocation through IWRS 
 
f 
 
 
 
 
 
 
 
 
 
 
 
Administer study treatmentg,h 
i,j 
f,i,j 
i,j 



 
 
 
Study treatment compliancek 





 
 
 
EFFICACY ASSESSMENTS 
Patient Global Assessment of Disease Activity 
(VAS) 
 



 
 
 

 


Patient Assessment of Pain (VAS) 
 



 
 
 

 


HAQ-DI 
 

 
 
 
 
 
 
 

 


SF-36, EQ-5D, FACIT-Fatigue, and WPS-RA 
 

 


 
 
 

 


Joint counts (Independent Joint Assessment)l 


 

 
 


 


Assessment of nonrespondersl 


 



 




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Assessments 
OLE 
Baseline 
Open-Label Treatment Period 
EoT 
Safety Follow-Up Period 
Visit 
1a 
2 
3 
4 
5 
6 
7 
8 
9 
10 
SFU-1 
SFU-2 
SFU-3 
Week 
24 
26 
28 
36 
44 
52 
64 
76 
88 
106 (+2b) 108 (+4b) 112 (+8b) 126 (+22b) 
Visit Window (days) 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±7 
±7 
±7 
Physician Global Assessment (VAS) 
 

 

 
 
 

 


CRP 
 

 

 
 
 

 


ESR 
 

 

 
 
 

 


Safety Assessments 
AEs/SAEsn 







IGRAo 

 
 
 
 
 
 
 
 

 
 
 
Pregnancy testp 


 
 

 
 





INR, aPTT, fibrinogenq 


 
 

 

 





Lipid panel (fasting)r 


 
 

 

 





CV risk panels 


 
 

 

 





CV risk assessmentt 


 
 









Hematologyu 

 
 

 
 


 


Chemistry panelv 

 

 
 





HbA1cw (only for subjects with diabetes 
mellitus) 













Urinalysisx 


 
 

 

 


 
 
 
PK blood samples 
 y 
 



 

 


 
 
 
ADAs 
  

 
 

 

 
 

 
 
 
ANA and anti dsDNA antibody 
 

 
 

 

 
 

 
 
 
Assess injection site reactions 

 
 
 
 
 
 
 

 
 

TB risk questionnaire 


 
 
 
 
 
 
 

 
 

Chest X-rayz 


 
 
 
 
 
 
 

 
 

12-lead ECG 


 
 
 
 
 
 
 

 
 
 


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Assessments 
OLE 
Baseline 
Open-Label Treatment Period 
EoT 
Safety Follow-Up Period 
Visit 
1a 
2 
3 
4 
5 
6 
7 
8 
9 
10 
SFU-1 
SFU-2 
SFU-3 
Week 
24 
26 
28 
36 
44 
52 
64 
76 
88 
106 (+2b) 108 (+4b) 112 (+8b) 126 (+22b) 
Visit Window (days) 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±7 
±7 
±7 
Subject Diaryaa 

 
 
 
 
 
 
 

 
 

Abbreviations:  ADA = antidrug antibody; AEs = adverse events; ALT = alanine aminotransferase; ANA = antinuclear antibody; ApoB = apolipoprotein B; 
ApoA1 = apolipoprotein A1; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; BNP = brain natriuretic peptide; BP = blood 
pressure; CRP = C-reactive protein; CV = cardiovascular; dsDNA = double-stranded DNA; ECG = electrocardiogram; EoT = End of Treatment; EQ-
5D = European Quality of Life-5 Dimensions; ESR = erythrocyte sedimentation rate; FACIT-Fatigue = Functional Assessment of Chronic Illness 
Therapy-Fatigue Scale; GGT = gamma-glutamyl transferase; HAQ-DI = Health Assessment Questionnaire-Disability Index; HbA1c = glycosylated hemoglobin; 
HDL = high-density lipoprotein; IEC = Independent Ethics Committee; IGRA = interferon-gamma release assay; INR = international normalized ratio; IRB = 
Institutional Review Board; IWRS = Interactive Web Response System; LDL = low-density lipoprotein; NT-proBNP = N-terminal pro-hormone of brain 
natriuretic peptide; OKZ = olokizumab; OLE = open-label extension; PFS = pre-filled syringe(s); PK = pharmacokinetic(s); PRO = patient-reported outcomes; 
RBC = red blood count; SAE = serious adverse event; SC = subcutaneous(ly); SF-36 = Short Form-36; SJC = swollen joint count; TB = tuberculosis; TJC = 
tender joint count; WBC = white blood count; WPS-RA = Work Productivity Survey – Rheumatoid Arthritis; VAS = Visual Analog Scale. 
a. 
All subjects will begin the OLE study at Visit 1.  The baseline visit for the OLE study is the same visit as the Week 24 visit in the core studies. 
b. The number of weeks (+2, +4, +8, or +22) after the last dose of the study treatment. 
c. 
Complete physical examination should be performed at these visits (Section 7.4.7.1). 
d. Vital signs include temperature, heart rate, BP, and respiratory rate. 
e. 
Subjects (and their caregivers, if applicable) will be trained to administer the study treatment at Visit 1, and the Investigator must observe the first 2 
administrations (Visits 1 and 2 for subjects receiving OKZ 64 mg q2w or Visits 1 and 3 for subjects receiving OKZ 64 mg q4w) to ensure that proper 
procedures are followed.  This training may be repeated at any visit to the study site if requested by the subject or caregiver, or if deemed appropriate by 
the Investigator. 
f. 
Study treatment allocation and administration at Visit 2 (Week 26) is only for subjects assigned to the OKZ 64 mg q2w treatment group. 
g. If desired, SC injections may be rotated among the thighs and abdomen. 
h. Study treatment will be administered every 2 or 4 weeks (according to assigned OKZ treatment regimen) through the last dose of study treatment at 
Week 104 (not shown on this Schedule of Events). 
i. 
Subjects will remain at the study site for at least 2 hours after the first injection of study treatment (Visit 1 [OLE Baseline/Week 24]) and for at least 
30 minutes after the second administration of study treatment (Visit 2 [Week 26] for subjects receiving OKZ 64 mg q2w and Visit 3 [Week 28] for 
subjects receiving OKZ 64 mg q4w) to be assessed for the onset of any systemic injection reactions (see Section 7.4.3.2 and Appendix 3 [Section 13.3]). 
j. 
Administration of study treatment must be observed by the Investigator for the first 2 administrations of OKZ 64 mg q2w (Visit 1 [Week 24] and Visit 2 
[Week 26]) or OKZ 64 mg q4w (Visit 1 [Week 24] and Visit 3 [Week 28]). 
k. Starting from Visit 4 (Week 36), subjects must return to the study site eiher all used and unused vials of study treatment or empty cartons of used PFS 
and unused PFS at each scheduled visit.  Compliance will be assessed by the Investigator based on the number of used vials or PFS cartons as 
applicable. 


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l. 
Joint assessor will be independent to the rest of the study team.  An independent joint assessor, blinded to other study assessments as well as the dosing 
regimen, will be identified at each study site to perform the SJC and TJC.  To ensure consistent joint evaluation throughout the study, individual subjects 
should be evaluated by the same joint assessor as in the core studies for all study visits whenever possible. 
m. Starting at Visit 4 (Week 36) and then at all onsite visits until the end of the open-label Treatment Period (Visit 10 [EoT/Week 106]), all subjects will be 
assessed for response to treatment, with nonresponders defined as subjects who do not improve by at least 20% in SJC and TJC (66-68 joint assessment) 
from the Core Baseline assessment. 
n. Adverse events and SAEs are reported from OLE Baseline. 
o. At scheduled visits, IGRA testing should be performed only for subjects who had a negative IGRA result at the previous assessments (including 
Week 22 assessment of the core study) unless other approach is required by local practice. 
p. Required for females of childbearing potential only.  May be repeated more frequently (i.e., between study visits) if required by local practices, 
IRB/IECs or local regulations, if a menstrual cycle is missed, or if potential pregnancy is otherwise suspected.  If more frequent testing is required, the 
study site will provide the patient with further guidance and a home testing kit. 
q. Samples for INR, aPTT, and fibrinogen should be collected prior to all other blood samples. 
r. 
Lipid panel includes total cholesterol, HDL, LDL, triglycerides, lipoprotein (a), apolipoproteins (ApoB, ApoA1, and ApoB:ApoA1 ratio), and 
adiponectin. 
s. 
Cardiovascular risk panel includes NT-proBNP, BNP, and homocysteine. 
t. 
Cardiovascular risk assessment includes alcohol use with an evaluation of average number of drinks consumed weekly, tobacco use with an evaluation 
of average number of tobacco products consumed daily, central obesity, use of any lipid-lowering medication or any other CV agents, prior history of 
CV events and diabetes, family history of premature CV disease (age <55 years for males and <65 years for females), and other risks. 
u. Hematology includes RBC, WBC with differential, hemoglobin, hematocrit, and platelet count. 
v. At all visits, subjects must attend study sites after fasting for at least 9 hours (water and concomitant medications are permitted).  Chemistry panel 
includes urea nitrogen, creatinine, fasting glucose, calcium, sodium, potassium, chloride, total protein, total bilirubin, direct bilirubin, indirect bilirubin, 
ALT, AST, alkaline phosphatase, GGT, and albumin. 
w. Glycosylated hemoglobin will be assessed at Visits 2, 6, 8, and 10 only for subjects with a confirmed diagnosis of diabetes mellitus prior to Visit 2 
(Week 26).  If a diagnosis of diabetes mellitus is confirmed after Visit 2 (Week 26), then HbA1c will be assessed at all subsequent visits as indicated in 
the Schedule of Events. 
x. Urinalysis includes specific gravity, pH, protein, glucose, ketones, blood, and leukocyte esterase. 
y. The Visit 1 (OLE Baseline/Week 24) PK samples are the last samples to be collected in the core studies.  These samples must be collected prior to 
administration of OKZ, and the samples will be analyzed and included in the data set of the core study in which the subject participated, according to the 
procedures detailed in the core study protocol.  The PK sample will not be analyzed as part of the OLE data set. 
z. 
If chest X-ray (both posteroanterior and lateral) was performed within 8 weeks, the assessment should not be repeated at the scheduled visit. 
aa. At Visit 1 (OLE Baseline/Week 24), Subject Diary will be distributed, and subjects will be trained to properly complete the Subject Diary.  At Visit 1 
(OLE Baeline/Week 24) and at each scheduled visit during the open-label Treatment Period (Visits 2 through 9), the Investigator will provide the 
subject with preprinted dates for each dose of study treatment that will be administered prior to the next scheduled visit.  Following each administration 
of study treatment, the subject will record the date, time, and location of each study treatment administration; the identity of the person who 
administered the study treatment; any problems experienced during the injection; and any complaints, signs, or symptoms that occur during or after the 
injection.  Investigators will collect and review the Subject Diary at Visits 2 (Week 26) through 10 (EoT/Week 106). 


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5.2 
Discussion of Study Design 
After completing the 24-week double-blind Treatment Period in 1 of the 3 core studies, an 
estimated 1880 subjects will be randomized to 1 of 2 open-label treatment groups: 
1. OKZ 64 mg q4w:  SC injection of OKZ 64 mg q4w + MTX 
2. OKZ 64 mg q2w:  SC injection of OKZ 64 mg q2w + MTX 
Subjects will be randomized based on the treatment received in the core studies.  Subjects 
who received OKZ (q2w or q4w) in the core study in which they participated (including 
subjects who received placebo in Study CL04041025 and were re-randomized to OKZ at 
Week 16) will receive the same OKZ treatment regimen in the OLE study.  Subjects who 
received placebo (Study CL04041022 and Study CL04041023) or adalimumab 
(Study CL04041023) in the core study in which they participated will be randomized in a 
1:1 ratio to OKZ 64 mg q2w or OKZ 64 mg q4w regimens in the OLE study. 
The total duration of OKZ treatment will depend on the subject’s treatment assignment in the 
core studies: 
 
Subjects randomized to OKZ in the 3 core studies (CL04041022, CL04041023, and 
CL04041025) will complete 106 total weeks of treatment with OKZ. 
 
Subjects randomized to placebo in Study CL04041022 and to placebo or adalimumab 
in Study CL04041023 will complete 82 total weeks of treatment with OKZ. 
 
Subjects randomized to placebo in Study CL04041025 will transition to OKZ at Week 
16 and complete 8 weeks of double-blind treatment with OKZ during the core study; 
these subjects will complete 90 total weeks of treatment with OKZ. 
Subcutaneous injections of OKZ 64 mg will be administered q2w or q4w throughout the 
open-label Treatment Period, and all subjects (and their caregivers, if applicable) will be 
trained at Visit 1 (OLE Baseline/Week 24) to administer OKZ (see Section 6.8).  
Administration of study treatment will be observed by study site staff during the first 2 
scheduled visits (Visit 1 [Week 24] and Visit 2 [Week 26] for subjects receiving OKZ 64 mg 
q2w, and Visit 1 [Week 24] and Visit 3 [Week 28] for subjects receiving OKZ 64 mg q4w).  
Detailed guidance on study treatment administration procedures will be provided in the 
Pharmacy Manual and Subject Leaflet. 
For the first 12 weeks (up to Visit 4 [Week 36]) of the open-label Treatment Period, all 
subjects will be required to remain on a stable dose of background MTX at 15 to 25 mg/week 
(or ≥10 mg/week if there is documented intolerance to higher doses) with a stable route of 


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administration (oral, SC, or intramuscular [IM]), and subjects who were assigned rescue 
medication (sulfasalazine and/or hydroxychloroquine) in the core studies will be asked to 
continue these medications without a change in dose.  Background therapy may be adjusted 
only for safety reasons according to Investigator discretion before Visit 4 (Week 36) of the 
OLE study. 
Throughout the study, concomitant treatment with folic acid ≥5 mg per week or equivalent is 
required for all subjects. 
The Investigator may, at their discretion and based on local practice, adjust therapy after 
Visit 4 (Week 36) (see Section 6.13.3), which may include adjustments to background 
therapy (i.e., MTX for all subjects, sulfasalazine and/or hydroxychloroquine for subjects 
assigned rescue medication in the core studies, and oral corticosteroids [if applicable]), 
parenteral corticosteroids, and modification of NSAIDs. 
Dose tapering of oral corticosteroids or NSAIDs is permitted according to Investigator 
discretion before Visit 4 (Week 36) (see Section 6.13.3). 
Subjects will return to the study site periodically for safety and response assessments as per 
Table 1.  Adverse events will be assessed throughout the study period and evaluated using 
the CTCAE version 4.0. 
The last dose of open-label study treatment in the OLE study will be administered at 
Week 104.  After completion of the 82-week, open-label Treatment Period, subjects will 
enter the 20-week Safety Follow-Up Period.  During the Safety Follow-Up Period, subjects 
will return for 3 visits at +4, +8, and +22 weeks after the last dose of study treatment. 
Subjects who discontinue study treatment prematurely will be required to come to Visit 10 
(EoT/Week 106) 2 weeks after the last dose of the study treatment for scheduled 
assessments.  These subjects will subsequently be followed for an additional 20 weeks (i.e., 
22 weeks after the final dose of study treatment) for a Safety Follow-Up Period. 
There will be ongoing monitoring of safety events, including laboratory findings, by R-
Pharm International or its designee.  In addition, safety will be assessed throughout the study 
by an independent Data Safety Monitoring Board (DSMB) (see Section 7.4.4 for further 
details). 
5.2.1 
Cardiovascular Risk Assessment 
The RA population is known to have an increased risk of cardiovascular (CV) events.  In 
order to fully assess the CV risks associated with OKZ, the following approach will be 
implemented: 


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1. Potential MACE will be adjudicated by an independent Cardiovascular 
Adjudication Committee (CVAC) according to a predefined charter.  The charter 
will define the criteria, data, and source documentation required to adjudicate all 
MACE. 
2. Baseline (of the core study) CV risks including individual risk factors (e.g., tobacco 
use, presence of hypertension, diabetes mellitus, and lipid profile) will be assessed. 
3. Known CV risk factors will be monitored and assessed to detect any trends over 
long-term exposure.  A CV risk assessment will be performed at OLE Baseline and 
at Visits 6 (Week 52), 8 (Week 76), and 10 (EoT/Week 106).  The CV risk 
assessment includes: 
 
Alcohol use with evaluation of average number of drinks consumed weekly 
 
Tobacco use with evaluation of average number of tobacco products consumed 
daily 
 
Central obesity 
 
Use of any lipid-lowering medication or any other CV agents 
 
Prior history of CV events and diabetes 
 
Family history of premature CV disease (age of diagnosis <55 years for males 
and <65 years for females) 
 
Other risks 
Cardiovascular risk assessment data will be provided to the CVAC for review and 
adjudication of MACE (see Section 7.4.4.2). 
5.2.2 
Safety Follow-up Assessments 
Given the long half-life of OKZ (approximately 31 days), subjects will be followed up for 
approximately 5 OKZ half-lives (i.e., 22 weeks) after the final dose of study treatment. 
For subjects remaining on randomized therapy until the last scheduled dose of study 
treatment, Visit 10 (EoT Visit) will be performed at Week 106 and extended Safety 
Follow-Up procedures will be performed at visits scheduled +4, +8, and +22 weeks after the 
last dose of study treatment (i.e., Visits SFU-1 [Week 108], SFU-2 [Week 112], and SFU-3 
[Week 126], respectively). 
Subjects who discontinue treatment early require a full safety assessment at Visit 10 
(EoT/Week 106) (see Section 5.4.2), which will take place 2 weeks after the last study 


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treatment administration.  These subjects will subsequently be followed for an additional 
20 weeks (i.e., 22 weeks after the final dose of study treatment) during a Safety Follow-Up 
Period (see Section 5.4.3). 
All subjects will be reminded of study contact information to report potential SAEs and are 
to inform the Investigator if they experience such events during the Safety Follow-Up Period 
(Section 7.4.5.4). 
5.3 
Selection of Study Population 
The study population will consist of subjects with moderately to severely active RA who 
previously completed 24 weeks of double-blind treatment in one of the core CREDO studies. 
This is an international study, and it is expected that approximately 1880 subjects will be 
randomized at approximately 250 sites across Russia, Belarus, the US, Europe, UK, Asia, 
and Latin America. 
5.3.1 
Inclusion Criteria 
Subjects may be enrolled in the study only if they meet all of the following criteria: 
1. Subject must be willing and able to sign informed consent 
2. Subject must have completed the 24-week double-blind Treatment Period in 1 of the 
3 core studies (CL04041022, CL04041023, or CL04041025). 
3. Subject must have maintained their stable dose (and route) of MTX 15 to 25 mg/week (or 
≥10 mg/week if there is documented intolerance to higher doses) during the core study 
and plan to maintain the same dose and route of administration for ≥12 additional weeks. 
4. Subjects must be willing to take folic acid or equivalent throughout the study. 
5.3.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will not be eligible for the study: 
1. Subject with any medically important condition in the core study (e.g., clinically 
significant laboratory values, frequent AEs or SAEs, infection SAEs, and/or other 
concurrent severe and/or uncontrolled medical condition) which would make this subject 
unsuitable for inclusion in the OLE study in the Investigator’s judgement. 
2. Subject has evidence of active TB 
3. Subject with a positive or repeated indeterminate interferon-gamma release assay (IGRA) 
result at Week 22 of the core study 


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 Subjects may be enrolled in the OLE study if they fulfill all 3 of the following criteria 
prior to the first dose of study treatment: 
a. Active TB is ruled out by a certified TB specialist or pulmonologist who is 
familiar with diagnosing and treating TB (as acceptable per local practice); 
b. The subject starts prophylaxis for latent TB infection (LTBI) according to 
country-specific/Centers for Disease Control and Prevention (CDC) guidelines 
(see Appendix 4 [Section 13.4]) (treatment with isoniazid for 6 months is not an 
appropriate prophylactic regime for this study and it should not be used); and 
c. The subject is willing to complete the entire course of recommended LTBI 
therapy (see Appendix 4 [Section 13.4]). 
4. Subject has planned surgery during the first 12 weeks of the OLE study 
5. Female subjects who are pregnant or lactating, or who are planning to become pregnant 
during the study or within 6 months of the last dose of study treatment 
6. Female subjects of childbearing potential (unless permanent cessation of menstrual 
periods, determined retrospectively after a woman has experienced 12 months of natural 
amenorrhea as defined by the amenorrhea with underlying status [e.g., correlative age] or 
6 months of natural amenorrhea with documented serum follicle-stimulating hormone 
levels >40 mIU/mL and estradiol <20 pg/mL) who are 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 is 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 core study 
 In the case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by documented follow-up hormone level assessment 


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 Total abstinence if it is the preferred and constant lifestyle of the subject.  Thus, 
periodic abstinence such as ovulation, symptothermal, postovulation, calendar 
methods, and withdrawal are not acceptable methods of contraception. 
 Male sterilization surgery:  at least 6 months prior to the first dose of study treatment 
in the core study (with the appropriate postvasectomy documentation of the absence 
of sperm in the ejaculate).  For female subjects, the vasectomized male should 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, 
or diaphragm with spermicide) in combination with the following:  established oral, 
injected, or implanted hormone methods of contraception or contraceptive patch 
7. Subject is unwilling or unable to follow the procedures outlined in the protocol 
8. Other medical or psychiatric conditions, or laboratory abnormalities that may increase the 
potential risk associated with study participation and administration of the study 
treatment, or that may affect study results interpretation and, as per Investigator’s 
judgement, make the subject ineligible. 
5.3.3 
Subject Restrictions 
The following restrictions may affect a subject’s ability to participate in this study: 
 
Availability to attend visits according to the protocol within the allowed window 
period specified in Table 1 
 
Ability to perform self-administration of study treatment, availability of caregiver to 
administer study treatment, or ability to visit study site to administer study treatment 
 
Concomitant medication restrictions as described in Section 6.13 
 
Fasting (water and concomitant medications are permitted) for at least 9 hours prior to 
all study visits 
The Investigator (or designee) should review these restrictions with the subject when 
assessing eligibility to determine any potential challenges in the subject’s ability to comply 
with the protocol.  Subjects not able to comply with the above mentioned restrictions should 
not be enrolled into the study. 


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5.3.4 
Premature Subject Withdrawal 
All subjects are 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 occurs for any reason, the Investigator must make 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 case report form 
(eCRF). 
Subjects will be completely withdrawn from study treatment and all assessments in the 
following cases: 
 Withdrawal of informed consent 
 Death of subject 
 Subject lost to follow-up 
 Note:  If the subject is lost to follow-up, the Investigator should attempt to contact 
the subject until the last scheduled Safety Follow-Up Visit.  The date of study 
termination for the subject is the date of last contact with subject. 
If the subject withdraws from the study and withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  R-Pharm International may retain and continue to use any data collected before 
such withdrawal of consent. 
Investigators are strongly encouraged to discuss the withdrawal of a subject with R-Pharm 
International or R-Pharm International’s designee in advance whenever possible. 
5.4 
Study Procedures 
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside of the control of the Investigator that may make it unfeasible to 
perform the test.  In these cases, the Investigator will take all steps necessary to ensure the 
safety and wellbeing of the subject. 
The timing for all study visits during the open-label Treatment Period is relative to 
OLE Baseline.  The timing for all study visits during the Safety Follow-Up Period 
(Visits SFU-1, SFU-2, and SFU-3) is relative to the last dose of study treatment (+4, +8, and 
+22 weeks, respectively). 


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As much as possible, subjects should be seen for all scheduled visits on the designated day.  
There is a ±5 day visit window for all study visits with the exception of the 3 Safety 
Follow-Up Visits (±7 days). 
If a subject misses a visit and comes for an Unscheduled Visit, procedures for the assessment 
of safety and efficacy should be performed according to the most recent visit that was 
omitted.  When a protocol-required procedure cannot be performed, the Investigator will 
document in the source documents the reason for this and any corrective and preventive 
actions that he/she has taken to ensure that normal processes are adhered to as soon as 
possible.  The study team should be informed of these incidents in a timely fashion. 
The assessments to be performed at each study visit should be conducted in the standard 
order listed below.  At all visits, the PRO questionnaires should be performed first, prior to 
any discussion between the subject and study site staff. 
The standard order should be: 
 
All PRO questionnaires (prior to any discussion between the subject and study site 
staff) 
 Patient Global Assessment of Disease Activity (Visual Analog Scale [VAS]) 
 Patient Assessment of Pain (VAS) 
 HAQ-DI 
 SF-36 
 EQ-5D 
 FACIT-Fatigue 
 WPS-RA (this PRO is conducted by study site staff after the subject completes all 
other PROs) 
 
Joint counts (Independent Joint Assessment) 
 
Soliciting of AE information 
 
Physician Global Assessment (VAS) 
 
All other assessments 
In the following sections, assessments are listed for each visit according to this order. 


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5.4.1 
Open-label Treatment Period Visits:  Visit 1 (OLE Baseline/Week 24) 
through Visit 9 (Week 88) 
5.4.1.1 
Visit 1 (OLE Baseline/Week 24) 
Written informed consent for the OLE study must be obtained prior to the performance of 
any protocol-specific procedures at Visit 1 (OLE Baseline/Week 24).  The Investigator at 
each study site will ensure that each subject has been provided with full and adequate oral 
and written information about the nature, purpose, and available details of possible risks and 
benefits of the study. 
Subjects must also be notified that they are free to discontinue from the study treatment or 
the whole study at any time.  The Investigator will discuss with the subject the importance of 
attending all scheduled study site visits, including the EoT Visit and Safety Follow-Up 
Visits, regardless of whether the subject chooses to discontinue from the study treatment, or 
not.  The subject should be given the opportunity to ask questions and allowed adequate time 
to consider the written information provided.  The Investigator must retain the original, 
signed informed consent form (ICF) for the study file.  A copy of the signed ICF must be 
given to the subject.  Once informed consent has been obtained, the subject’s eligibility to 
enter the study will be verified in accordance with the inclusion and exclusion criteria (refer 
to Sections 5.3.1 and 5.3.2, respectively). 
If a subject meets all study eligibility criteria, the Investigator will randomize the subject via 
the Interactive Web Response System (IWRS) to one of the two open-label treatment groups 
(see Section 5.2).  Subjects will keep the same subject number that they were assigned during 
the core study.   
Visit 1 (OLE Baseline/Week 24) in the OLE study is the same as the Visit 15 (EoT/Week 24) 
visit in the core CREDO studies.  Any assessments specified for the OLE Baseline Visit that 
duplicate the assessments specified for Week 24 in the core studies should only be performed 
once. 
In addition to obtaining subject informed consent, the following assessments should be 
performed: 
 
Check eligibility criteria. 
 
Randomize subject (Via IWRS) 
 
Administer Patient Global Assessment of Disease Activity (VAS) (see Section 7.1.3). 
 
Administer Patient Assessment of Pain (VAS) (see Section 7.1.4). 
 
Administer HAQ-DI (see Section 7.1.10.1). 


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 
Administer SF-36, EQ-5D, FACIT-Fatigue, and WPS-RA (see Section 7.1.10). 
 
Perform joint counts (Independent Joint Assessment) (see Section 7.1.2). 
 Joint assessor will be independent to the rest of the study team.  An independent joint 
assessor, blinded to other study assessments as well as the dosing regimen, will be 
identified at each study site to perform the swollen joint count (SJC) and tender joint 
count (TJC).  To ensure consistent joint evaluation throughout the study, individual 
subjects should be evaluated by the same joint assessor for all study visits whenever 
possible. 
 
Assess AEs/SAEs. 
 
Assess injection site reactions that have occurred since the previous injection (see 
Section 7.4.3.5). 
 
Administer Physician Global Assessment (VAS) (see Section 7.1.5). 
 
Record details of contraceptive history/status. 
 
Record concomitant medications and concomitant non-drug therapies. 
 
Administer TB risk questionnaire (see Section 7.4.9). 
 
Record height and weight (see Section 7.4.7.3). 
 
Record vital signs (see Section 7.4.7.2). 
 BP and heart rate also need to be reassessed 1 and 2 hours postdose. 
 
Perform complete physical examination (see Section 7.4.7.1). 
 
Perform CV risk assessment (see Section 7.4.7.4). 
 
Perform 12-lead electrocardiogram (ECG) (see Section 7.4.7.4). 
 
Perform chest X-ray (see Section 7.4.7.6). 
 Chest X-ray need not be conducted if performed and evaluated within 8 weeks prior 
to Visit 1 (OLE Baseline/Week 24), and if the films or images are available and 
included in the subject’s source documents. 
 
Collect samples for international normalized ratio (INR), activated partial 
thromboplastin time (aPTT), and fibrinogen (see Section 7.4.6.1). 
 
Measure ESR (see Section 7.4.6.1). 


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 
Collect sample to measure CRP level (see Section 7.4.6.1). 
 
Collect samples for lipid panel and CV risk panel (see Section 7.4.6.1). 
 
Collect samples for chemistry panel, hematology assessments, antinuclear antibodies 
(ANA), and double-stranded DNA (dsDNA) antibodies (see Section 7.4.6.1). 
 
Collect PK sample prior to the first dose of study treatment (see Section 7.2). 
 
Collect sample for analysis of ADAs (see Section 7.3). 
 
Perform urine pregnancy test for females of childbearing potential only. 
 
Perform urinalysis (see Section 7.4.6.1). 
 
Allocate study treatment through the IWRS. 
 
Distribute Subject Diary and train subjects to properly complete the Subject Diary (see 
Section 5.5). 
 
Perform training for study treatment preparation, storage, and administration (see 
Section 6.8). 
 
Administer study treatment. 
 Study treatment will be administered by the subject (or caregiver, if applicable) at this 
visit, and the Investigator must observe this administration to ensure that proper 
procedures are followed 
 Subcutaneous injections may be rotated among the thighs and abdomen. 
 All subjects will remain at the study site for at least 2 hours after the injection to be 
assessed for onset of any systemic injection reactions. 
5.4.1.2 
Visit 2 (Week 26) 
The following assessments will be performed at Visit 2 (Week 26): 
 
Assess AEs/SAEs and injection site reactions that have occurred since the previous 
visit. 
 
Record details of contraceptive history/status. 
 
Record concomitant medications and concomitant non-drug therapies. 
 
Record weight. 


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 
Record vital signs. 
 
Perform partial physical examination (see Section 7.4.7.1). 
 
Collect samples for chemistry panel and hematology assessments. 
 
Collect sample for glycosylated hemoglobin (HbA1c) assessment (subjects with 
confirmed diabetes mellitus only). 
 
Collect and review Subject Diary. 
 
For OKZ 64 mg q2w treatment group only: 
 Allocate study treatment through the IWRS. 
 Perform training for study treatment preparation, storage, and administration 
 Administer study treatment. 
o Study treatment will be administered by the subject (or caregiver, if applicable) at 
this visit, and the Investigator must observe this administration to ensure that 
proper procedures are followed 
o Subjects will remain at the study site for at least 30 minutes after the injection to 
be assessed for onset of any systemic injection reactions. 
5.4.1.3 
Visit 3 (Week 28) 
The following assessments will be conducted at Visit 3 (Week 28): 
 
Assess AEs/SAEs and injection site reactions that have occurred since the previous 
visit. 
 
Record details of contraceptive history/status. 
 
Record concomitant medications and concomitant non-drug therapies. 
 
Record weight. 
 
Record vital signs. 
 
Perform partial physical examination. 
 
Collect samples for chemistry panel and hematology assessments. 
 
Perform urine pregnancy test for females of childbearing potential only. 


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 
Collect and review Subject Diary. 
 
Allocate study treatment through the IWRS. 
 In addition to study treatment for Visit 3 (Week 28) administration, subjects will 
receive 1 vial or 1 pre-filled syringe (PFS) of OKZ for each dose that is scheduled to 
be administered prior to Visit 4 (Week 36). 
 
Perform training for study treatment preparation, storage, and administration 
(OKZ 64 mg q4w treatment group only). 
 
Administer study treatment. 
 Study treatment will be administered by the subject (or caregiver, if applicable) at this 
visit, and the Investigator must observe this administration to ensure that proper 
procedures are followed (observation is obligatory for OKZ 64 mg q4w treatment 
group only) 
 Subjects in the OKZ 64 mg q4w treatment group will remain at the study site for at 
least 30 minutes after the injection to be assessed for onset of any systemic injection 
reactions. 
5.4.1.4 
Visit 4 (Week 36) 
Starting at Visit 4 (Week 36) and then at all onsite visits until the end of the open-label 
Treatment Period, all subjects will be assessed for response to treatment, with nonresponders 
defined as subjects who do not improve by at least 20% in SJC and TJC (66-68 joint 
assessment) from the Core Baseline assessment.  Investigators will be requested to review 
carefully the response status at these time points and make appropriate actions based on local 
guidelines regarding management of the subjects, including possible adjustments in 
background therapy (see Section 6.13.3) or discontinuation of study treatment (see 
Section 6.11). 
The following assessments will be conducted at Visit 4 (Week 36): 
 
Administer Patient Global Assessment of Disease Activity (VAS). 
 
Administer Patient Assessment of Pain (VAS). 
 
Administer HAQ-DI. 
 
Administer SF-36, EQ-5D, FACIT-Fatigue, and WPS-RA. 
 
Perform joint counts (Independent Joint Assessment). 


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 
Assess AEs/SAEs and injection site reactions that have occurred since the previous 
visit. 
 
Administer Physician Global Assessment (VAS). 
 
Record details of contraceptive history/status. 
 
Record concomitant medications and concomitant non-drug therapies. 
 
Administer TB risk questionnaire. 
 
Record weight. 
 
Record vital signs. 
 
Perform partial physical examination. 
 
Measure ESR. 
 
Collect sample to measure CRP level. 
 
Collect samples for chemistry panel and hematology assessments. 
 
Collect sample for analysis of ADAs. 
 
Perform urine pregnancy test for females of childbearing potential only. 
 
Collect sample for urinalysis. 
 
Collect and review Subject Diary. 
 
Assess treatment compliance (see Section 6.7). 
 Subjects who received vials must return all used/unused vials to the study site. 
 Subjects who received PFS must return carton of all used/unused PFS to the study 
site. 
 
Allocate study treatment through the IWRS. 
 In addition to study treatment for Visit 4 (Week 36) administration, subjects will 
receive 1 vial or 1 PFS of OKZ for each dose that is scheduled to be administered 
prior to Visit 5 (Week 44). 
 
Administer study treatment. 


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5.4.1.5 
Visit 5 (Week 44) 
The following assessments will be conducted at Visit 5 (Week 44): 
 
Administer Patient Global Assessment of Disease Activity (VAS). 
 
Administer Patient Assessment of Pain (VAS). 
 
Administer HAQ-DI. 
 
Perform joint counts (Independent Joint Assessment). 
 
Assess Treatment Response 
 
Assess AEs/SAEs and injection site reactions that have occurred since the previous 
visit. 
 
Administer Physician Global Assessment (VAS). 
 
Record details of contraceptive history/status. 
 
Record concomitant medications and concomitant non-drug therapies. 
 
Record weight. 
 
Record vital signs. 
 
Perform partial physical examination. 
 
Collect sample to measure CRP level. 
 
Measure ESR. 
 
Collect samples for chemistry panel and hematology assessments. 
 
Perform urine pregnancy test for females of childbearing potential only. 
 
Collect and review Subject Diary. 
 
Assess treatment compliance. 
 
Allocate study treatment through the IWRS. 
 In addition to study treatment for Visit 5 (Week 44) administration, subjects will 
receive 1 vial or 1 PFS of OKZ for each dose that is scheduled to be administered 
prior to Visit 6 (Week 52). 
 
Administer study treatment. 


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5.4.1.6 
Visit 6 (Week 52) 
The following assessments will be conducted at Visit 6 (Week 52): 
 
Administer Patient Global Assessment of Disease Activity (VAS). 
 
Administer Patient Assessment of Pain (VAS). 
 
Administer HAQ-DI. 
 
Administer SF-36, EQ-5D, FACIT-Fatigue, and WPS-RA. 
 
Perform joint counts (Independent Joint Assessment). 
 
Assess Treatment Response 
 
Assess AEs/SAEs and injection site reactions that have occurred since the previous 
visit. 
 
Administer Physician Global Assessment (VAS). 
 
Record details of contraceptive history/status. 
 
Record concomitant medications and concomitant non-drug therapies. 
 
Administer TB risk questionnaire. 
 
Record weight. 
 
Record vital signs. 
 
Perform complete physical examination. 
 
Perform CV risk assessment. 
 
Perform 12-lead ECG. 
 
Perform chest X-ray. 
 Chest X-ray need not be conducted if performed and evaluated within 8 weeks prior 
to Visit 6 (Week 52), and if the films or images are available and included in the 
subject’s source documents. 
 
Measure ESR. 
 
Collect sample to measure CRP level. 
 
Collect samples for lipid panel. 


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 
Collect samples for chemistry panel, hematology assessments, ANAs, and dsDNA 
antibodies. 
 
Collect sample for HbA1c assessment (subjects with confirmed diabetes mellitus only). 
 
Perform IGRA testing only for subjects who had a negative IGRA result at the 
previous assessments (including Week 22 assessment of the core study) unless another 
approach is required by local practice.  If results are indeterminate, the IGRA can be 
repeated once. 
 
Collect sample for analysis of ADAs. 
 
Perform urine pregnancy test for females of childbearing potential only. 
 
Collect sample for urinalysis. 
 
Collect and review Subject Diary. 
 
Assess treatment compliance 
 
Allocate study treatment through the IWRS. 
 In addition to study treatment for Visit 6 (Week 52) administration, subjects will 
receive 1 vial or 1 PFS of OKZ for each dose that is scheduled to be administered 
prior to Visit 7 (Week 64). 
 
Administer study treatment. 
5.4.1.7 
Visit 7 (Week 64) 
The following assessments will be conducted at Visit 7 (Week 64): 
 
Administer Patient Global Assessment of Disease Activity (VAS). 
 
Administer Patient Assessment of Pain (VAS). 
 
Administer HAQ-DI. 
 
Administer SF-36, EQ-5D, FACIT-Fatigue, and WPS-RA. 
 
Perform joint counts (Independent Joint Assessment). 
 
Assess Treatment Response 
 
Assess AEs/SAEs and injection site reactions that have occurred since the previous 
visit. 


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 
Administer Physician Global Assessment (VAS). 
 
Record details of contraceptive history/status. 
 
Record concomitant medications and concomitant non-drug therapies. 
 
Record weight. 
 
Record vital signs. 
 
Perform partial physical examination. 
 
Measure ESR. 
 
Collect sample to measure CRP level. 
 
Collect samples for chemistry panel and hematology assessments. 
 
Perform urine pregnancy test for females of childbearing potential only. 
 
Collect and review Subject Diary. 
 
Assess treatment compliance. 
 
Allocate study treatment through the IWRS. 
 In addition to study treatment for Visit 7 (Week 64) administration, subjects will 
receive 1 vial or 1 PFS of OKZ for each dose that is scheduled to be administered 
prior to Visit 8 (Week 76). 
 
Administer study treatment. 
5.4.1.8 
Visit 8 (Week 76) 
The following assessments will be conducted at Visit 8 (Week 76): 
 
Administer Patient Global Assessment of Disease Activity (VAS). 
 
Administer Patient Assessment of Pain (VAS). 
 
Administer HAQ-DI. 
 
Administer SF-36, EQ-5D, FACIT-Fatigue, and WPS-RA. 
 
Perform joint counts (Independent Joint Assessment). 
 
Assess Treatment Response 


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 
Assess AEs/SAEs and injection site reactions that have occurred since the previous 
visit. 
 
Administer Physician Global Assessment (VAS). 
 
Record details of contraceptive history/status. 
 
Record concomitant medications and concomitant non-drug therapies. 
 
Administer TB risk questionnaire. 
 
Record weight. 
 
Record vital signs. 
 
Perform partial physical examination. 
 
Perform CV risk assessment. 
 
Perform 12-lead ECG. 
 
Collect samples for INR, aPTT, and fibrinogen. 
 
Measure ESR. 
 
Collect sample to measure CRP level. 
 
Collect samples for lipid panel and CV risk panel. 
 
Collect samples for chemistry panel and hematology assessments. 
 
Collect sample for HbA1c assessment (subjects with confirmed diabetes mellitus only). 
 
Collect sample for analysis of ADAs. 
 
Perform urine pregnancy test for females of childbearing potential only. 
 
Collect sample for urinalysis. 
 
Collect and review Subject Diary. 
 
Assess treatment compliance. 
 
Allocate study treatment through the IWRS. 
 In addition to study treatment for Visit 8 (Week 76) administration, subjects will 
receive 1 vial or 1 PFS of OKZ for each dose that is scheduled to be administered 
prior to Visit 9 (Week 88). 


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 
Administer study treatment. 
5.4.1.9 
Visit 9 (Week 88) 
The following assessments will be conducted at Visit 9 (Week 88): 
 
Administer Patient Global Assessment of Disease Activity (VAS). 
 
Administer Patient Assessment of Pain (VAS). 
 
Administer HAQ-DI. 
 
Administer SF-36, EQ-5D, FACIT-Fatigue, and WPS-RA. 
 
Perform joint counts (Independent Joint Assessment). 
 
Assess Treatment Response 
 
Assess AEs/SAEs and injection site reactions that have occurred since the previous 
visit. 
 
Administer Physician Global Assessment (VAS). 
 
Record details of contraceptive history/status. 
 
Record concomitant medications and concomitant non-drug therapies. 
 
Record weight. 
 
Record vital signs. 
 
Perform partial physical examination. 
 
Measure ESR. 
 
Collect sample to measure CRP level. 
 
Collect samples for chemistry panel and hematology assessments. 
 
Perform urine pregnancy test for females of childbearing potential only 


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 
Collect and review Subject Diary. 
 
Assess treatment compliance. 
 
Allocate study treatment through the IWRS. 
 In addition to study treatment for Visit 9 (Week 88) administration, subjects will 
receive 1 vial or 1 PFS of OKZ for each dose that is scheduled to be administered 
prior to Visit 10 (EoT/Week 106). 
 
Administer study treatment. 
5.4.2 
Visit 10/End of Treatment (2 Weeks After the Last Dose of the Study 
Treatment)/(Week 106) 
Visit 10 (EoT/Week 106) will be performed at Week 106 for subjects who complete all 
scheduled study visits or 2 weeks after the last dose of study treatment for subjects who 
discontinue study treatment prematurely. 
The following assessments will be performed at Visit 10 (EoT/Week 106) for all subjects: 
 
Administer Patient Global Assessment of Disease Activity (VAS). 
 
Administer Patient Assessment of Pain (VAS). 
 
Administer HAQ-DI. 
 
Administer SF-36, EQ-5D, FACIT-Fatigue, and WPS-RA. 
 
Perform joint counts (Independent Joint Assessment). 
 
Assess Treatment Response 
 
Administer Physician Global Assessment (VAS). 
 
Record details of contraceptive history/status. 
 
Record concomitant medications and concomitant non-drug therapies. 
 
Administer TB risk questionnaire. 
 
Assess AEs/SAEs (and injection site reactions) that have occurred since the previous 
visit. 
 
Record weight. 
 
Record vital signs. 


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Perform complete physical examination. 
 
Perform CV risk assessment. 
 
Perform 12-lead ECG. 
 
Perform chest X-ray. 
 Chest X-ray need not be conducted if performed and evaluated within 8 weeks prior 
to Visit 10 (EoT/Week 106), and if the films or images are available and included in 
the subject's source documents. 
 
Collect samples for INR, aPTT, and fibrinogen. 
 
Measure ESR. 
 
Collect sample to measure CRP level. 
 
Collect samples for lipid panel and CV risk panel. 
 
Collect samples for chemistry panel, hematology assessments, ANAs, and dsDNA 
antibodies. 
 
Collect sample for HbA1c assessment (subjects with confirmed diabetes mellitus only). 
 
Perform IGRA testing only for subjects who had a negative IGRA result at the 
previous assessments (including Week 22 assessment of the core study) unless another 
approach is required by local practice.  If results are indeterminate, the IGRA can be 
repeated once. 
 
Collect sample for analysis of ADAs. 
 
Perform urine pregnancy test for females of childbearing potential only. 
 
Collect sample for urinalysis. 
 
Collect and review Subject Diary. 
 
Assess treatment compliance. 
 
Change subject status in the IWRS 
 


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5.4.3 
Safety Follow-Up:  Visits SFU-1, SFU-2, and SFU-3 
5.4.3.1 
Visit SFU-1 (Week 108 or 4 Weeks after the Last Dose of the Study Treatment) 
The following assessments will be conducted 4 weeks after the last dose of the study 
treatment: 
 
Record AEs/SAEs. 
 
Record details of contraceptive history/status. 
 
Record concomitant medications and concomitant non-drug therapies. 
 
Record weight. 
 
Record vital signs. 
 
Perform partial physical examination. 
 
Measure ESR. 
 
Collect sample to measure CRP level. 
 
Collect samples for chemistry panel and hematology assessments. 
 
Perform urine pregnancy test for females of childbearing potential only. 
5.4.3.2 
Visit SFU-2 (Week 112 or 8 Weeks after the Last Dose of the Study Treatment) 
The following assessments will be conducted 8 weeks after the last dose of the study 
treatment: 
 
Record AEs/SAEs. 
 
Record details of contraceptive history/status. 
 
Record concomitant medications and concomitant non-drug therapies. 
 
Administer TB risk questionnaire. 
 
Record weight. 
 
Record vital signs. 
 
Perform partial physical examination. 
 
Measure ESR. 
 
Collect sample to measure CRP level. 


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 
Collect samples for chemistry panel and hematology assessments. 
 
Perform urine pregnancy test for females of childbearing potential only. 
5.4.3.3 
Visit SFU-3 (Week 126 or 22 Weeks after the Last Dose of the Study Treatment) 
The following assessments will be conducted 22 weeks after the last dose of the study 
treatment: 
 
Record AEs/SAEs 
 
Record details of contraceptive history/status. 
 
Record concomitant medications and concomitant non-drug therapies. 
 
Record weight. 
 
Record vital signs. 
 
Perform complete physical examination. 
 
Perform 12-lead ECG. 
 
Collect samples for INR, aPTT, and fibrinogen. 
 
Collect samples for lipid panel and CV risk panel. 
 
Collect samples for chemistry panel, hematology assessments, ANAs, and dsDNA 
antibodies. 
 
Perform urine pregnancy test for females of childbearing potential only. 
 
Collect sample for urinalysis. 
5.4.4 
Unscheduled Visit  
It is at the Investigator’s discretion to initiate an Unscheduled Visit, if deemed necessary by 
the Investigator for the subject’s safety and well-being.  At this visit, any of the assessments 
from the Schedule of Events may be performed dependent on the presenting reason.  
R-Pharm International’s designee should be informed of these incidents in a timely fashion. 
5.5 
Subject Diary 
At Visit 1 (OLE Baseline/Week 24), a Subject Diary will be distributed to all subjects and 
subjects will be trained to properly complete the Subject Diary. 


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At Visit 1 (OLE Baseline/Week 24) and at each scheduled visit during the open-label 
Treatment Period (Visits 2 [Week 26] through 9 [Week 88]), the Investigator will provide the 
subject with preprinted dates for each dose of study treatment that will be administered prior 
to the next scheduled visit.  Visit 2 date and further CREDO 4 visit dates should be 
calculated from the actual CREDO 4 Randomization date.  Following each administration of 
study treatment, the subject will record the actual date, time, and location of study treatment 
administration in the Subject Diary; the identity of the person who administered the study 
treatment; any problems that occur during the injection; and any complaints, signs, or 
symptoms that occur during or after the injection. 
The Subject Diary will instruct subjects to contact the Investigator if they experience any 
problems with the injection or if they experience any significant signs or symptoms during or 
after the injection. 
The Investigator will collect completed pages of the Subject Diary at Visits 2 (Week 26) 
through 10 (EoT/Week 106).  Completed pages of the Subject Diary will serve as source 
documents, and the Investigator will transfer the data, including the date, time, and location 
of each SC injection; the identity of the person who administered the study treatment; and 
any departures from the intended regimen from the Subject Diary into the appropriate page(s) 
of the eCRF.  The Investigator will also review any complaints, signs, or symptoms recorded 
in the Subject Diary and record any AEs in the eCRF, as appropriate. 
The Subject Diary will not be used during the Safety Follow-Up Period. 


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6. STUDY TREATMENTS 
6.1 
Study Treatment Administered 
Study Treatment 
All eligible subjects will be randomized to 1 of the 2 OKZ treatment groups as described in 
Sections 5.2 and 6.5.  A detailed description of the study treatment (OKZ) is provided in 
Section 6.2. 
Background Therapy 
As per inclusion criterion No. 3 (see Section 5.3.1), subjects must have been treated with 
MTX at a dose of 15 to 25 mg/week (or ≥10 mg/week if there is documented intolerance to 
higher doses) during the core study with a stable dose and mode of administration (oral, SC, 
or IM).  For the first 12 weeks of the OLE study (i.e., through Week 36), the dose of MTX 
should remain unchanged and may be adjusted only for safety reasons according to 
Investigator discretion (see guidelines in Appendix 1 [see Section 13.1]).  After Visit 4 
(Week 36), the Investigator may adjust the MTX dosage and route, per local guidelines. 
Subjects who were prescribed rescue medication(s) (sulfasalazine and/or 
hydroxychloroquine) during the core studies will be asked to continue these medications at 
the same dose for the first 12 weeks of the OLE study (i.e., through Visit 4 [Week 36]).  
After Visit 4 (Week 36), the Investigator may adjust these background medications if deemed 
appropriate. 
Additional details regarding background therapy, including adjustments to background 
therapy that are permitted after Visit 4 (Week 36), are provided in Section 6.13.3. 
6.2 
Identity of Study Treatment 
Olokizumab will be supplied by R-Pharm International or its designee. 
6.2.1 
Olokizumab  
Olokizumab is a humanized (CDR-grafted) mAb of the IgG4/kappa isotype with the serine in 
the heavy chain hinge region being replaced with a proline residue.  The OKZ drug substance 
consists of a preparation of purified recombinant humanized mAb (CDP6038; L04041) 
presented as a solution of 160 mg/mL OKZ in 30 mM histidine hydrochloride, 60 mM 
sodium chloride, 200 mM sorbitol, and 0.03% polysorbate 80 at pH 5.6.  The OKZ drug 
substance is the fully formulated product, which is sterilized by filtration and aseptically 
filled in vials or syringes to obtain the drug product. 


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Olokizumab is presented as a sterile solution for SC injection in the following formats: 
 
A 2 mL clear Type I glass vial with target volume of 0.4 mL.  The vial is closed with a 
chlorobutyl stopper and sealed with an aluminum seal with a polypropylene flip-off 
cap. 
 
The PFS is composed of a 1 mL clear Type I glass barrel vial with target volume of 
0.4 mL. 
The components and composition of the OKZ drug product are presented in Table 2. 
Table 2 
Components and Composition of OKZ (CDP6038; L04041) Drug Product 
Ingredient 
Quantity (per mL) 
Function 
OKZ drug substance 
160.000 mg 
Active ingredient 
Sodium chloridea 
3.51 mg 
Tonicity 
Polysorbate 80a 
0.3 mg 
Stabilizer 
Histidine hydrochoridea 
6.29 mg 
Buffer 
Sorbitola 
36.434 mg 
Stabilizer 
Water for injectiona 
qs to 1.0 mL 
Solvent 
Abbreviations:  OKZ = Olokizumab; qs = quantum satis (sufficient quantity). 
a.  Added during the drug substance manufacturing process. 
6.3 
Packaging and Labeling 
Study treatment will be supplied in cartons containing 1 vial or 1 PFS of OKZ.  Study 
treatment will be packaged and labeled according to Good Manufacturing Practices and all 
applicable local country regulations with information on the study protocol number, drug 
identification, storage conditions, and dosage information. 
6.4 
Storage 
The Investigator or designee is responsible for the safekeeping and correct storage of the 
study treatment at the study site. 
Olokizumab will be shipped refrigerated at +2°C to +8°C (36°F to 46°F). Olokizumab should 
be stored at +2°C to +8°C (36°F to 46°F) in a secure, temperature-controlled refrigerator.  
Olokizumab will be supplied centrally.  Please refer to the Pharmacy Manual for additional 
details on storage requirements. 
With study treatment that is dispensed to subjects for administration of OKZ at home, 
subjects will receive a Subject Leaflet containing details of the correct storage and 
transportation of study treatment. 


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6.5 
Method of Assigning Subjects to Treatment Group 
Subjects will be randomized using the IWRS (an automated web randomization system) to 
1 of 2 treatment groups (OKZ 64 mg q2w or OKZ 64 mg q4w).  The IWRS will allocate the 
treatment group and assign the study treatment based on the treatment a subject received in 
the core studies.  Subjects who received OKZ in the core study in which they participated 
(including subjects who received placebo in Study CL04041025 and were re-randomized to 
OKZ at Week 16) will receive the same OKZ treatment regimen in the OLE study (OKZ 
64 mg q2w or OKZ 64 mg q4w).  Subjects who received placebo (Study CL04041022 and 
Study CL04041023) or adalimumab (Study CL04041023) in the core study in which they 
participated will be randomized in a 1:1 ratio to receive OKZ 64 mg q2w or OKZ 64mg q4w 
in the OLE study. 
The IWRS system will also manage study site drug supply and subject drug dispensation.  
Study staff will request study treatment assignments via the IWRS for all subsequent 
treatment study visits.  Further details on the IWRS and requirements for each study visit can 
be found in the separate IWRS Manual. 
6.6 
Study Treatment Accountability 
The pharmacist (or delegate) at the study site is responsible for maintaining an adequate 
record of study treatment that is received, distributed, and returned by subjects to the study 
site at each scheduled visit (all used/unused vials, unused PFS, and/or used PFS cartons).  
The study treatment accountability records must be kept current, available for monitoring by 
the study monitor, and available for inspection at any time.  Study treatment materials at the 
study site should be kept in a secured location. 
Used study treatment must be discarded as a biohazard, and the handling, disposal, and 
destruction details will be detailed within the Pharmacy Manual. 
The Investigator is responsible for maintaining an adequate record of study treatment 
administration (see Section 6.8) and study treatment compliance (see Section 6.7). 
Detailed instructions on drug accountability are provided within the Pharmacy Manual. 
6.7 
Treatment Compliance 
The Investigator should promote compliance by stating that compliance is necessary for the 
subject’s safety and the validity of the study data.  The prescribed dosage, timing, and mode 
of administration may not be changed. 
A monitor will review the pharmacy records at each study site including the drug dispensing 
records.  The pharmacist (or designee) should record all study treatment dispensed to subjects 


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and all used/unused vials, unused PFS, and/or used PFS cartons returned by subjects to the 
study site.  The monitor will verify the dispensing records against vials/PFS cartons to ensure 
that the subject received the correct treatment and dose, and that the dosing schedule is 
correct.  Errors that are identified will be communicated to the study site staff to ensure that 
the errors are not repeated.  The monitor’s report will include details of any missed doses, 
errors in dose, treatment errors, or scheduling errors and the associated explanations.  All 
supplies and pharmacy documentation must be made available throughout the study for the 
monitor’s review. 
Subjects will record details of study treatment administration in the Subject Diary (see 
Section 5.5).  Subjects will be required to return all used/unused vials and/or used PFS 
cartons to the study site at each scheduled visit.  Subject compliance with the study treatment 
will be assessed by study site staff at each visit during the Treatment Period, with compliance 
defined as the administration of the study treatment conforming to 80% to 100% of the plan, 
in accordance with the requirements specified in the Protocol dosing of investigational drug, 
in addition to the following: 
 
For subjects in the OKZ 64 mg q2w treatment group, no more than 2 consecutive 
missed injections during the Treatment Period. 
 
For subjects in the OKZ 64 mg q4w treatment group, no consecutive missed injections 
during the Treatment Period. 
Any subject who deviates from the dosing schedule or misses any scheduled study treatment 
should be reported to R-Pharm International and/or R-Pharm International’s designee 
promptly. 
6.8 
Preparation and Administration of Study Treatment 
Each subject will be provided with the following materials as applicable: 
 
Study treatment will be administered in one of the following forms (as described in 
Section 6.2.1): 
 Olokizumab vials and sterile disposable syringes and needles for SC injection, OR 
 Olokizumab PFS. 
 
A container for disposal of biomedical waste (i.e., used PFS/syringes/needles). 
 
Cooler bag for OKZ transportation. 
Subjects will receive a Subject Leaflet containing instructions on study treatment preparation, 
administration, storage, transportation, and disposal and return of used/unused 


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vials/PFS/syringes/needles to the study site.  The Subject Leaflet will instruct the subject to 
contact the Investigator in the event that difficulties arise with the administration of study 
treatment.  The Subject Leaflet will also contain detailed instructions regarding what to do if 
there is a problem with a vial or PFS. 
The number of PFS or vials, syringes, and needles received by the subject at each visit will 
depend upon the treatment group to which the subject is assigned; the subject will receive 
1 PFS or 1 vial with sterile disposable syringe and needle for SC injection of study treatment 
that is scheduled to occur prior to the next scheduled visit.  Subjects will be instructed that a 
new PFS or vial, syringe, and needle for SC injection should be used for each administration 
of study treatment, and that the PFS or vials, syringes, or needles should not be re-used. 
Subjects will be instructed to return used/unused study medication as follow: 
 
For subjects who receive vials, all used/unused vials (if any) must be returned to the 
study site at the next scheduled visit.  Subjects will be instructed that all used syringes 
and needles should be disposed of in the supplied container for disposal of biomedical 
waste. 
 
For subjects who receive PFS, empty PFS cartons and unused PFS (if any) should be 
returned to the study site at the next scheduled visit.  Subjects will be instructed that 
all used PFS should be disposed of in the supplied container for disposal of biomedical 
waste. 
Subjects who receive vials/needles/syringes will be advised that the syringes should be 
prepared in a way timed to avoid exceeding the stipulated stability time of the prepared 
product, and the solution may remain in the syringe for a maximum of 4 hours prior to its 
administration. 
Both the PFS and prepared syringes should be warmed at room temperature prior to study 
treatment administration. 
Subcutaneous injections of OKZ 64 mg will be administered by the subject (or caregiver, if 
applicable) q2w or q4w throughout the open-label Treatment Period.  Administration of 
study treatment by a caregiver (i.e., relative or other free-of-charge person) should be limited 
and only take place if the subject encounters difficulties with the injection or if the subject is 
unable to self-administer the study treatment. 
Study site staff will train all study subjects on the self-administration of OKZ during their 
first 2 study visits (Visit 1 [Week 24] and Visit 2 [Week 26] for subjects receiving 
OKZ 64 mg q2w, and Visit 1 [Week 24] and Visit 3 [Week 28] for subjects receiving OKZ 
64 mg q4w). For study subjects who have a caregiver who has consented to study 


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participation, that caregiver should be present during the above mentioned visits, and trained 
by site staff, to administer the OKZ to the subject. If the subject has a caregiver who is not 
present at one or both training visits, the site staff can provide training at a later study visit. 
Injections of study treatment administered by the subject or caregiver (if applicable) must be 
observed by study site staff during the first 2 scheduled administrations (Visit 1 [Week 24] 
and Visit 2 [Week 26] for subjects receiving OKZ 64 mg q2w, and Visit 1 [Week 24] and 
Visit 3 [Week 28] for subjects receiving OKZ 64 mg q4w) to ensure that proper procedures 
are followed.  This training may be repeated at any visit to the study site if requested by the 
subject (or caregiver, if applicable), or if deemed appropriate by the Investigator.  In the 
event that a subject is unable to self-administer study treatment and a caregiver is not 
available, the subject may visit the study site to receive a scheduled injection.  Subjects will 
record details of study treatment administration in the Subject Diary as detailed in 
Section 5.5. 
If desired, the subject may rotate SC injections among the thighs and abdomen.  All subjects 
will remain at the study site for at least 2 hours after the first administration of study 
treatment (Visit 1 [OLE Baseline/Week 24]), and for at least 30 minutes after the second 
administration of study treatment (Visit 2 [Week 26] for subjects receiving OKZ 64 mg q2w 
and Visit 3 [Week 28] for subjects receiving OKZ 64 mg q4w) to be assessed for the onset of 
any systemic injection reactions as described in Section 7.4.3.2.  For injections administered 
by the subject (or caregiver, if applicable), subjects will record in the Subject Diary (see 
Section 5.5) any complaints, signs, or symptoms that occur during or after the injection. 
In all cases, there must be at least 1 week between all doses of study treatment. 
If a subject misses a scheduled dose, study treatment should be administered as soon as 
possible, while ensuring that there will be at least 1 week between the current injection and 
the next scheduled injection.  If the remaining interval between the current dose and the next 
scheduled dose appears to be less than 1 week, then the current dose should be skipped.  If 
the subject is unable to administer study treatment in the allowed window, or if the subject is 
aware in advance that they will miss a scheduled dose (e.g., due to travel, etc), the subject 
should contact the Investigator for guidance.  The Investigator can contact the Medical 
Monitor for discussion on a case-by-case basis. 
In the case of an AE that requires interruption of study treatment administration, as assessed 
clinically by the Investigator or as required by the protocol (see Appendix 1 [Section 13.1]), 
study treatment administration can be delayed, while ensuring that there will be at least 
1 week between the current dose and the next scheduled dose.  If the subject cannot be dosed 
within the allowed window due to lack of resolution of the AE, then the current dose should 
be skipped.  Study treatment administration should resume at the next scheduled dosing date 


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when interruption of study treatment administration is no longer required, based on 
resolution of the AE and Investigator judgement. 
Detailed instructions for the Investigator on study treatment preparation, handling, and 
administration are provided in the Pharmacy Manual. 
6.9 
Selection and Timing of Dose for Each Subject 
Subjects will be assigned study treatment (see Section 5.2) as discussed in Section 6.5. 
6.10 Dose Adjustments  
Dose adjustments for OKZ are not allowed in this study. 
Dose adjustments for OKZ are not allowed in this study. For guidelines regarding dose 
adjustments of MTX and any cDMARDs prescribed as rescue medication during the core 
studies, refer to Section 6.1.  
6.11 Discontinuation of Study Treatment 
All subjects are free to discontinue study treatment at any time, for any reason, specified or 
unspecified, and without prejudice to further treatment. 
If discontinuation of study treatment occurs for any reason, the Investigator must make every 
effort to determine the primary reason for a subject’s discontinuation of study treatment and 
record this information on the source documents and appropriate eCRF. 
In all cases, if a subject discontinues from the study treatment, the subject should be 
encouraged to return for the EoT and Safety Follow-Up Visits (as detailed in Sections 5.4.2 
and 5.4.3).  All Safety Follow-Up assessments should be performed unless the subject also 
withdraws informed consent to participate in the study (see Section 5.3.4).  If a subject that 
discontinues study treatment does not return for the scheduled EoT or Safety Follow-Up 
Visits, every effort should be made to contact the subject.  In all circumstances, every effort 
should be made to document subject outcome. 
6.11.1 
Temporary Discontinuation of Study Treatment 
Temporary discontinuation of study treatment is required for the situations described below. 
The Investigator should contact the Medical Monitor for guidance regarding restarting study 
treatment. 


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Study treatment will be held/interrupted if: 
 
Results from the repeat laboratory testing are not available at the time of the next 
scheduled dose 
 
ALT and/or AST remains >3× ULN with total bilirubin ≤2× ULN after repeat 
laboratory testing. 
 
Subjects have an active or clinically significant infection. 
 
Subject has a suspected malignancy (with the exception of local and resected basal or 
squamous cell carcinoma of the skin), after confirmation with the Medical Monitor. 
Temporary interruption of study treatment should also be considered if, at the discretion of 
the Investigator, it is necessary for safety reasons (e.g., negative trends during laboratory 
monitoring or remaining abnormalities after retesting which do not require premature 
discontinuation of the study treatment but could be harmful for the patient according to the 
Investigator’s judgement [Section 7.4.6.2], or other clinically significant newly diagnosed 
co-morbidity that requires additional assessments for clarification of the diagnosis, and the 
severity of which could worsen if study treatment is continued). 
6.11.2 
Permanent Discontinuation of Study Treatment 
The criteria for enrollment are to be followed explicitly. 
If a subject who does not meet enrollment criteria is inadvertently enrolled, R-Pharm 
International or R-Pharm International’s designee must be informed immediately, and the 
subject may be discontinued from study treatment. 
If, in the opinion of the Investigator, a subject is consistently noncompliant with the protocol 
in regards to study procedures, use of concomitant medications, or dosing with the study 
treatment, R-Pharm International or R-Pharm International’s designee must be informed as 
soon as it can be possible, and the case will be reviewed by R-Pharm International on a 
case-by-case basis and the noncompliant subject can be discontinued from the study 
treatment. 
If the Investigator judges that the subject’s health is deteriorating or not improving, the 
Investigator can elect to discontinue the subject from the study treatment.  Appropriate 
standard of care, at the discretion of the Investigator, will be initiated. 
In addition to the above, study treatment will be discontinued in the following circumstances: 
 
Investigator decides that the subject should be discontinued from the study treatment.  
If this decision is made because of an intolerable AE or a clinically significant 


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laboratory value, the study treatment is to be discontinued, appropriate measures are to 
be taken, and R-Pharm International or R-Pharm International’s designee is to be 
notified. 
 
Subject is unwilling to continue the study treatment.  If the subject discontinues from 
the study treatment, the Investigator should inquire about the reason for discontinuing. 
 
Subject presents with any of the following elevated LFTs (see also Appendix 1 
[Section 13.1]): 
 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.  The elevation should be continuous for ≥2 consecutive weeks.  If the 
level decreases for some time within 2 weeks, subject permanent discontinuation is 
not mandated, but left under Investigator discretion.  Resuming the IMP should be 
discussed on a case by case basis. 
 ALT or AST elevations >3× ULN and total bilirubin value >2× ULN at any time 
 AST or ALT elevations >3× ULN accompanied by symptoms which, as determined 
by the Investigator, are the result of hepatic injury (e.g., fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, eosinophilia [>5%]) 
 
Subject presents with any of the following laboratory abnormalities: 
 Absolute neutrophil count <500×106/L (<500/mm3) 
 Two sequential lymphocyte counts <500×106/L (<500/mm3) 
 Platelet count <50×109/L (<50,000/mm3 or <50,000×106/L) 
 Two sequential hemoglobin values ≤8.0 g/dL and decreased ≥20 g/L (2 g/dL) below 
OLE Baseline 
 Creatinine value >2× ULN 
 
Subject has confirmation of a pregnancy during the study, as evidenced by a positive 
pregnancy test. 
 
R-Pharm International, a regulatory agency, or an ethical committee stops the study 
for any reason. 
 
Subject has a GI perforation. 


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 
Subject diagnosed with diverticulitis  
 
Subject has a confirmed active TB. 
 
Subject has a positive IGRA result or repeated indeterminate IGRA results during the 
study, unless active TB is ruled out and the Medical Monitor confirms that study 
treatment can be resumed as described below: 
 Subjects may resume the administration of study treatment if active TB is ruled out 
by a certified TB specialist or pulmonologist who is familiar with treating TB (as 
acceptable per local practice).  The subject must also start prophylactic LTBI therapy 
according to country-specific/CDC guidelines (see Appendix 4 [Section 13.4]) and 
agree to complete the entire course of recommended LTBI therapy.  Study treatment 
should not be administered until active TB is ruled out and the subject starts LTBI 
therapy. 
 
Subject has a severe or life-threatening infection that requires hospitalization. 
 
Subject has a malignancy (with the exception of local and resected basal or squamous 
cell carcinoma of the skin), after confirmation with the Medical Monitor. 
6.12 Blinding 
This is an open-label study.  The subjects, Investigators, study site staff, and Sponsor will not 
be blinded. 
An independent CVAC and DSMB will be established for this study to assess safety on an 
ongoing basis (see Section 7.4.4).  Members of the CVAC will be blinded to treatment group.  
Members of the DSMB will be partially blinded to treatment group:  they will be aware of 
which subjects are in the same treatment group, but they will not be aware of the treatment 
assigned to each group.  However, members of the DSMB may be unblinded in the event that 
safety monitoring identifies an issue that needs to be addressed at the treatment group level 
(see Section 7.4.8). 
6.13 Prior and Concomitant Treatments 
For the first 12 weeks of the OLE study (i.e., through Visit 4 [Week 36]), background 
therapy requirements (ie, concomitant treatment with MTX and with permitted rescue 
medication(s) prescribed in the core studies) are detailed in Section 6.1. 
Concomitant treatment with folic acid ≥5 mg per week or equivalent is required for all 
subjects. 
Other specifically allowed medications are discussed in Section 6.13.2. 


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Specific treatments prohibited during the course of the study are described in Table 3.  Other 
medications and non-drug therapies not listed within Table 3 that are considered necessary 
for the subject’s safety and well-being may be given at the discretion of the Investigator and 
recorded in the appropriate sections of the eCRF.  Doses, route of applications, duration of 
treatment, and reasons for prescription are also to be recorded. 
A caution regarding cytochrome P (CYP) and transporter proteins is discussed in 
Section 6.13.1. 
Table 3 
Prohibited Medications 
Treatment 
Restriction 
cDMARDs other than MTX 
 
Treatment with cDMARDs other than MTX, including leflunomide, is 
prohibited during the entire study, with the exception of sulfasalazine 
and/or hydroxychloroquine if they were assigned as rescue medication 
during the core study. 
o 
During the first 12 weeks of the OLE study (i.e., up to Visit 4 
[Week 36]), cDMARD background therapy (MTX for all subjects; 
sulfasalazine and/or hydroxychloroquine for subjects assigned 
rescue medication in the core studies) should remain unchanged and 
may be adjusted only for safety reasons according to Investigator 
discretion.  Subjects from CL04041025 are exempt from this 
restriction. 
o 
After the first 12 weeks of the OLE study (i.e., after Visit 4 
[Week 36]), dose modifications of a subject’s existing background 
cDMARD therapy are permitted, if deemed appropriate by the 
Investigator, per local guidelines (see Section 6.13.3).  Subjects that 
did not receive sulfasalazine and/or hydroxychloroquine in the core 
studies should not be assigned these medications in the OLE study. 
bDMARDs/kinase inhibitors 
 
Treatment with bDMARDs or kinase inhibitors is prohibited during the 
entire study. 
Corticosteroids 
 
During the first 12 weeks of the OLE study (i.e., up to Visit 4 
[Week 36]): 
o 
The use of parenteral corticosteroids (with the exception of IA 
corticosteroids) is prohibited. 
o 
The use of oral corticosteroids >10 mg/day prednisone or equivalent 
is prohibited.  Dose tapering is permitted according to 
Investigator discretion; other changes in dose are prohibited 
unless the Investigator changes the dose for safety reasons. 
 
After the first 12 weeks of the OLE study (i.e., after Visit 4 [Week 36]), 
a change in the route of administration of corticosteroids or a dose 
adjustment of oral corticosteroids is permitted, including transient dose 
increases with dose tapering as soon as possible after the dose increase 
(see Section 6.13.3), per Investigator discretion and local practice. 


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Treatment 
Restriction 
NSAIDs 
 
Initiation of new NSAIDs is prohibited during the first 12 weeks of the 
OLE study. 
o 
Stable doses of NSAIDs are permitted during the first 12 weeks of 
the OLE study if the subject received these NSAIDs during the core 
study (see Section 6.13.2).  Dose tapering is permitted according 
to Investigator discretion; other changes in dose are prohibited 
unless the Investigator changes the dose for safety reasons.  
Switching of NSAIDs is not allowed.  However, if the subject has 
an AE that requires discontinuation of the NSAID, an alternative 
NSAID may be initiated per the local label (if not contraindicated). 
 
After the first 12 weeks of the OLE study (i.e., after Visit 4 [Week 36]), 
dose modification and switching of NSAIDs is permitted (see 
Section 6.13.3), per Investigator discretion and local guidelines. 
 
Aspirin use at daily doses up to 325 mg is permitted throughout the 
study if indicated for CV protection.  At this dose, aspirin will not be 
considered an NSAID. 
Analgesics 
 
Analgesics, including opioids, are prohibited during the first 12 weeks of 
the OLE study with the following exception (see Section 6.13.2): 
o 
Paracetamol/acetaminophen:  Maximum 2000 mg per day 
(maximum 1000 mg per dose).  Paracetamol/acetaminophen are not 
to be taken within 24 hours prior to joint assessment, including 
OLE Baseline assessment. 
 
After the first 12 weeks of the OLE study (i.e., after Visit 4 [Week 36]), 
analgesics and opioids are permitted. 
Hyaluronic acid 
 
Intra-articular hyaluronic acid is prohibited during the first 12 weeks of 
the OLE study. 
 
After the first 12 weeks of the OLE study (i.e., after Visit 4 [Week 36]), 
IA hyaluronic acid is permitted. 
o 
Joints that receive IA hyaluronic acid should be omitted from all 
subsequent joint assessments (Sections 7.1.2, 7.1.6, and 7.1.7) and 
should be rated with their pre-injection status for the remainder of 
the study. 
Vaccination 
 
Live and live attenuated vaccines are prohibited during the entire study. 
Abbreviations:  bDMARD = biologic disease-modifying anti-rheumatic drug; cDMARD = conventional 
disease-modifying anti-rheumatic drug; CV = cardiovascular; IA = intra-articular; MTX = methotrexate; 
NSAID = non-steroidal anti-inflammatory drug; OLE = open-label extension. 
6.13.1 
Olokizumab Potential Impact on Cytochrome P and Transporter Pathways 
Based on nonclinical data (refer to the most recent version of the Investigator’s Brochure), it 
is possible that OKZ may reverse IL-6-mediated inhibition of CYP or transporter pathways 
such as CYP1A1/2, 2B6, 2C9, 3A4/5, and 2C19 and sodium/taurocholate co-transporting 
polypeptide.  If CYP or transporter activity is de-suppressed (i.e., increased to any relevant 
extent), this may result in decreased level of drugs eliminated by these pathways.  As such, 
OKZ may have clinical relevance for CYP substrates with narrow therapeutic index and for 


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which a change in effectiveness may be undesirable.  Investigators are advised to monitor 
substrates with a narrow therapeutic index (as noted in their respective package inserts/drug 
labels) and to contact the Medical Monitor to discuss any potential concerns about 
concomitant medications. 
6.13.2 
Allowed Medications 
The following medications are allowed (non-exhaustive list), including clarifications of the 
above prohibited medications: 
 
Inhaled corticosteroids 
 
Topical corticosteroids 
 
Oral corticosteroids 
 Doses of ≤10 mg/day of prednisone or equivalent are permitted during the first 
12 weeks of the OLE study, with dose tapering permitted according to Investigator 
discretion.  Other dose adjustments are not permitted during the first 12 weeks of the 
OLE study unless the Investigator changes the dose for safety reasons. 
 Dose modification is permitted after Visit 4 (Week 36) (see Section 6.13.3), per the 
Investigator’s discretion and local practice, including transient dose increases with 
dose tapering as soon as possible after the dose increase. 
 Investigator should take into consideration the AEs associated with the continuous 
use of corticosteroids (e.g., diabetes mellitus, infections, GI perforations) 
 
IM or IV corticosteroids 
 Permitted after Visit 4 (Week 36) (see Section 6.13.3) 
 
Intra-articular (IA) corticosteroids 
 Permitted in a maximum of 3 joints within the study period, not to exceed one 
injection every 6 months.  The cumulative dose for the 3 injections must not exceed 
40 mg methylprednisolone or equivalent.  Joints treated with IA corticosteroids must 
be rated with their pre-injection status for the remainder of the study and should be 
omitted from all subsequent joint assessments (see Sections 7.1.2, 7.1.6, and 7.1.7). 
 
Intra-articular hyaluronic acid 
 Permitted after Visit 4 (Week 36).  Joints treated with IA hyaluronic acid must be 
rated with their pre-injection status for the remainder of the study and should be 
omitted from all subsequent joint assessments (see Sections 7.1.2, 7.1.6, and 7.1.7). 


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 
NSAIDs 
 Stable doses of NSAIDs are permitted during the first 12 weeks of the OLE study if 
the subject received these NSAIDs during the core study, with dose tapering 
permitted according to Investigator discretion.  Other dose adjustments are not 
permitted during the first 12 weeks of the OLE study unless the Investigator changes 
the dose for safety reasons.  Switching of NSAIDs is not allowed prior to Visit 4 
(Week 36) of the OLE study.  However, if the subject has an AE that requires 
discontinuation of the NSAID, an alternative NSAID may be initiated per the local 
label (if not contraindicated). 
 Dose modification and switching of NSAIDs are permitted after Visit 4 (Week 36) 
(see Section 6.13.3). 
 
Analgesics 
 Prior to Visit 4 (Week 36), subjects may be treated with paracetamol/acetaminophen 
up to amaximum dose of 2000 mg per day (maximum 1000 mg per dose) or up to the 
maximum dose in the local label, whichever is lower.  Paracetamol/acetaminophen 
are not to be taken within 24 hours prior to joint assessment, including OLE Baseline 
assessment. 
 After Visit 4 (Week 36), analgesics (including opioids) are permitted. 
 
Inactivated vaccines can be administered in accordance with the standard of care. 
 The effect of OKZ on vaccine response, including inactivated vaccines, is unknown. 
6.13.3 
Modification of Background Therapy 
During the first 12 weeks of the OLE study, background MTX (all subjects) and 
sulfasalazine and/or hydroxychloroquine (for subjects assigned rescue medication starting at 
Week 14 in the core studies) should remain unchanged and may be adjusted only for safety 
reasons according to Investigator discretion (see Appendix 1 [Section 13.1] for guidelines on 
MTX dose reduction).  Subjects from CL04041025 are exempt from this restriction, and have 
their background therapy may be adjusted at the Investigator’s discretion.  
For subjects who receive background sulfasalazine and/or hydroxychloroquine, periodic 
safety evaluations for toxicity resulting from sulfasalazine and/or hydroxychloroquine should 
be undertaken as per the drug label and local guidelines.  The maximum allowed doses of 
sulfasalazine and hydroxychloroquine are: 
 
Sulfasalazine:  3 g per day 


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 
Hydroxychloroquine:  400 mg per day 
Dose tapering of background oral corticosteroids and NSAIDs (if applicable) is permitted 
according to Investigator discretion, but the dose should otherwise remain unchanged unless 
the Investigator changes the dose for safety reasons. 
After the first 12 weeks of the OLE study (i.e., after Visit 4 [Week 36]), the Investigator may 
modify background therapy, if deemed appropriate, per local guidelines.  Modifications to 
background therapy may include: 
 
Modification of MTX for all subjects 
 
Modification of sulfasalazine and/or hydroxychloroquine for subjects assigned rescue 
medication starting at Week 14 in the core studies 
 Sulfasalazine and/or hydroxychloroquine may not be prescribed to subjects who did 
not receive these rescue medications in the core studies. 
 
Modification of oral corticosteroids (including initiation of doses ≤10 mg/day of 
prednisone or equivalent) 
 
Administration of IM or IV corticosteroids 
 
Modification of NSAIDs (including switching of NSAIDs) 
6.14 Medical Treatment for Subjects after End of Treatment Period 
After completion of the 82-week, open-label Treatment Period, or after premature 
discontinuation of study treatment, subjects will enter the Safety Follow-Up Period.  It is the 
responsibility of the Investigator to choose adequate treatment. 


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7. EFFICACY, SAFETY, PHARMACOKINETIC, AND 
HEALTH OUTCOME ASSESSMENTS 
7.1 
Efficacy Assessments 
7.1.1 
American College of Rheumatology 20%/50%/70% Response Criteria 
ACR20/ACR50/ACR70 will not be calculated by the Investigator during the course of the 
study, but will be computed in the statistical database for analysis purposes. 
The number of subjects who achieve an ACR20, ACR50, or ACR70 response at various time 
points will be calculated.  The calculations are based on a ≥20%, ≥50%, and ≥70% 
improvement from baseline in the SJC assessed in 66 joints and in the 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:  
 
Patient Global Assessment of Disease Activity (VAS) 
 
Patient Assessment of Pain (VAS) 
 
HAQ-DI 
 
Physician Global Assessment (VAS) 
 
Level of acute phase reactant (CRP or ESR, using level of CRP in this study) 
7.1.2 
66-68 Joint Assessment 
The 66-68 joint assessment evaluates 66 joints for swelling and 68 joints for tenderness and 
pain on motion.  The hip joints can be assessed for tenderness, but not for swelling.  The 
following joints are included: 
 
Temporomandibular, sternoclavicular, acromioclavicular, shoulders, elbows, wrists, 
interphalangeal (IP) on digit 1, distal interphalangeals on digits 2 to 5, proximal 
interphalangeals (PIP) on digits 2 to 5, metacarpophalangeal (MCP) on digits 1 to 5, 
hips (tenderness only), knees, ankles and tarsus, metatarsals, IP on toe 1, PIP on toes 
2 to 5, and metatarsophalangeals (MTP) on toes 1 to 5. 
As noted in Table 1, the joint assessor will be independent to the rest of the study team.  An 
independent joint assessor, blinded to other study assessments as well as the dosing regimen, 
will be identified at each study site to perform the SJC and TJC.  To ensure consistent joint 
evaluation throughout the study, individual subjects should be evaluated by the same joint 
assessor as in the core studies for all study visits, whenever possible. 


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Artificial, missing, and ankylosed joints are excluded from both tenderness and swelling 
assessments.  If joints are missing or not able to be assessed, the number of joints will be 
weighted by the actual number of assessable joints, and the missing or not assessable joints 
should be marked as “not assessed” for all subsequent joint assessments for the remainder of 
the study.  If a subject receives IA corticosteroids or IA hyaluronic acid (see Section 6.13.2), 
any treated joints should be omitted from all subsequent joint assessments and should be 
rated with their pre-injection status for the remainder of the study. 
7.1.3 
Patient Global Assessment of Disease Activity (Visual Analog Scale) 
Subjects will assess the overall disease activity by responding to the following: 
 
Considering all the ways in which illness and health conditions may affect you at this 
time, please make a mark below to show how you are doing, using a 100 mm VAS 
where 0 is “very well” and 100 is “very poorly”. 
7.1.4 
Patient Assessment of Pain (Visual Analog Scale) 
Subjects will rate their short-term arthritis pain by responding to the question: 
 
How much pain are you experiencing because of your illness AT THIS TIME? Place a 
vertical (I) mark on the line to indicate the severity of the pain, using a 100 mm VAS 
where 0 is “no pain” and 100 is “severe pain”. 
7.1.5 
Physician Global Assessment (Visual Analog Scale) 
The Investigator will rate the overall status of the subject for the day of the visit, with respect 
to RA signs and symptoms and the functional capacity of the subject.  The Investigator will 
respond to the following: 
 
Mark an X on the line below to indicate disease activity (independent of the patient’s 
self-assessment).  A 100 mm VAS will be used, where 0 is “no disease activity” and 
100 is “maximal disease activity”. 
7.1.6 
Disease Activity Score 28-Joint Count (C-Reactive Protein) 
The DAS28 (CRP) will not be calculated by the Investigator during the course of the study, 
but will be computed in the statistical database for analysis purposes. 
The DAS28 (CRP) will be 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 


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The 28 joints evaluated for the SJC and TJC are as follows: 
 
Shoulders, elbows, wrists, IP on digit 1, PIP on digits 2 to 5, MCP on digits 1 to 5, and 
knees 
Details of the joint assessment process are provided in Section 7.1.2. 
7.1.7 
Disease Activity Score 28-Joint Count (Erythrocyte Sedimentation Rate) 
The DAS28 (ESR) will not be calculated by the Investigator during the course of the study, 
but will be computed in the statistical database for analysis purposes. 
The DAS28 (ESR) will be calculated using the SJC (28 joints), TJC (28 joints), 
ESR (mm/hour), and the Patient Global Assessment of Disease Activity (VAS) (in mm) 
according to the following formula: 
DAS28 (ESR) = 0.56 × √(TJC) + 0.28 × √(SJC) + 0.70 × lognat (ESR) + 0.014 × Patient 
Global Assessment of Disease Activity (VAS) 
The 28 joints evaluated for the SJC and TJC are as follows: 
 
Shoulders, elbows, wrists, IP on digit 1, PIP on digits 2 to 5, MCP on digits 1 to 5, and 
knees 
Details of the joint assessment process are provided in Section 7.1.2. 
7.1.8 
Simplified Disease Activity Index 
The SDAI will not be calculated by the Investigator during the course of the study, but will 
be computed in the statistical database for analysis purposes. 
The SDAI will be calculated using the SJC (28 joints), TJC (28 joints), CRP (mg/dL), the 
Patient Global Assessment of Disease Activity (VAS) (in cm), and the Physician Global 
Assessment (VAS) (in cm) according to the following formula: 
SDAI = SJC + TJC + Patient Global Assessment of Disease Activity (VAS) + Physician 
Global Assessment (VAS) + CRP 
7.1.9 
Clinical Disease Activity Index 
The CDAI will not be calculated by the Investigator during the course of the study, but will 
be computed in the statistical database for analysis purposes. 


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The CDAI will be 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) 
7.1.10 
Health Assessments and Patient-Reported Outcomes  
The PROs that will be utilized for efficacy assessments are discussed in this section. 
7.1.10.1 
Health Assessment Questionnaire – Disability Index 
The HAQ-DI is a patient-reported questionnaire that provides an assessment of the impact of 
the disease and its treatment on physical function.  The HAQ-DI assesses the degree of 
difficulty experienced in 8 domains of daily living activities using 20 questions.  The 
domains are dressing and grooming, arising, eating, walking, hygiene, reach, grip, and 
common daily activities, and each domain (activity) consists of 2 or 3 items.  For each 
question, the level of difficulty is scored from 0 to 3 where 0 = without any difficulty, 
1 = with some difficulty, 2 = much difficulty, and 3 = unable to do.  Each category is 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 is 0 or 1, but a device related to that category is used, or help from 
another person is provided for the category, then the category score is increased to 2.  If the 
category score is already a 2 (or above), the score in that category remains 2 with or without 
any aids or device use.  If the subject does not provide an answer for any questions within a 
category, no score will be provided for that category.  The HAQ-DI will be 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 have responses, no disability score will be calculated. 
The HAQ-DI will also include patient assessments of pain and health on a scale of 0 to 100. 
7.1.10.2 
Short Form-36 
The SF-36 health survey is a patient-reported survey of health; it is commonly used in health 
economics as a variable in the quality-adjusted life year (QALY) calculation to determine the 
cost-effectiveness of a health treatment.  The SF-36 consists of 8 scaled scores, which are the 
weighted sums of the questions in their section.  Each scale is directly transformed into a 0 to 
100 scale on the assumption that each question carries equal weight.  The lower the score the 
more disability.  The higher the score, the less disability (i.e., a score of zero is equivalent to 
maximum disability and a score of 100 is equivalent to no disability). 


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The 8 domains of the SF-36 are as follows: 
 
Vitality 
 
Physical functioning 
 
Bodily pain 
 
General health perceptions 
 
Physical role functioning 
 
Emotional role functioning 
 
Social role functioning 
 
Mental health 
7.1.10.3 
European Quality of Life – 5 Dimensions 
The conceptual basis of the EQ-5D is the holistic view of health, including both the medical 
definition and the fundamental importance of independent physical, emotional, and social 
functioning.  The concept of health in EQ-5D also encompasses both positive aspects 
(well-being) and negative aspects (illness). 
The EQ-5D consists of a questionnaire and a VAS and is a self-rated health status.  The 
EQ-5D records the subject’s perceptions of their own current overall health, and can be used 
to monitor changes with time.  The self-assessment questionnaire is a description of 
5 dimensions (i.e., mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression).  The subject is asked to grade their own current level of function in each 
dimension into 1 of 5 degrees of disability (extreme, severe, moderate, slight, or none).  The 
combination of these with the conditions “death” and “unconscious” enables a description of 
3127 different health states.  Each health state can be ranked and transformed as a single 
score called the utility. 
The EQ-5D health states may be converted into a single summary index by applying a 
formula that attaches values to each of the levels in each dimension.  The index can be 
calculated by deducting the appropriate weights from 1, the value for full health (i.e., state 
11111).  Value sets have been derived for EQ-5D in several countries using the European 
Quality of Life-5 Dimensions Visual Analog Scale (EQ-5D VAS) valuation technique or the 
time trade-off valuation technique. 


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7.1.10.4 
Work Productivity Survey – Rheumatoid Arthritis 
The WPS-RA measures the impact of RA and treatment on subject productivity within and 
outside the home during the previous month.  It contains 9 questions addressing employment 
status, productivity within and outside the home, and daily activities.  One item of the 
WPS-RA addresses current labor market participation.  This is a strong indicator of work 
ability because not working implies complete loss of paid productivity.  There are also 
normative and comparative data available on employment status.  Two items capture 
self-reported work absences due to arthritis, and 2 items capture the same concept but applied 
to non-paid work.  These are separated into full and partial days (i.e., days of work missed 
and days with productivity reduced by at least half).  Additional items capture the 
respondent's estimate of the extent to which arthritis has interfered with the subject’s work 
productivity (paid and non-paid) on a scale of 0 to 10, the number of days in the last month 
outside help was hired because of arthritis, and the number of days in the last month family, 
social, or leisure activities were missed because of arthritis. 
7.1.10.5 
Functional Assessment of Chronic Illness Therapy – Fatigue Scale 
FACIT-Fatigue is a 13-item tool that measures an individual’s level of fatigue during their 
usual daily activities during the most recent week.  The level of fatigue is measured on a 
4-point Likert scale. 
The sum of the scoring (total score) will be used for the statistical evaluation.  If an item is 
not scored, the total score will be set to missing. 
7.2 
Pharmacokinetics 
There will be no collection of blood samples for the determination of OKZ concentration in 
plasma in this study. 
 
The Week 24 sample is the last sample to be collected in the core studies.  This sample 
must be collected prior to administration of OKZ in the OLE study, and the sample 
will be analyzed and included in the data set of the core study in which the subject 
participated, according to the procedures detailed in the core study protocol.  This 
sample will not be analyzed as part of the OLE data set. 
To provide documentation that the Week 24 PK sample was collected prior to the first dose 
of study treatment in this study, the date and time of OKZ administration at Week 24 will be 
captured in each subject’s eCRF. 
Although there will be no collection of blood samples in this study for the determination of 
OKZ concentration in plasma, blood samples that are collected for immunogenicity analysis 
(see Section 7.3) may also be used to determine OKZ concentrations in plasma if it is 


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determined that such evaluation may provide additional information regarding subject safety 
and efficacy of OKZ (e.g., due to unexpected immunogenicity results). 
7.3 
Immunogenicity 
Immunogenicity will be assessed by evaluating the impact of ADAs on subject safety and 
efficacy of OKZ.  Blood samples for analysis of the incidence and titer of antibodies to OKZ 
and the incidence of any neutralizing antibodies to OKZ in plasma will be collected at the 
times shown in Table 1. 
The actual sample collection date and exact time will be entered on the Immunogenicity 
Blood Collection eCRF page.  Sampling problems will be noted in the Comments section of 
the eCRF.  All blood samples will be taken by either direct venipuncture or an indwelling 
cannula inserted in a forearm vein.  A Laboratory Manual will be provided to the Investigator 
with detailed information on sample collection, handling, and shipment of the ADA samples.  
Tubes and preprinted labels will be provided by the central laboratory to the study sites. 
Antidrug antibody samples from all subjects who received OKZ will be analyzed, using 
appropriately validated methods, by R-Pharm International or R-Pharm International’s 
designee.  Samples will initially be screened for antibodies.  A confirmation assay will be 
used to confirm the positive status for samples that scored potentially positive by the 
Screening assay.  In confirmed positive samples, the relative titer of the antibody will be 
determined as well as whether the confirmed positive sample represents a neutralizing 
antibody. 
7.4 
Safety 
Safety assessments will consist of monitoring and recording all AEs, including SAEs, 
nonserious AESIs, and pregnancies; measurement of safety laboratory assessments; 
measurement of vital signs, ECGs, physical examinations; and other tests that are deemed 
critical to the safety evaluation of the study in all subjects who receive at least 1 dose of 
study treatment.  As discussed in Section 7.4.2.3, any pregnancy that occurs while a subject 
is enrolled in the study will also be monitored and reported according to the appropriate 
regulations. 
The Investigator remains responsible for following, through an appropriate health care 
option, AEs that are serious and nonserious that caused the subject to discontinue before 
completing the study.  Any AE, including any AE still ongoing at the end of the study, 
should be followed until it has resolved, it has a stable sequelae, the Investigator determines 
that it is no longer clinically significant, or the subject is lost to follow-up.  If no follow-up is 
provided, the Investigator must provide a justification. 


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In addition to records of observations made at specific times, unexpected signs and 
symptoms and concomitant medications will be recorded in the clinical study records 
throughout the study.  The Investigator will also collect completed pages of the Subject Diary 
(see Section 5.5) at Visits 2 (Week 26) through 10 (EoT/Week 106), and the Investigator will 
review any complaints, signs, or symptoms experienced by the subject in association with 
administration of study treatment.  Completed pages of the Subject Diary will serve as source 
documents, and information will be recorded on the appropriate pages of the eCRF.  The 
Subject Diary will not be used during the Safety Follow-Up Period.  Further routine medical 
assessments in addition to those specified in Table 1 may take place during the study as 
clinically indicated (e.g., chest X-rays to investigate lung lesions, ECG, etc). 
Safety measures in this study include, but are not limited to, SAEs, AEs, vital signs, body 
weight, and laboratory evaluations, and if required, this information must be present in the 
AE/SAE report made by the Investigator. 
7.4.1 
Adverse Events 
For the purposes of this study, an AE will be defined as any untoward medical occurrence in 
a subject or clinical investigation subject administered a pharmaceutical product and which 
does not necessarily have a causal relationship with this treatment.  An AE can therefore be 
any of the following: 
 
Any unfavorable and unintended sign, symptom, or disease temporally associated with 
the use of a medicinal product, whether or not considered related to the medicinal 
product. 
 If the Investigator determines a laboratory abnormality to be clinically significant, it 
is considered a laboratory AE; however, if the abnormal laboratory value is consistent 
with a current diagnosis (or signs or symptoms if a diagnosis is not possible) and is 
not a clinically significant worsening from the baseline laboratory parameter, it 
should be documented accordingly without being reported as a separate laboratory 
AE. 
 
Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition). 
The Investigator is responsible for recording all AEs observed during the study starting at 
Visit 1 (OLE Baseline/Week 24).  All AEs are recorded throughout the study until the last 
visit of the subject.  The Investigator is responsible for the appropriate medical care of the 
subjects during the entire study. 


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Each AE is to be evaluated for duration, severity, seriousness, and causal relationship to the 
investigational drug.  For all AEs, the Investigator must pursue and obtain information 
adequate both to determine the outcome of the AE and to assess whether it meets the criteria 
for classification as an SAE.  The Investigator is required to assess causality as described 
below. 
Severity 
The severity of AEs will be characterized according to the CTCAE grades and definitions 
summarized in Table 4. 
Table 4 
CTCAE Grades and Corresponding AE Severity 
CTCAE Grade 
Corresponding AE Severity  
Grade 1   
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2  
Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL 
Grade 3  
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL 
Grade 4   
Life-threatening consequences; urgent intervention indicated 
Grade 5   
Death related to AE 
Abbreviations:  ADL = activities of daily living; AE = adverse event; CTCAE = Common Terminology Criteria 
for Adverse Events. 
Causality Assessment 
The Investigator is responsible for making an assessment of the causal relationship between 
the study treatment and the AE.  Investigators should use their knowledge of the subject, the 
circumstances surrounding the event, and an evaluation of any potential alternative causes to 
determine whether or not an AE is considered to be related to the study treatment.  The 
causal relationship between the study treatment and the AE must be characterized as 
“related” or “not related”.  The following guidance should be taken into consideration: 
 
Temporal relationship of event onset to the initiation of the study treatment. 
 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of the study treatment, or reintroduction of the study treatment. 
 
Known association of the event with the study treatment, or with similar treatments. 
 
Known association of the event with the disease under study. 


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 
Presence of risk factors in the subject or use of concomitant medications known to 
increase the occurrence of the event. 
 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event. 
The Investigator should report the relatedness of each event based on the most likely causal 
relationship, and the study site staff is responsible for obtaining any missing information. 
7.4.1.1 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all subject evaluation time points.  Examples of nondirective questions from 
the Investigator to the subject include the following: 
 
“How have you felt since your last clinic visit?” 
 
“Have you had any new or changed health problems since you were last here?” 
7.4.2 
Serious Adverse Events 
An SAE experience or reaction is any untoward medical occurrence (whether considered to 
be related to the study treatment or not) that at any dose: 
 
Results in death 
 
Is life-threatening (the subject is at a risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were more severe) 
 
Requires subject hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital abnormality/birth defect 
 
Other medically significant events, which do not meet any of the criteria above, but 
may jeopardize the subject and may require medical or surgical intervention to prevent 
1 of the other serious outcomes listed in the definition above. 
 Examples of such events are blood dyscrasias (e.g., neutropenia or anemia requiring 
blood transfusion, etc) or convulsions that do not result in hospitalization. 
 Confirmed cases of active TB should be recorded and reported as SAEs. 
 Potential hepatotoxicity events that fulfill any of the following criteria should be 
recorded and reported as SAEs: 


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 ALT >3× ULN and total bilirubin >2× ULN 
 ALT >8× ULN at any time, regardless of total bilirubin or accompanying 
symptoms 
 ALT >5× ULN for ≥2 weeks, regardless of total bilirubin or accompanying 
symptoms.  The elevation should be continuous for ≥2 consecutive weeks.  If the 
level decreases for some time within 2 weeks, subject permanent discontinuation 
is not mandated, but left under Investigator discretion.  Resuming the IMP should 
be discussed on a case by case basis. 
 ALT >3× ULN, accompanied by symptoms which, as determined by the 
Investigator, are the result of hepatic injury (e.g., fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, eosinophilia [>5%]). 
Any AE that results in an unplanned hospitalization or prolonged hospitalization should be 
documented and reported as an SAE.  The following hospitalization scenarios are examples 
of events not considered to be SAEs: 
 
Hospitalization for a pre-existing condition, provided that any of the following criteria 
are met: 
 Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition or 
 Elective or preplanned treatment for a pre-existing condition that is unrelated to 
the indication under study and has not worsened since the start of study treatment. 
 
Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of an SAE given above and not resulting in hospital admission. 
 
Social reasons and respite care in the absence of any deterioration in the subject’s 
general condition. 
Any SAEs occurring after a subject has received the last dose of study treatment will be 
collected and reported to R-Pharm International’s designee through the end of the Safety 
Follow-Up Period (i.e., for a period of 22 weeks after the last dose of study treatment), 
regardless of the Investigator’s opinion of causality.  The Investigator must also inform 
participating subjects of the need to inform the Investigator of any SAE that occurs within 
this period.  Any SAE with a start date after the Safety Follow-Up Period is not required to 
be reported unless the Investigator thinks that the event may be related to either the study 
treatment, study treatment administration, or a protocol procedure. 
All deaths that occur during the protocol-specified AE reporting period, regardless of 
relationship to the study treatment, must be recorded on the SAE page in the eCRF and 


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immediately reported to R-Pharm International or their’s designee.  This includes death 
attributed to progression of RA. 
Death should be considered an outcome and not a distinct event.  The event or condition that 
caused or contributed to the fatal outcome should be recorded as the description of event on 
the SAE page in the eCRF.  Generally, only 1 such event leading to death should be reported. 
The use of the term “sudden death” as the description of an event should be used, for 
example, in case of presence of such cardiovascular diagnosis in the source documents or 
occurrence of an unexpected cardiac death within scenarios as described in Potential MACE 
Reporting Site Manual.  If the cause of death is unknown and cannot be ascertained at the 
time of reporting, “unexplained death” should be recorded on the SAE page as the 
description of the event in the eCRF.  If the cause of death later becomes available (e.g., after 
autopsy), “unexplained death” should be replaced by the established cause of death. 
7.4.2.1 
Lack of Efficacy or Worsening of Rheumatoid Arthritis 
Medical occurrences or symptoms of deterioration that are anticipated as part of RA should 
be recorded as an AE if judged by the Investigator to have unexpectedly worsened in severity 
or frequency or changed in nature at any time during the study.  When recording an 
unanticipated worsening of RA on the AEs eCRF page, it is important to convey the concept 
that the condition has changed by including applicable descriptors (e.g., “accelerated RA”).  
Events that are clearly consistent with the expected pattern of progression of the underlying 
disease, as determined by the Investigator, should not be recorded as AEs; these data will be 
captured as efficacy assessment data only.  Every effort should be made to document 
progression using objective criteria.  If there is any uncertainty as to whether an event is an 
AE or due to disease progression, it should be reported as an AE. 
Any worsening of RA that meets the criteria for seriousness should be reported as an SAE. 
7.4.2.2 
Overdose 
Study treatment overdose is the accidental or intentional use of the drug in an amount higher 
than the dose being studied.  An overdose or incorrect administration of study treatment is 
not an AE unless it results in untoward medical effects.  Any study treatment overdose or 
incorrect administration of study treatment should be noted on the Study Drug 
Administration eCRF.  All AEs associated with an overdose or incorrect administration of 
study treatment should be recorded on the AEs eCRF page. 


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7.4.2.3 
Reporting and Follow-up Requirements for Pregnancies 
Pregnancies in Female Subjects 
A urine pregnancy test will be conducted on all females of childbearing potential as 
presented in the Schedule of Events (Table 1). 
If a subject becomes pregnant after the administration of any study treatment, R-Pharm 
International and/or R-Pharm International’s designee should be informed immediately.  
Study treatment should be discontinued as soon as the pregnancy is known, and the following 
should be completed: 
 
The subject should immediately discontinue further administration of study treatment. 
 
The subject should return for an EoT Visit. 
 
All scheduled safety assessments must be performed unless contraindicated by 
pregnancy (harmful to fetus) or the subject withdraws informed consent. 
The Investigator must inform the subject of information currently known about potential 
risks and about available treatment alternatives.  The pregnancy should be followed up to 
determine outcome including spontaneous or voluntary termination, details of the birth, and 
the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications. 
Full details will be recorded on a Pregnancy Report eCRF and submitted via the Electronic 
Data Capture (EDC) system, and reporting details will be detailed in the Study Manual.  The 
Investigator will update the Pregnancy Report eCRF with additional information as soon as 
the outcome of the pregnancy is known. 
If the outcome of the pregnancy is an SAE then this must be additionally reported as an SAE 
on the appropriate eCRF page. 
Pregnancies in Female Partners of Male Subjects 
Male subjects will be instructed through the ICF to immediately inform the Investigator if 
their partner becomes pregnant during the study and up to 3 months after the subject received 
the last injection of study treatment.  A Pregnancy Report eCRF should be completed by the 
Investigator within 1 working day after learning of the pregnancy and submitted via the EDC 
system.  Attempts should be made to collect and report details of the course and outcome of 
any pregnancy in the partner of a male subject exposed to the study treatment.  The pregnant 
partner will need to sign an Authorization for Use and Disclosure of Pregnancy Health 
Information to allow for follow-up on her pregnancy.  Once the authorization has been 


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signed, the Investigator will update the Pregnancy Report eCRF with additional information 
on the course and outcome of the pregnancy.  An Investigator who is contacted by the male 
subject or his pregnant partner may provide information on the risks of the pregnancy and the 
possible effects on the fetus, to support an informed decision in cooperation with the treating 
physician and/or obstetrician. 
7.4.3 
Adverse Events of Special Interest 
The following safety concerns were identified as AESIs based upon either the safety data 
available to date (refer to the most recent version of the Investigator’s Brochure) for OKZ or 
drug class-related events for a biologic IL-6 inhibitor: 
 
Infections (particularly serious infections), including TB and opportunistic infections 
 Confirmed cases of active TB must also be recorded as an SAE. 
 
Malignancies 
 The Investigator will be asked to provide relevant medical 
information/documentation (e.g., pathology/histology reports) on all malignancy 
cases, whether considered serious or not, as these cases will be recorded in the safety 
database. 
 
Elevation of blood lipids (e.g., hypercholesterolemia, blood cholesterol increased, 
blood triglycerides increased, hypertriglyceridemia, and elevation of LDL) 
 
Systemic injection reactions and hypersensitivity reactions, including anaphylaxis 
 Refer to Appendix 3 (Section 13.3) for details on diagnosing anaphylaxis. 
 
GI perforation 
 
CV events 
 
Neutropenia, thrombocytopenia, leukocytopenia, and pancytopenia 
 
Hepatotoxicity 
 The Investigator will be asked to provide relevant medical 
information/documentation (e.g., laboratory test results, including tests for viral 
hepatitis and, if performed, liver biopsy) on all hepatotoxicity cases, whether 
considered serious or not, as these cases will be recorded in the safety database (see 
Section 7.4.3.4). 
 
Injection site reactions 


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 
Demyelination in peripheral or central nervous system 
 
Autoimmune disorders. 
All of the events listed above will be analyzed as AESIs; some of these events are further 
detailed below. 
7.4.3.1 
Infections 
Frequency, duration, and severity of infectious complications along with those requiring 
treatment (e.g., antibiotic, antiviral, etc) will be monitored and evaluated.  Investigators will 
also educate subjects, parents, and/or caregivers about the symptoms of infections and will 
provide instructions on dealing with these infections. 
Physicians should exercise caution when considering the use of OKZ in subjects with a 
history of recurring infection or with underlying conditions (e.g., diabetes) that may 
predispose subjects to infections.  Study Treatment should not be administered to subjects 
with active or clinically significant infection.  Vigilance for timely detection of serious 
infection is recommended for subjects receiving biologic agents for treatment of RA, as signs 
and symptoms of acute inflammation may be lessened due to suppression of the acute phase 
reaction.  Subjects must be instructed to contact their physician immediately when any 
symptom suggesting infection appears, in order to assure rapid evaluation and appropriate 
treatment.  The Investigator may be asked to provide relevant medical 
information/documentation (e.g., result of bacterial examination or cultures). 
Any infection that meets the criteria for seriousness should be reported as an SAE. 
7.4.3.2 
Systemic Injection Reactions, Including Anaphylaxis 
A systemic injection reaction is any untoward medical hypersensitivity-like event, other than 
injection site reactions, occurring during or after study treatment administration that can be at 
least possibly attributed to the study treatment.  Systemic injection reactions are further 
classified as acute and delayed based on timing and presentation of symptoms typical for 
hypersensitivity reactions. 
Acute and delayed reactions to the study treatment should be reported according to the 
judgment of the Investigator, based on the typical clinical features. 
Any systemic allergic reaction that meets the criteria for seriousness should be reported as an 
SAE. 
Subjects will be observed for AEs at the study site for at least 2 hours after the first 
administration of study treatment (Visit 1 [OLE Baseline/Week 24]) and for at least 30 


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minutes after the second administration of study treatment (Visit 2 [Week 26] for subjects 
receiving OKZ 64 mg q2w and Visit 3 [Week 28] for subjects receiving OKZ 64 mg q4w).  
For injections administered by the subject (or caregiver, if applicable), subjects will record in 
the Subject Diary (see Section 5.5) any complaints, signs, or symptoms that occur during or 
after the injection.  Subjects will be asked to contact the Investigator if any significant 
reactions occur within the 2 hours following study treatment injection. 
Acute injection reactions are usually defined as at least 1 of the following signs or symptoms 
occurring during or within 2 hours of the study treatment injection: 
 
Hypotension 
 
Urticaria 
 
Flushing 
 
Facial or hand edema 
 
Throat tightness, oral cavity, or lip edema 
 
Headache 
 
Shortness of breath. 
The Investigator should report any AE of acute systemic injection reaction as 
“anaphylaxis” if it meets the Clinical Criteria for Diagnosing Anaphylaxis, as specified 
in Appendix 3 (Section 13.3). 
The study site must have adequate arrangements to manage anaphylactic reactions. 
Delayed injection reactions are usually defined as at least 2 of the following 4 signs or 
symptoms occurring within 1 day to 14 days following the injection: 
 
Rash 
 
Fever (more than 100°F [38°C]) 
 
Polyarthralgias 
 
Myalgias. 
7.4.3.3 
Gastrointestinal Perforation 
Timely diagnosis and appropriate treatment may reduce the potential for complications of 
diverticulitis and thus reduce the risk of GI perforations.  Therefore, subjects should be made 
aware of the symptoms potentially indicative of diverticular disease, and they should be 


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instructed to alert their healthcare provider as soon as possible if these symptoms arise.  
Permanent discontinuation of OKZ is required for subjects who develop diverticulitis and/or 
GI perforation. 
Any GI perforation or diverticulitis that meets the criteria for seriousness should be reported 
as an SAE. 
7.4.3.4 
Hepatotoxicity 
The Investigator will be asked to provide relevant medical information/documentation (e.g., 
laboratory test results) for all serious and non-serious cases of potential hepatotoxicity. 
Potential hepatotoxicity is defined as laboratory results that fulfill any of the following 
criteria (in all cases, AST may be substituted for ALT if ALT results are not available): 
 
ALT >3× to ≤5× ULN 
 
ALT >5× ULN 
 
ALT >3× ULN and total bilirubin >2× ULN 
Laboratory results that satisfy any of the criteria for potential hepatotoxicity should be 
followed by a repeat test within 72 hours, which must include total bilirubin, direct and 
indirect bilirubin, gamma-glutamyl transferase (GGT), INR, alkaline phosphatase, creatine 
phosphokinase, and hematology assessment.  After that, testing should be repeated at least 
weekly and followed until resolution, stabilization, or return to baseline values.  Additional 
testing may be limited to ALT, AST, alkaline phosphatase, and bilirubin if all other 
laboratory results are within normal limits.  The number of LFTs included in each repeat 
testing may be further reduced to include only those parameters which remain abnormal (i.e., 
abnormalities that stabilize, resolve, or return to within baseline values do not require repeat 
testing). 
Potential hepatotoxicity events that fulfill any of the following criteria must also be recorded 
as SAEs in the eCRF (in all cases, AST may be substituted for ALT if ALT results are not 
available): 
 
ALT >3× ULN and total bilirubin >2× ULN 
 
ALT >8× ULN at any time, regardless of total bilirubin or accompanying symptoms 
 
ALT >5× ULN for ≥2 weeks, regardless of total bilirubin or accompanying symptoms.  
The elevation should be continuous for ≥2 consecutive weeks.  If the level decreases 
for some time within 2 weeks, subject permanent discontinuation is not mandated, but 


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left under Investigator discretion.  Resuming the IMP should be discussed on a case by 
case basis. 
 
ALT >3× ULN, accompanied by symptoms which, as determined by the Investigator, 
are with the result of hepatic injury (e.g., fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, eosinophilia [>5%]) 
For SAEs of potential hepatotoxicity, the Investigator should contact the Medical Monitor for 
guidance, as additional tests are needed to investigate all potential causes of liver toxicity 
(e.g., alcohol use, hepatitis infection, biliary tract disease, and concomitant medications).  
Work-up includes, but is not limited to: 
 
Obtaining a more detailed history of symptoms and prior or concurrent diseases. 
 
Obtaining a history of concomitant drug use (including nonprescription medications 
and herbal/dietary supplement preparations), alcohol use, recreational drug use, and 
special diets. 
 
Ruling out acute viral hepatitis (types A, B, C, D, and E), cytomegalovirus, 
Epstein-Barr virus, autoimmune or alcoholic hepatitis, nonalcoholic steatohepatitis, 
hypoxic/ischemic hepatopathy, and biliary tract disease. 
 
Obtaining a history of exposure to environmental chemical agents. 
 
Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct 
bilirubin, biliary tract ultrasonography/imaging results, liver biopsy). 
 
Considering gastroenterology or hepatology consultations. 
All additional investigations should be recorded in the eCRF via the EDC system, and all 
records should be kept as source documents at the study site. 
7.4.3.5 
Injection Site Reactions  
An injection site reaction is any untoward medical event occurring at the injection site during 
or after study treatment administration that can be at least possibly attributed to the study 
treatment (i.e., the relationship cannot be ruled out). 
An assessment of pain, redness, swelling, induration, hemorrhage, and itching at the injection 
site will be performed.  At all specified visits (see Table 1), the assessment of injection site 
reactions that have occurred since the previous visit will be made by the Investigator prior to 
any administration of study treatment.  Injection site reactions noticed after on-site study 
treatment administration, when the subject is still on site or already at home and recorded 


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them in their diary, will be also reported.  All local reactions that are observed will be 
monitored until they resolve. 
7.4.4 
Study Committees 
An independent DSMB and CVAC will be established for this study. 
Members of the DSMB and CVAC will consist of at least 3 independent experts appointed 
by R-Pharm International based on their expertise.  Committee members will not be 
Investigators in the study, nor will they have any conflict of interest with R-Pharm 
International or its designee.  Members of the DSMB and CVAC will only serve on their 
appointed committee. 
Further details (e.g., frequency of data reviews and study committee composition and 
membership) will be provided in the predefined DSMB Charter and a separate CVAC 
Charter. 
7.4.4.1 
Data Safety Monitoring Board 
The independent DSMB members will perform ongoing safety surveillance and provide 
recommendations to R-Pharm International regarding study conduct.  These 
recommendations will be based mainly on the review of data for AEs and laboratory 
parameters.  Members of the DSMB will be partially blinded:  they will be aware of which 
subjects are in the same treatment group, but they will not be aware of the treatment assigned 
to each group.  Members of the DSMB can request full unblinding of safety data if they 
consider it necessary. 
7.4.4.2 
Cardiovascular Adjudication Committee 
The CVAC will be responsible for evaluating MACE and will remain blinded to treatment 
assignment.  The importance of the CVAC is to ensure that all potential MACE that have 
been reported are judged uniformly by a single group, using the same adjudication criteria. 
Data on the following fatal and nonfatal potential MACE (as further defined in the CVAC 
Charter) will be collected and the events will be adjudicated by the CVAC (as well as 
assessed by the DSMB): 
 
Death 
 
Non-fatal myocardial infarction 
 
Non-fatal stroke of all classifications 
 
Transient ischemic attack 


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 
Hospitalization for unstable angina requiring unplanned revascularization 
 
Non-fatal coronary revascularization procedures 
7.4.5 
Reporting of Adverse Events 
Study site personnel will record any change in the condition(s), occurrence, and nature of any 
AEs, including clinically significant signs and symptoms of the disease under treatment in 
the study.  Ongoing AEs (i.e., AEs that started during the core study) should be recorded as 
an AE in the OLE study only if the frequency, severity, or character of the condition worsens 
during the OLE study.  When recording such events on the AEs eCRF page, it is important to 
convey the concept that the pre-existing condition has changed by including applicable 
descriptors (e.g., “more frequent headaches”).  All AEs related to protocol procedures must 
be reported to R-Pharm International’s designee. 
Investigators will seek information on AEs at each subject contact.  The Investigator will also 
review the Subject Diary (Visits 2 [Week 26] through 10 [EoT/Week 106] only), where the 
subject will record any complaints, signs, or symptoms related to administration of the study 
treatment.  All AEs, whether reported by the subject or noted by study site staff, will be 
recorded in the subject’s medical record and on the AEs eCRF page. 
All AEs that occur at or after Visit 1 (OLE Baseline/Week 24), regardless of severity, are to 
be recorded on the appropriate AE pages in the eCRF (either serious or nonserious).  The 
Investigator should complete all the details requested including dates of onset, severity, 
action taken, outcome, and relationship to study treatment.  Each event should be recorded 
separately. 
Investigators will be instructed to report to R-Pharm International’s designee their 
assessment of the potential relatedness of each AE to protocol procedure and/or study 
treatment via the eCRF. 
Study site staff will record any dosage of study treatment that exceeds the assigned dosage in 
the protocol via eCRF. 
Any clinically significant findings from laboratory test results, vital sign measurements, other 
procedures, etc. should be reported to R-Pharm International’s designee via eCRF, EDC, 
and/or designated data transmission methods.  Investigators should use correct medical 
terminology/concepts when recording AEs on the AEs eCRF page, avoiding colloquialisms 
and abbreviations.  Only 1 AE term should be recorded in the event field on the AEs eCRF 
page.  For AEs other than injection-related reactions, a diagnosis (if known) should be 
recorded on the AEs eCRF page rather than individual signs and symptoms (e.g., record only 
liver failure or hepatitis rather than jaundice, asterixis, and elevated transaminases).  


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However, if a constellation of signs and/or symptoms cannot be medically characterized as a 
single diagnosis or syndrome at the time of reporting, each individual event should be 
recorded on the AEs eCRF page.  If a diagnosis is subsequently established, all previously 
reported AEs based on signs and symptoms should be nullified and replaced by 1 AE report 
based on the single diagnosis, with a starting date that corresponds to the starting date of the 
first symptom of the eventual diagnosis. 
Each AE is to be evaluated for date and time to onset, duration, severity, seriousness, and 
potential relatedness to the study treatment and/or study procedure (i.e., any procedure 
required by the study protocol).  The action taken and the outcome must also be recorded in 
the AE page of the eCRF. 
7.4.5.1 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data.  However, if any subject responses 
suggestive of a possible AE are identified during study site review of the PRO 
questionnaires, study site staff will alert the Investigator, who will determine if the criteria 
for an AE have been met and will document the outcome of this assessment in the subject's 
medical record per study site practice.  If the event meets the criteria for an AE, it will be 
reported on the AEs eCRF. 
Information contained within the subject diary (see Section 5.5) will not be considered PRO 
data. 
7.4.5.2 
Reporting of Serious Adverse Events 
All SAEs that occur at or after Visit 1 (OLE Baseline/Week 24), regardless of the 
Investigator’s assessment on causality, must be recorded on the relevant pages of the eCRF 
and reported to R-Pharm International according to protocol requirements. 
Investigators must report the SAE within 24 hours of first becoming aware of the event.  All 
SAEs must be reported via the EDC system by completing the relevant eCRF pages in 
English.  In the event that the EDC system is not functioning, SAEs must be reported within 
24 hours of first becoming aware of the event using the back-up paper SAE report form 
(instructions provided in the Investigator binders).  Once the EDC system is operating 
normally again, Investigators must enter the SAE in the eCRF pages.  All SAEs should be 
followed up as detailed in Section 7.4.5.5, and the timelines and procedure for follow-up 
reports are the same as those for the initial report.  R-Pharm International’s designee is 
responsible for managing the safety database. 
R-Pharm International will be alerted of all SAEs occurring during a subject’s follow-up 
regardless of the Investigator’s assessment of causality.  SAEs occurring after a subject has 


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received the last dose of study treatment will be collected and reported to R-Pharm 
International’s designee through the end of the Safety Follow-Up Period (i.e., for a period of 
22 weeks after the last dose of study treatment), regardless of the Investigator’s opinion of 
causality.  The Investigator must also inform participating subjects of the need to inform the 
Investigator of any SAE that occurs within this period.  Any SAE with a start date after the 
Follow-Up Period is not required to be reported unless the Investigator thinks that an event 
may be related to either the study treatment, study treatment administration, or a protocol 
procedure. 
7.4.5.3 
Reporting of Serious Adverse Events to Regulatory Authorities and 
Investigators 
R-Pharm International’s designee will be responsible for reporting all suspected unexpected 
serious adverse reactions (SUSARs) and any other applicable SAEs to regulatory authorities, 
ethics committees, and Investigators, in accordance with national regulations in the countries 
where the study is conducted.  Relative to the first awareness of the event by/or further 
provision to R-Pharm International’s designee, SUSARs will be submitted within 7 days for 
fatal and life-threatening events and 15 days for other SUSARs, unless otherwise required by 
national regulations.  R-Pharm International’s designee will also prepare an expedited report 
for other safety issues where these might materially alter the current benefit-risk assessment 
of OKZ or that would be sufficient to consider changes in the study treatment administration 
or in the overall conduct of the study.  The study site will also forward a copy of all 
expedited reports to the relevant Independent Ethics Committee (IEC) or Institutional 
Review Board (IRB) in accordance with national regulations. 
7.4.5.4 
Follow-up of Adverse Events 
Any AEs that occur at or after Visit 1 (OLE Baseline/Week 24) until the end of the Safety 
Follow-Up Period (i.e., 22 weeks after the last dose of study treatment) will be followed up 
to resolution.  Resolution means that the subject has returned to a baseline state of health, the 
Investigator does not expect any further improvement or worsening of the AE, or the subject is lost to 
follow-up.  The Investigator should follow each SAE until the event is resolved or returned to 
the baseline, the event is assessed as stable by the Investigator, the subject is lost to 
follow-up, or the subject withdraws consent.  For AEs with a causal relationship to the study 
treatment, R-Pharm International or its designee must concur with the Investigator’s 
assessment. 
For SAEs, nonserious AESIs, and pregnancies, R-Pharm International’s designee may 
follow-up by telephone, fax, electronic mail, and/or a monitoring visit to obtain additional 
case details and outcome information (e.g., from hospital discharge summaries, consultant 


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reports, or autopsy reports) in order to perform an independent medical assessment of the 
reported case. 
7.4.5.5 
Follow-up of Serious Adverse Events by the Investigator 
Any SAEs that occur at or after Visit 1 (OLE Baseline/Week 24) until the end of the Safety 
Follow-Up Period (i.e., 22 weeks after the last dose of study treatment) regardless of the 
Investigator’s opinion of causality, will be followed up.  The Investigator should follow each 
SAE until the event has resolved to the baseline grade or better, the event is assessed as 
stable by the Investigator, the subject is lost to follow-up, or the subject withdraws consent.  
If the subject is lost to follow-up, the SAE will be categorized based on the Investigator’s last 
assessment.  Every effort should be made to follow all SAEs considered to be related to OKZ 
or study-related procedures until an outcome can be reported. 
During the study, resolution of SAEs (with dates) should be documented on the SAE page of 
the eCRF and in the subject’s medical record to facilitate source data verification.  If, after 
follow-up, return to the baseline status or stabilization cannot be established, an explanation 
should be recorded on the SAE page of the eCRF. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
7.4.6 
Clinical Laboratory Evaluations 
Clinical laboratory tests will be reviewed for results of potential clinical significance at all 
time points throughout the study.  The Investigator will evaluate any change in laboratory 
values.  If the Investigator determines a laboratory abnormality to be clinically significant, it 
is considered a laboratory AE; however, if the abnormal laboratory value is consistent with a 
current diagnosis (or signs or symptoms if a diagnosis is not possible) and is not a clinically 
significant worsening from the baseline laboratory parameter, it should be documented 
accordingly without being reported as a separate laboratory AE.  The central laboratory will 
analyze the samples.  Further details of the procedures to be followed for sample collection, 
storage, and shipment will be documented in a Laboratory Manual.  Additional and repeat 
laboratory testing not specified in Table 1 may be performed at the discretion of the 
Investigator to ensure that the safety of subjects is protected. 
7.4.6.1 
Laboratory Parameters 
Unless otherwise noted, the central laboratory will be used in this study to analyze routine 
blood samples.  Blood samples will be collected according to the study Schedule of Events in 
Table 1. 
 
CRP 


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 
ESR:  Blood for ESR will be obtained at scheduled visits and tested locally. 
 
Hematology:  Red blood cell count, total and differential white blood cell count, 
hemoglobin, hematocrit, and platelet count 
 
INR, aPTT, and fibrinogen 
 
Chemistry panel:  Urea nitrogen, creatinine, fasting glucose, calcium, sodium, 
potassium, chloride, total protein, total bilirubin, direct bilirubin, indirect bilirubin, 
ALT, AST, alkaline phosphatase, GGT, and albumin 
 
HbA1c is required only for subjects with a confirmed diagnosis of diabetes mellitus. 
 
Urinary pregnancy testing (human chorionic gonadotropin) is required only for women 
who are of childbearing potential.  Urinary pregnancy testing will be conducted locally 
using dipsticks provided by the central laboratory.  Pregnancy testing may be repeated 
more frequently than specified in Table 1 (i.e., between study visits) if required by 
local practices, IRB/IECs or local regulations, or as deemed necessary by Investigator.  
If more frequent testing is required, the study site will provide the patient with further 
guidance and testing kit. 
 
Urinalysis:  Specific gravity, pH, protein, glucose, ketones, blood, and leukocyte 
esterase 
 
Lipid panel:  Total cholesterol, HDL, LDL, triglycerides, lipoprotein (a), 
apolipoproteins (apolipoprotein B [ApoB], apolipoprotein A1 [ApoA1], and 
ApoB:ApoA1 ratio), and adiponectin 
 
Cardiovascular risk panel:  N-terminal pro-hormone of brain natriuretic peptide 
(NT-proBNP), brain natriuretic peptide (BNP), and homocysteine 
 
IGRA 
 All subjects who had a negative IGRA result at Screening of the core study will have 
an IGRA performed at Week 22 of the core study (2 weeks prior to OLE Baseline), 
and the result is to be known prior to OLE Baseline to determine the subject’s 
eligibility for the OLE study (see exclusion criterion No. 3 in Section 5.3.2). 
 For all post-OLE Baseline visits where IGRA is scheduled, the test will be performed 
only for subjects who had a negative IGRA result at the previous assessments 
(including Week 22 assessment of the core study) unless another approach is required 
by local practice.  If results are indeterminate, the IGRA can be repeated once. 
 Details of the assessment are provided in the Laboratory Manual. 


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 
ADAs:  The actual sample collection date and exact time will be entered on the 
Immunogenicity Blood Collection eCRF page.  Sampling problems will be noted in 
the Comments section of the eCRF.  All blood samples will be taken by either direct 
venipuncture or an indwelling cannula inserted in a forearm vein.  A Laboratory 
Manual will be provided to the Investigators with detailed information on sample 
collection, handling and shipment.  Tubes and preprinted labels will be provided by 
the central laboratory to the study sites. 
Details regarding collection of samples, shipment of samples, reporting of results, laboratory 
reference ranges, and alerting abnormal values will be supplied to the study site before study 
site initiation in a Laboratory Manual. 
The laboratory sheets will be filed with the subject’s source documents. 
7.4.6.2 
Mandatory Retesting of Laboratory Abnormalities 
The following laboratory abnormalities require prompt retesting after the initial abnormal 
result is reported to the study site (within 72 hours of receiving abnormal LFT results and 
within 5 days of receiving all other abnormal results): 
 
Any single ALT and/or AST elevation >3× ULN, regardless of total bilirubin (repeat 
laboratory testing must include total bilirubin, direct and indirect bilirubin, GGT, INR, 
alkaline phosphatase, creatine phosphokinase, and hematology assessment) 
 
Neutrophil count <1000×106/L (<1000/mm3) 
 
Lymphocyte count <500×106/L (<500/mm3) 
 
Platelet count <100,000 platelets/mm3 
 
Any single hemoglobin value <8.0 g/dL or one that drops ≥20 g/L (2 g/dL) below 
OLE Baseline 
Clinically significant laboratory abnormalities should be re-tested and followed until 
resolution, stabilization, or return to baseline values and information will be recorded on the 
appropriate pages of the eCRF. 
7.4.7 
Vital Signs, Physical Findings, and Other Safety Assessments 
7.4.7.1 
Physical Examination 
A complete physical examination will be performed at Visit 1 (OLE Baseline/Week 24), 
Visit 6 (Week 52), Visit 10 (EoT/Week 106), and Safety Follow-Up Visit SFU-3 
(Week 126), as indicated in Table 1.  A complete physical examination will include 


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evaluation of general appearance, skin, head, eyes, ears, nose and throat, lymph nodes, 
respiratory, CV, GI including hepatobiliary assessment, musculoskeletal, endocrine system, 
neurological systems, and urogenital system. 
At all other visits, a partial physical examination will be performed assessing the following:  
general appearance, skin (including site of study treatment injection), respiratory, CV, and 
GI. 
All significant findings that are present at OLE Baseline must be reported on the “Adverse 
Events Ongoing from Core Study” page of the eCRF.  Significant findings detected after 
randomization to the OLE study that meet the definition of an AE must be recorded on the 
relevant “Adverse Event” page of the eCRF. 
7.4.7.2 
Vital Signs 
Vital signs (temperature, heart rate, BP, and respiratory rate) will be measured as indicated in 
Table 1, and when clinically indicated.  Whenever possible, vital sign assessments should be 
performed by the same study site staff member and using the same validated device(s) 
throughout the study.  Blood pressure and heart rate should be measured after the subject 
rests 5 minutes in a sitting position. 
Not every vital sign abnormality qualifies as an AE.  A vital sign result should be reported as 
an AE if it meets any of the following criteria: 
 
Results in a change in RA treatment (e.g., dosage modification, treatment interruption, 
or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
Clinically significant in the Investigator’s judgment 
It is the Investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality should 
be classified as an AE. 
7.4.7.3 
Body Weight and Height 
Body weight (to the nearest 0.1 kilogram [kg]) and height (in cm) will be recorded at the time 
points specified in Table 1.  Body weight and height should be measured in indoor clothing 
without shoes.  Whenever possible, body weight measurement should be performed by the 
same study site staff member and using the same validated scale throughout the study.  The 
subject’s body mass index will be calculated automatically in the eCRF. 


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7.4.7.4 
Cardiovascular Risk Assessment 
Cardiovascular risks factors (alcohol use with evaluation of average number of drinks 
consumed weekly, tobacco use with evaluation of average number of tobacco products 
consumed daily, central obesity, use of any lipid-lowering medication or any other CV 
agents, prior history of CV events and diabetes, family history of premature CV disease [age 
<55 years for males and <65 years for females], and other risks) will be recorded at the time 
points specified in Table 1.  The CV risk assessment data will be provided to the CVAC for 
use in the review and adjudication of MACE (see Sections 5.2.1 and 7.4.4.2) 
7.4.7.5 
Electrocardiogram 
A standard 12-lead ECG will be performed at the time points specified in Table 1. 
Subjects should rest in a supine position in a controlled, calm environment for at least 
15 minutes prior to the recording and should be motionless during the recording. 
The Investigator (if certified) or a certified designee will evaluate whether the ECG is normal 
or abnormal and whether it is clinically significant, if abnormal.  Clinically relevant 
abnormalities, including the baseline ECG, should be recorded on the AE eCRF page. 
All ECG records collected during the study should have a printed copy kept as a source 
document at the study site (if the ECG record is printed on thermal paper, a photocopy 
should be made). 
7.4.7.6 
Evaluation of Chest X-ray 
A chest X-ray (both lateral and posteroanterior) will be performed at all time points specified 
in Table 1.  A chest X-ray need not be conducted if one has been performed and evaluated by 
a certified specialist to confirm the absence of TB or other pulmonary infection within 
8 weeks prior to a specified timepoint, and if the films or images are available and included 
in the subject's source documents; if no such chest X-ray is available, this should be 
performed.  The Investigator should consult with a certified TB specialist or pulmonologist 
who is familiar with diagnosing and treating TB (as acceptable per local practice), if 
required.  Films or images available at OLE Baseline and collected during the study should 
be evaluated by a certified specialist and kept as source documents. 
7.4.8 
Safety Monitoring 
R-Pharm International’s designee will monitor safety data throughout the course of the study.  
The designee will review trends, laboratory data, and AEs at periodic intervals. 
In the event that ongoing safety monitoring uncovers an issue that needs to be addressed at 
the treatment group level, members of the DSMB (an external advisory group for this study 


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formed to protect the integrity of data) can conduct analyses of unblinded safety data.  See 
also Section 7.4.4 for details regarding the DSMB. 
7.4.9 
Tuberculosis Risk Questionnaire 
The questionnaire “Tuberculosis Risk Questionnaire” (see Appendix 2 [Section 13.2]) should 
be used as a source document.  The questionnaire will be completed at Visits 1 (OLE 
Baseline/Week 24), 4 (Week 36), 6 (Week 52), 8 (Week 76), 10 (EoT/Week 106), and SFU-2 
(Week 112) as noted in Table 1. 
If question No. 1 (Does the subject have a new diagnosis of active TB disease) of the TB risk 
questionnaire is answered with “Yes” at Visit 1 (OLE Baseline/Week 24), the subject is not 
allowed to enter the study (see exclusion criterion No. 2, Section 5.3.2).  A “Yes” response to 
any of the other questions within the questionnaire at Screening should trigger further careful 
assessment to determine the subject’s risk of TB disease. 
At any visit after Visit 1 (OLE Baseline/Week 24), a “Yes” response should be treated as 
follows: 
 
Question 1:  If a subject answers “Yes” study treatment should be discontinued if 
active TB is confirmed (see Section 6.11). 
 
Questions 2 through 6:  If a subject answers “Yes” to any question, they should be 
assessed (TB risk questionnaire and physical examination) 12 weeks from the time of 
exposure to determine if the subject developed TB.  The Investigator should consult with 
a certified TB specialist or pulmonologist, if needed. 
 
Questions 7 through 12:  If a subject answers “Yes” to any question, this should 
trigger a careful assessment to determine if the subject developed TB 
(see Section 7.4.10). 
This risk questionnaire is not to be used to exclude TB disease or confirm diagnosis. 
7.4.10 
Management of Tuberculosis 
Subjects that develop evidence of latent or active TB once enrolled in the study (and 
receiving study treatment) must immediately discontinue further administration of study 
treatment, and the subject should be examined by certified TB specialist or pulmonologist 
who is familiar with diagnosing and treating TB (as acceptable per local practice). 
If active is confirmed, the subject must permanently discontinue study treatment (see 
Section 6.11).  Confirmed active TB is an SAE that must be recorded on the relevant pages 


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of the eCRF and provided to the Sponsor in accordance with SAE reporting requirements.  
Details regarding follow-up of SAEs are provided in Section 7.4.5.5. 
If latent TB is confirmed, the subject may resume the administration of study treatment if 
active TB is ruled out by a certified TB specialist or pulmonologist who is familiar with 
diagnosing and treating TB (as acceptable per local practice), the subject starts prophylactic 
treatment of LTBI according to country-specific/CDC guidelines (see Appendix 4 
[Section 13.4]), and the subject agrees to complete the entire course of recommended LTBI 
therapy.  Study treatment should not be administered until active TB is ruled out, the subject 
starts prophylactic LTBI therapy, and the Investigator receives confirmation from the 
Medical Monitor if the subject deviated from the allowed injection window.  Confirmed 
latent TB should be recorded as an AE on the relevant pages of the eCRF.  Details regarding 
follow-up of AEs are provided in Section 7.4.5.4. 
7.5 
Appropriateness of Measurements 
All assessments made in this study are standard, widely used, and generally recognized as 
reliable, accurate, and relevant. 


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8. QUALITY CONTROL AND QUALITY ASSURANCE 
According to the Guidelines of Good Clinical Practice (GCP) (CHMP/International Council 
for Harmonisation [ICH]/135/1995), R-Pharm International and R-Pharm International’s 
designee are responsible for implementing and maintaining quality assurance and quality 
control systems with written standard operating procedures (SOPs). 
Quality control will be applied to each stage of data handling. 
The following steps will be taken to ensure the accuracy, consistency, completeness, and 
reliability of the data: 
 
Investigator meetings 
 
Central laboratories for clinical laboratory parameters 
 
Study site initiation visit 
 
Early study site visits after enrollment 
 
Routine study site monitoring 
 
Ongoing study site communication and training 
 
Data management quality control checks 
 
Continuous data acquisition and cleaning 
 
Internal review of data 
 
Quality control check of the final clinical study report 
In addition, R-Pharm International’s (or designee’s) Clinical Quality Assurance Department 
may conduct periodic audits of the study processes, including study site, study site visits, 
central laboratories, vendors, clinical database, and final clinical study report.  When audits 
are conducted, access must be authorized for all study-related documents including medical 
history and concomitant medication documentation to R-Pharm International’s designee and 
regulatory authorities. 
8.1 
Monitoring 
R-Pharm’s designee will perform all monitoring functions within this clinical study.  The 
designee’s monitors will work in accordance with established SOPs and have the same rights 
and responsibilities as monitors from R-Pharm International.  Monitors will establish and 
maintain regular contact between the Investigator and R-Pharm International. 


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Monitors will evaluate the competence of each study site, informing R-Pharm International 
about any problems relating to facilities, technical equipment, or medical staff.  During the 
study, monitors will check that written informed consent has been obtained from all subjects 
correctly and that data are recorded correctly and completely.  Monitors are also entitled to 
compare entries in eCRFs with corresponding source data and to inform the Investigator of 
any errors or omissions.  Monitors will also control adherence to the protocol at the study 
site.  They will arrange for the supply of study treatment and ensure appropriate storage 
conditions are maintained. 
Monitoring visits will be conducted according to all applicable regulatory requirements and 
standards.  Regular monitoring visits will be made to each study site while subjects are 
enrolled in the study.  The monitor will make written reports to R-Pharm International on 
each occasion contact with the Investigator is made, regardless of whether it is by phone or in 
person. 
During monitoring visits, entries in the eCRFs will be compared with the original source 
documents (source data verification). 
For further details of study monitoring, please refer to the Clinical Operations Plan and the 
Pharmacy Monitoring Guidelines. 
Data Management/Coding 
Data generated within this clinical study will be handled according to the relevant SOPs of 
the Data Management and Biostatistics departments of R-Pharm International’s designee. 
An EDC system will be used for this study, meaning that all eCRF data will be entered in 
electronic forms at the study site.  Data collection will be completed by authorized study site 
staff designated by the Investigator.  Appropriate training and security measures will be 
completed with the Investigator and all authorized study site staff prior to the study being 
initiated and any data being entered into the system for any study subjects. 
All data must be entered in English.  The eCRFs should always reflect the latest observations 
on the subjects participating in the study.  Therefore, the eCRFs are to be completed as soon 
as possible during or after the subject’s visit.  To avoid interobserver variability, every effort 
should be made to ensure that the same individual who made the initial baseline 
determinations completes all efficacy and safety evaluations.  The Investigator must verify 
that all data entries in the eCRFs are accurate and correct.  If some assessments are not done, 
or if certain information is not available or not applicable or unknown, the Investigator 
should indicate this in the eCRF.  The Investigator will be required to electronically sign off 
on the clinical data. 


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Electronic case report form records will be automatically appended with the identification of 
the creator, by means of their unique User ID.  Specified records will be electronically signed 
by the Investigator to document his/her review of the data and acknowledgement that the data 
are accurate.  This will be facilitated by means of the Investigator’s unique User ID and 
password; date and time stamps will be added automatically at the time of electronic 
signature.  If an entry on an eCRF requires change, the correction should be made in 
accordance with the relevant software procedures.  All changes will be fully recorded in a 
protected audit trail, and a reason for the change will be required. 
The monitor will review the eCRFs and evaluate them for completeness and consistency.  
The eCRF will be compared with the source documents to ensure that there are no 
discrepancies between critical data.  All entries, corrections, and alterations are to be made by 
the responsible Investigator or his/her designee.  The monitor cannot enter data in the eCRFs.  
Once clinical data of the eCRF have been submitted to the central server, corrections to the 
data fields will be audit trailed, meaning that the reason for change, the name of the person 
who performed the change, together with time and date will be logged.  Roles and rights of 
the study site staff responsible for entering the clinical data into the eCRF will be determined 
in advance.  If additional corrections are needed, the responsible monitor or Data Manager 
will raise a query in the EDC application.  The appropriate study site staff will answer 
queries sent to the Investigator.  This will be audit trailed by the EDC application meaning 
that the name of study site staff, time, and date stamp are captured. 
The eCRF is essentially considered a data entry form and should not constitute the original 
(or source) medical records unless otherwise specified.  Source documents are all documents 
used by the Investigator or hospital that relate to the subject’s medical history, that verify the 
existence of the subject, the inclusion and exclusion criteria, and all records covering the 
subject’s participation in the study.  They include laboratory notes, ECG results, memoranda, 
pharmacy dispensing records, subject files, etc. 
The Investigator is responsible for maintaining source documents.  These will be made 
available for inspection by the monitor at each monitoring visit.  The Investigator must 
submit a completed eCRF for each subject who receives study treatment, regardless of 
duration.  All supportive documentation submitted with the eCRF, such as laboratory or 
hospital records, should be clearly identified with the study and subject number.  Any 
personal information, including subject name, should be removed or rendered illegible to 
preserve individual confidentiality. 
Adverse events and medical history will be coded using the most recent version of the 
Medical Dictionary for Regulatory Activities (MedDRA).  Concomitant medications will be 
coded using the World Health Organization Drug Dictionary Enhanced (WHO DDE). 


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8.2 
Quality Assurance Audit 
Study sites, the study database, and study documentation may be subject to a Quality 
Assurance audit during the course of the study by R-Pharm International or R-Pharm 
International’s designee on behalf of R-Pharm International.  In addition, inspections may be 
conducted by regulatory bodies at their discretion. 


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9. STATISTICS 
9.1 
Determination of Sample Size 
 All subjects who previously completed 24 weeks of double-blind treatment in the core 
studies will be eligible to enroll in this OLE study.  It is estimated that approximately 
1880 subjects will be randomized in the OLE study to 1 of 2 treatment groups (OKZ 64 mg 
q4w or OKZ 64 mg q2w) in a 1:1 ratio. 
9.2 
Data to be Analyzed 
Data handling will be the responsibility of R-Pharm International’s designee.  The data will 
be inspected for inconsistencies by performing validation checks. 
9.3 
Analysis Populations 
 
Safety Population:  The Safety population will include all subjects who receive at least 
1 dose of study treatment during the OLE study.  Subjects in the Safety population will 
be analyzed according to the treatment they actually received. 
 A combined analysis of safety data from all subjects participating in the core studies 
and the OLE study will be conducted separately and details will be included in a 
separate Statistical Analysis Plan (SAP) for an Integrated Summary of Safety (ISS).  
Results of the ISS will be reported separately and will not be included in the Clinical 
Study Report of this study. 
 
Modified Intent-to-Treat (mITT) Population:  The mITT population will include all 
subjects who sign an ICF for participation in the OLE study, are randomized in the 
OLE study, and receive at least 1 dose of study treatment in the OLE study.  Subjects 
will be analyzed according to the treatment group to which they were randomized in 
the OLE study.  The mITT population will be the primary efficacy analysis 
population. 
 
Per Protocol (PP) Population:  The PP population will include all mITT subjects who 
do not have any major protocol violations.  Subjects will be analyzed according to the 
OLE treatment group to which they were randomized.  Major protocol violations and 
the inclusion of subjects in the PP population will be finalized prior to database lock.  
The PP population will be used for supportive analyses of selected efficacy endpoints. 


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9.4 
Statistical Methods 
This section provides a high-level description of the analyses planned in this study.  Details 
of any analysis, interim or final, will be specified in the SAP, to be written and finalized prior 
to database lock.  The statistical analysis will be performed by R-Pharm International’s 
designee.  All statistical analyses will be conducted using SAS® version 9.2 or higher for 
Windows. 
All data collected in the clinical database will be presented in subject data listings. 
Data collected after the modification of background therapy (as described in Section 6.13.3) 
will be used in all analyses. 
Data collected during the core studies for subjects enrolled in the OLE study may be 
programmatically combined with the OLE study database for selected analyses. 
All analyses of safety and efficacy will be descriptive; no inferential analyses will be 
performed. 
Continuous endpoints will be summarized using descriptive statistics such number of 
available values (n), mean, median, minimum, maximum, and standard deviation in each 
treatment group and overall, as appropriate.  Categorical endpoints will be summarized by 
the number and percentage of subjects in each category. 
Data will be summarized based on treatment groups reflecting randomized or actual 
treatment (for efficacy or safety analyses, respectively) during the core and OLE studies as 
follows: 
a. OKZ 64 mg q4w (OLE):  All subjects in the OKZ 64 mg q4w group in the OLE 
b. OKZ 64 mg q2w (OLE):  All subjects in the OKZ 64 mg q2w group in the OLE 
c. OKZ 64 mg q4w (core/OLE):  Subjects from the OKZ 64 mg q4w group in the core 
study and continuing on OKZ 64 mg q4w in OLE.  For subjects enrolling from the 
CL04041025 core study, inclusion in the OKZ 64 mg q4w group in the core study 
will be based on the initial treatment period prior to Week 16 (i.e., placebo subjects 
re-randomized to receive OKZ 64 mg q4w at Week 16 will not be included in this 
group). 
d. OKZ 64 mg q2w (core/OLE):  Subjects from the OKZ 64 mg q2w group in the core 
study and continuing on OKZ 64 mg q2w in OLE.  For subjects enrolling from the 
CL04041025 core study, inclusion in the OKZ 64 mg q2w group in the core study 
will be based on the initial treatment period prior to Week 16 (i.e., placebo subjects 


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re-randomized to receive OKZ 64 mg q2w at Week 16 will not be included in this 
group). 
e. Placebo – OKZ 64 mg q4w (OLE):  Subjects from the placebo group in the core 
studies CL04041022 and CL04041023 that are assigned to the OKZ 64 mg q4w in the 
OLE. 
f. Placebo – OKZ 64 mg q2w (OLE):  Subjects from the placebo group in the core 
studies CL04041022 and CL04041023 that are assigned to the OKZ 64 mg q2w in the 
OLE. 
g. Placebo – OKZ 64 mg q4w (core/OLE):  Subjects from the placebo group in the core 
study CL04041025 (through Week 14) that are re-randomized to the OKZ 64 mg q4w 
group starting at Week 16 of the core study and continuing on OKZ 64 mg q4w in 
OLE. 
h. Placebo – OKZ 64 mg q2w (core/OLE):  Subjects from the placebo group in the core 
study CL04041025 (through Week 14) that are re-randomized to the OKZ 64 mg q2w 
group starting at Week 16 of the core study and continuing on OKZ 64 mg q2w in 
OLE. 
i. Adalimumab – OKZ 64 mg q4w (OLE):  Subjects from the adalimumab group in the 
core study CL04041023 that are assigned to the OKZ 64 mg q4w group in the OLE. 
j. Adalimumab – OKZ 64 mg q2w (OLE):  Subjects from the adalimumab group in the 
core study CL04041023 that are assigned to the OKZ 64 mg q2w group in the OLE. 
Subjects are considered to be part of the placebo group during the core study if they are 
randomized to or receive placebo as their overall study treatment, and not as monthly placebo 
injections administered to maintain the blind in the OKZ 64 mg q4w treatment groups. 
Note that treatment groups (c) through (j) are mutually exclusive; treatment groups (a) and 
(b) are aggregates representing all subjects treated with a specific OKZ regimen during the 
OLE study, regardless of the treatment received during the core study. 
Additional summaries of efficacy endpoints may be generated for subjects from each core 
study separately, which will be detailed in the SAP. 
9.4.1 
Definition of Baseline 
Unless otherwise specified, data will be analyzed for changes from both Core Baseline and 
OLE Baseline values.  The Core Baseline value for each parameter will be defined as the 
baseline value from the core study (i.e., the last available measurement prior to the first dose 


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of study treatment in the core study).  The OLE Baseline value will be defined as the last 
available measurement prior to the first OLE dose of study treatment.  For subjects from 
Study CL04041025 who receive placebo through Week 14 and are re-randomized to OKZ 
starting at Week 16 (groups [g] and [h] as defined in Section 9.4), additional analysis of 
change from the last pre-OKZ value (prior to the first dose of OKZ at Week 16) will also be 
performed. 
9.4.2 
Disposition of Study Subjects 
Disposition of study subjects will be summarized by treatment group (defined in Section 9.4) 
as the number and percentage of subjects enrolled (signed ICF for participation in the OLE 
study), randomized in the OLE study, included in each analysis population as defined in 
Section 9.3, completing the study treatment, and discontinuing from the study treatment 
overall and by reason for discontinuation, as well as completing the Safety Follow-Up Period 
or discontinuing during the Safety Follow-Up Period.  The number and percentage of 
subjects discontinuing study treatment by visit in each treatment group will also be 
summarized. 
A Kaplan-Meier plot of time to treatment discontinuation in each treatment group will be 
presented, where the time to treatment discontinuation will be calculated as the number of 
days from randomization at enrollment in the OLE study to the last dose of OLE study 
treatment.  Subjects who complete the open-label Treatment Period as planned through 
Visit 10 (EoT/Week 106) will be censored on the date of their last dose in the OLE study. 
Determination of major protocol deviations and inclusion of subjects in the analysis 
populations will be finalized and approved by R-Pharm International prior to database lock. 
9.4.3 
Demography and Baseline Characteristics 
Demographic information and baseline characteristics collected at baseline of the core 
studies will be summarized for the treatment groups defined in Section 9.4.  Key subject 
assessments at the time of enrollment in the OLE study (e.g., selected laboratory/safety 
assessments, ACR components, DAS28 [CRP], etc.) will also be summarized. 
9.4.4 
Prior and Concomitant Medications 
Concomitant medications will be summarized as the number and percentage of subjects by 
World Health Organization (WHO) drug class, preferred name, and treatment group.  
Medications will be coded using the WHO Drug dictionary, Anatomic Therapeutic Class 
(ATC) level 2, and preferred drug name. 


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Any medication that a subject started before the first dose of OLE study treatment and 
continued to take during the OLE study, and any medication that the subject began taking 
after the first dose of the OLE study treatment, will be classified as concomitant. 
Medications administered as a change in background therapy (as described in Section 6.13.3) 
will also be summarized as the number and percentage of subjects by WHO drug class, 
preferred name, and treatment group. 
Medications administered concomitantly during the core studies or prior to the core studies 
may also be summarized. 
9.4.5 
Exposure and Compliance 
Exposure to the OLE study treatment and compliance will be summarized descriptively by 
treatment group (see Section 9.4) for the Safety population based on treatment administration 
records in the Subject Diary and the return of used/unused study treatment (vials and/or PFS 
cartons) to the study site. 
For a given study period, exposure to open-label study treatment will be calculated as the 
number of doses received during the open-label study period.  The number of doses received 
will be calculated as a maximum of the number of injections recorded in the Subject Diary 
and the number of used vials and/or used PFS cartons returned by the subject to the study 
site. 
Duration of exposure will be defined as the total number of days a subject was exposed to 
study treatment in the open-label Treatment Period, calculated as: 
Date of last open-label dose – Date of first open-label dose + 1 day 
Overall compliance (expressed as a percentage) will be calculated as: 
(Exposure to open-label study treatment/number of doses subject was expected to 
receive) × 100 
Compliance will be calculated based on all planned doses (through completion or early 
discontinuation of treatment), as appropriate for each treatment group. 
9.4.6 
Safety Analyses 
Analysis of safety endpoints (see Section 4.1) will be based on the Safety population.  
Subjects in the Safety population will be analyzed according to the treatment they actually 
received. 


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All safety and tolerability data recorded during the study will be listed and summarized 
descriptively by the treatment groups described in Section 9.4, and over time, as appropriate.  
No imputation for missing safety data will be performed.  Further details will be provided in 
the SAP. 
All continuous safety parameters will be summarized at each OLE visit in terms of actual 
values at each time point, changes from Core Baseline values, and changes from OLE 
Baseline values, as appropriate.  All categorical safety parameters will be summarized in 
terms of number and percent of subjects in each category by OLE visit.  Core Baseline and 
OLE Baseline values will also be summarized for reference.  For subjects from Study 
CL04041025 who receive placebo through Week 14 and are re-randomized to OKZ starting 
at Week 16 (groups [g] and [h] as defined in Section 9.4), additional analysis of change from 
the last pre-OKZ value (prior to the first dose of OKZ at Week 16) will also be performed. 
Major components for the safety analysis will include: 
 
TEAEs will be solicited at every study visit, recorded, and coded according to most 
recent version of the MedDRA. 
 
SAEs 
 
AESIs 
 
MACE 
 
Laboratory parameters 
 
Vital signs and physical examination findings 
 
ECG and other specialized test findings 
In addition to the primary safety analysis, the incidence of AEs may be analyzed separately 
for subjects administered additional DMARDs (assigned as rescue medication during the 
core studies) and for subjects not receiving additional DMARDs as rescue medication. 
9.4.6.1 
Adverse Events 
All AEs will be analyzed in terms of descriptive statistics and qualitative analysis.  Adverse 
events will be listed for each subject and summarized by SOC and PT according to the latest 
version of the MedDRA.  In addition, summaries of AEs by severity (evaluated using the 
CTCAE version 4.0) and relationship to study treatment will be presented. 
An AE will be defined as treatment-emergent in the OLE study if its onset date or worsening 
in severity is on or after the date of first administration of the OLE study treatment.  In cases 


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where only partial information is available for the onset date of an AE, available date 
components will be used to determine treatment-emergent status; in the case of ambiguity, 
AEs will be considered treatment-emergent. 
The following summaries of subject incidence and number of events will be presented by the 
treatment groups defined in Section 9.4: 
 
Overall summary of TEAEs 
 
Summary of TEAEs by SOC and PT 
 
Summary of serious TEAEs by SOC and PT 
 
Summary of TEAEs leading to death by SOC and PT (if applicable) 
 
Summary of treatment-emergent AESIs (as defined in Section 7.4.3) by SOC and PT 
 
Summary of (adjudicated) MACE and individual MACE components 
 
Summary of TEAEs by SOC, PT, and maximum severity 
 
Summary of drug-related TEAEs by SOC and PT 
 
Summary of TEAEs leading to early treatment discontinuation by SOC and PT 
 
Summary of the most common TEAEs by PT (≥5% in any treatment group) 
 
Summary of TEAEs by Standardized MedDRA Queries narrow terms 
Safety/tolerability and AE data will be presented in individual listings. 
9.4.6.1.1 
Analysis of Treatment-Emergent Adverse Event Rates per 100 
Patient-years of Follow-up 
Summaries of TEAEs occurring in subjects in the safety population of this OLE study will 
also be provided based on combined AE data from the core studies and the OLE study, 
attributing each TEAE to the last study treatment received at/before the AE onset.  In other 
words, an AE will be defined as treatment-emergent under a given study treatment 
(OKZ 64 mg q4w, OKZ 64 mg q2w, placebo, or adalimumab) if AE’s onset date is on or 
after the date of first dose the corresponding treatment and prior to initiation of the next study 
treatment, if any (e.g., OKZ after placebo or adalimumab).  In order to account for 
differences in the duration of exposure and follow-up under each study treatment and across 
subjects, subject IRs and ERs will be summarized per 100 subject-years (SY) of follow-up 
(/100 SY) based on the OLE safety population and presented by study treatments as follows: 


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i. 
OKZ 64 mg q4w: subjects receiving OKZ 64 mg q4w during the core study or OLE.  
Only those TEAEs that first occur or worsen in severity after the first administration 
of OKZ 64 mg q4w (either in the core or OLE study) will be counted. 
ii. 
OKZ 64 mg q2w: subjects receiving OKZ 64 mg q2w during the core study or OLE.  
Only those TEAEs that first occur or worsen in severity after the first administration 
of OKZ 64 mg q2w (either in the core or OLE study) will be counted. 
iii. 
Placebo: subjects receiving placebo during the core study.  Only those TEAEs that 
first occur or worsen in severity after the first administration of placebo and prior to 
administration of OKZ will be counted.  Subjects are considered as receiving placebo 
during the core study if they are receiving placebo as their overall study treatment, 
and not as monthly placebo injections administered to maintain the blind in the OKZ 
64 mg q4w group. 
iv. 
Adalimumab: subjects receiving adalimumab as active control study treatment during 
the core study CL04041023.  Only those TEAEs that first occur or worsen in severity 
after the first administration of adalimumab and prior to administration of OKZ will 
be included. 
The following summaries will be provided: 
 IRs (/100 SY) and ERs (/100 SY) for TEAEs overall and by SOC  
 IRs (/100 SY) and ERs (/100 SY) for SAEs overall and by SOC and PT 
 IRs (/100 SY) and ERs (/100 SY) for AESIs overall and by SOC and PT 
 IRs (/100 SY) and ERs (/100 SY) for (adjudicated) MACE and individual MACE 
components 
 IRs (/100 SY) and ERs (/100 SY) for most frequent TEAEs (PT level IRs [/100 SY] 
≥5.0 in any treatment group) by SOC and PT 
IRs/100 SY for each specific AE term (referred to as “event” for brevity) under treatment j, 
corresponding to treatments (i) – (iv) described above, will be calculated as follows: 
𝐼𝑅𝑗 (/100 𝑆𝑌) = 𝑠𝑗 ∑𝑐𝑖,𝑗
𝑖
⁄
 
where 𝑠𝑗 is the number of subjects with the event that is treatment-emergent under treatment 
𝑗, and 𝑐𝑖,𝑗 is a truncated follow-up time (in 100-year units) for subject 𝑖 and treatment 𝑗 (i.e., 
the time from the subject’s date of first dose of treatment 𝑗 to the date of first occurrence of 
the event after start of treatment 𝑗 or end of follow-up period for treatment 𝑗, whichever 


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occurs earlier).  For OKZ treatments (OKZ 64 mg q4w and q2w), the end of follow-up period 
will be the date of last dose of OKZ treatment plus 155 days (5 half-lives of study treatment) 
or last contact with the subject, whichever occurs earlier.  For placebo and adalimumab 
treatments, the end of follow-up period will be the day before the start of OKZ treatment. 
ERs (/100 SY) for each specific AE term under treatment j will be calculated as follows: 
𝐸𝑅𝑗(/100 𝑆𝑌) = ∑𝑣𝑖,𝑗
𝑖
 
∑𝑡𝑖,𝑗
𝑖
⁄
 
where 𝑣𝑖,𝑗 is the number of treatment-emergent events that the subject 𝑖 experiences under 
treatment 𝑗, and 𝑡𝑖,𝑗 is a total follow-up time (in 100-year units) of subject 𝑖 for treatment 𝑗, 
i.e., from the date of subject’s first dose of treatment 𝑗 to the end of follow-up period for 
treatment 𝑗.  For OKZ treatments (OKZ 64 mg q4w and q2w), the end of follow-up period 
will be the date of last dose of OKZ treatment plus 155 days (5 half-lives of study treatment) 
or last contact with the subject, whichever occurs earlier.  For placebo and adalimumab 
treatments, the end of follow-up period will be the day before the start of OKZ treatment. 
Assuming the event process is Poisson distributed, exact 100*(1-α)% confidence intervals for 
𝐼𝑅𝑗 (/100 𝑆𝑌) and 𝐸𝑅𝑗 (/100 𝑆𝑌) will be calculated as follows (Sahai and Khurshid, 1993): 
Lower confidence limit: 𝐿𝐶𝐿=
𝜒2
𝛼/2,2𝐷
2𝐸
 for D>0, 0 otherwise, 
Upper confidence limit 𝑈𝐶𝐿=
𝜒2
1−𝛼/2,2𝐷+2
2𝐸
 
where 𝜒2
𝛼,𝑘 is the αth quantile of the Chi-square distribution with k degrees of freedom, and 
the D and E are the numerator and denominator of the rate. 
Summaries of 𝐼𝑅𝑗 (/100 𝑆𝑌) and 𝐸𝑅𝑗 (/100 𝑆𝑌) for the OKZ treatments (i) and (ii) may be 
further subdivided into 2 subgroups: subjects receiving adalimumab in the core study 
CL04041023 versus all other subjects. 
In addition to the above summaries of rates/100 SY, a plot of cumulative mean function 
(CMF) across study follow-up time will be produced for selected types of events for each 
treatment (i) – (iv).  The cumulative mean function at each time point t represents an 
estimated mean number of recurrent events expected by time t in a treatment group (Siddiqui, 
2009; Nelson, 2003).  Plots of CMF will be produced for SAEs overall and by SOC, AESIs 
overall and by SOC, as well as MACEs. 
9.4.6.1.2 
Time to First Major Adverse Cardiovascular Event 
For MACEs and individual components of MACE, time from the first dose of OKZ to first 
event will be summarized using a Kaplan-Meier product limit method.  This analysis will be 


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based on the OLE Safety population using combined data from the core studies and the OLE 
study. 
Time to first event will be computed for each specific type of event (MACE overall and 
individual components of MACE) as the number of days between the subject’s date of first 
dose of OKZ treatment either in the core or OLE study and the onset of the first event that is 
treatment-emergent under the OKZ treatment.  Subjects not experiencing an event of interest 
during the follow-up period associated with the OKZ treatment will be censored at the date 
of last contact. 
Summaries will be presented by treatment groups, as defined in Section 9.4.  Summaries will 
include plots of the estimated survival curves using the Kaplan-Meier method as well as 
Kaplan-Meier cumulative estimates of event-free rates at time points corresponding to 6, 12, 
18, 24, and 30 months after initiation of OKZ treatment.  Pointwise confidence intervals for 
these estimates will be computed using the log-log transformation method.  Kaplan-Meier 
estimates of mean event-free time and its log-log transformed confidence interval in each 
treatment group will also be produced.  A time limit of 127 weeks will be used for the 
estimation of mean event-free time if the largest observed time in data is censored.  
Descriptive statistics for the number of subjects with event, censored, and duration of 
follow-up for censored subjects will be provided. 
Additional details will be provided in the SAP. 
9.4.6.1.3 
Time to First Malignancy 
Analysis of time from the first dose of OKZ to the first malignancy will also be conducted 
using the Kaplan-Meier method in a similar manner as will be done for MACE (see 
Section 9.4.6.1.2). 
9.4.6.2 
Other Safety Analyses 
All clinical laboratory, vital signs, ECG, and physical examination data collected during the 
study will be summarized descriptively by treatment groups described in Section 9.4, and 
study visit, as appropriate.  Continuous safety parameters will be summarized in terms of 
actual values at each time point, and if appropriate, changes from the Core Baseline values, 
changes from OLE Baseline values, and changes from the last pre-OKZ values (see 
Section 9.4.1).  Categorical parameters will be summarized in terms of the number and 
percent of subjects in each category by visit. 
Laboratory values will be flagged as low, normal, or high relative to the normal range of each 
test.  Laboratory results will also be graded according to the CTCAE criteria (version 4.0) 
and will be considered as markedly abnormal if they meet the criteria of Grade 3 or higher.  


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The number and percent of subjects with treatment-emergent chemistry and hematology 
abnormalities (low or high) as well as with CTCAE Grade ≥2 results after the first dose of 
OLE study treatment will be summarized by laboratory parameter and by visit as well as 
during the OLE study overall based on the most extreme subject values. 
The number and percent of subjects with clinically significant urinalysis abnormalities will 
be summarized by parameter (specific gravity, pH, protein, glucose, ketones, blood, and 
leukocyte esterase) by visit as well as during the OLE study overall based on the most 
extreme subject values. 
Liver function parameters (AST, ALT, alkaline phosphatase, and total bilirubin) will be 
summarized categorically using different levels of elevation thresholds (multiples of normal 
range upper limit) as well as according to the criteria of Hy’s Law. 
Lipid parameters (total cholesterol, HDL, LDL, and triglycerides) will be summarized by 
means of descriptive statistics for the actual values and changes from Core Baseline and 
OLE Baseline over time. 
Clinically significant changes in vital signs will be identified and summarized for changes 
from the Core Baseline values, OLE Baseline values, and last pre-OKZ values (see 
Section 9.4.1). 
Categorical ECG findings (normal; abnormal, not clinically significant; and abnormal, 
clinically significant) will be summarized at each visit. 
9.4.7 
Analysis of Efficacy Endpoints 
Analysis of efficacy endpoints (see Sections 4.2) and PROs (see Section 7.1) will be based 
on the mITT population.  Supportive analyses will also be done using the PP population for 
the ACR20/50/70, SDAI ≤3.3, and DAS28 (CRP) <3.2 endpoints. 
All summaries will be presented by the treatment groups defined in Section 9.4, based on 
randomized treatment. 
All continuous efficacy and PRO endpoints will be summarized at each OLE visit in terms of 
actual values, changes from Core Baseline values, changes from OLE Baseline values, and 
changes from the last pre-OKZ values (see Section 9.4.1).  All categorical parameters and 
responder-type endpoints will be summarized in terms of number and percent of subjects in 
each category by OLE visit.  Core Baseline values, OLE Baseline values, and the last 
pre-OKZ values will also be summarized for reference.  Graphical summaries will also be 
presented for mean actual values over time by treatment group for selected endpoints 
(e.g., DAS28 [CRP]). 


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Binary endpoints that are based on changes from baseline (e.g., ACR20) will be analyzed 
based on changes from Core Baseline values, OLE Baseline values, and changes from the 
last pre-OKZ values. 
Missing efficacy data resulting from missed intermediate visits will be handled as described 
in Section 9.4.8. 
Missing data resulting from early treatment discontinuation will not be imputed, unless 
otherwise specified.  For binary efficacy endpoints, in addition to analyses based on observed 
data, summaries will also be provided considering all subjects who discontinue the OLE 
study treatment early as nonresponders at all post-discontinuation scheduled time points. 
9.4.8 
Handling of Missing Data 
Missing efficacy data resulting from missed intermediate visits will be imputed from the 
surrounding visits.  For binary efficacy endpoints, if the status at visits both before and after 
the missed visit is classified as responder, the subject will be considered a responder at the 
missed visit.  Otherwise, the subject will be considered a nonresponder.  If an assessment for 
a given binary endpoint at the last visit is missing for a completing subject, data from the 
2 previous visits will be used with the same logic for determining the response status.  For 
the ACR20/50/70 endpoints, if only some components of the response criteria are missing 
but the available components allow classifying the subject as a responder, the responder 
category will be used.  Otherwise, the method based on surrounding visits as described above 
will be applied.  Similarly, for all continuous endpoints, an average of values from the 
surrounding visits will be imputed for the missing visit. 
Missing efficacy data resulting from early treatment discontinuation will not be imputed. 
Missing safety data will not be imputed. 
9.4.9 
Pharmacokinetic/Pharmacodynamic Correlations 
No PK/PD correlations are planned for this study. 
9.4.10 
Immunogenicity 
Immunogenicity results, including overall ADA results (Screening, confirmatory, and titers, 
as appropriate), neutralizing ADA results, and the time course of antibodies (defined as the 
time to first observation of a positive ADA response) will be listed.  The number and 
percentage of subjects testing positive for ADAs or neutralizing antibodies will be 
summarized by dose treatment group over time.  If applicable, the time course of antibodies 
may be summarized by treatment group using appropriate descriptive statistics. 


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9.5 
Subgroup Analysis 
All subgroup analyses will be exploratory (post hoc) in nature.  The details of these analyses 
will be described in the SAP and provided prior to the database lock.  No specific subgroup 
analysis will be described in detail in the protocol. 
9.6 
Safety Monitoring Committees 
A DSMB and CVAC will oversee the study from a safety and CV monitoring perspective, as 
described in Section 7.4.4. 
9.7 
Interim Analysis 
For any interim data cuts or analyses which occur, the details will be specified in the SAP. 


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10. 
ETHICS 
10.1 Institutional Review Board/Independent Ethics Committee 
An IRB/IEC should approve the final protocol, including the final version of the ICFs and 
any other written information and/or materials to be provided to the subjects.  The 
Investigator will provide R-Pharm International or R-Pharm International’s designee with 
documentation of IRB/IEC approval of the protocol and the ICFs before the study may begin 
at the study site(s).  The Investigator should submit the written approval to R-Pharm 
International or its designee before enrollment of any subject into the study. 
R-Pharm International or its designee should approve any modifications to the ICF that are 
needed to meet local requirements. 
The Investigator will supply documentation to R-Pharm International or R-Pharm 
International’s designee of required IRB/IEC’s annual renewal of the protocol, and any 
approvals of revisions to the ICF or amendments to the protocol. 
The Investigator will report promptly to the IRB/IEC, any new information that may 
adversely affect the safety of subjects or the conduct of the study.  Similarly, the Investigator 
will submit written summaries of the study status to the IRB/IEC annually, or more 
frequently if requested by the IRB/IEC.  Upon completion of the study, the Investigator will 
provide the ethics committee with a brief report of the outcome of the study, if required. 
R-Pharm International or its designee will handle the distribution of any of these documents 
to the national regulatory authorities. 
R-Pharm International or its designee will provide Regulatory Authorities, IRBs/IECs, and 
Investigators with safety updates/reports according to local requirements, including SUSARs, 
where relevant. 
Each Investigator is responsible for providing the IRB/IEC with reports of any serious and 
unexpected adverse drug reactions from any other study conducted with the study treatment.  
R-Pharm International or its designee will provide this information to the Investigator so that 
he/she can meet these reporting requirements. 
10.2 Ethical Conduct of the Study 
The GCP is an international ethical and scientific quality standard for designing, conducting, 
recording, and reporting studies that involve the participation of human subjects.  The study 
will be conducted in compliance with GCP and the applicable national regulations so as to 


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assure that the rights, safety, and well-being of the participating study subjects are protected 
consistent with the ethical principles that have their origin in the Declaration of Helsinki. 
10.3 Subject Information and Informed Consent 
The ICFs (i.e., ICF for subjects and a separate ICF for caregivers [if applicable]) will be used 
to explain the risks and benefits of study participation to the subject in simple terms before 
the subject will be entered into the study.  The ICFs contains a statement that the consent is 
freely given, that the subject is aware of the risks and benefits of entering the study, and that 
the subject is free to withdraw from the study at any time.  Written consent must be given by 
the subject and/or legal representative after the receipt of detailed information on the study. 
All ICFs must be available in the local and vernacular languages required at the study site 
and include subject information sheets/brochures that outline the study procedures.  All ICFs 
must be signed and dated by the subject or a legally acceptable representative. 
For subjects who are unable to read and write, the subject information sheet and ICF should 
be read to the subject in his/her native language in the presence of an impartial witness who 
is literate and not affiliated with the study.  The subject having understood the information 
given to him/her in the presence of an impartial witness will thumbprint the ICF and the same 
will be countersigned by the impartial witness.  If the subject or legally acceptable 
representative cannot read then an impartial witness will witness and attest the entire consent 
process and will be required to sign the consent form.  Confirmation of a subject’s informed 
consent must also be documented in the subject’s medical record prior to any testing under 
this protocol, including Screening tests and assessments. 
The Investigator is responsible for ensuring that informed consent is obtained from each 
subject or legal representative and for obtaining the appropriate signatures and dates on the 
ICF prior to the performance of any protocol procedures and prior to the administration of 
study treatment.  The Investigator will provide each subject with a copy of the signed and 
dated consent form while the originals will be retained in the Investigator’s records. 
10.4 Subject Data Protection 
The ICF will incorporate or, in some cases, be accompanied by a separate document 
incorporating wording that complies with relevant data protection and privacy legislation.  R-
Pharm International or R-Pharm International’s designee will not provide individual results 
to subjects, any insurance company, any employer, their family members, general physician, 
or any other third party, unless required to do so by law. 
Information about study subjects will be kept confidential and managed according to the 
regulatory requirements. 


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11. 
STUDY ADMINISTRATION 
11.1 Administrative Structure 
A list of the key individuals from R-Pharm International and R-Pharm International’s 
designee who will contribute to this study and their roles will be available in the Study 
Reference Manual, kept on file, and updated as required. 
The telephone and fax number of the study medical contact are listed in the Investigator 
Folder provided to each study site. 
The 24-hour emergency medical contact number for this study is +1 512 652 0191 or +1 973 
659 6677 or +3 318 699 0019). 
11.2 Study and Study Site Closure 
Upon completion of the study, the monitor will conduct the following activities in 
conjunction with the Investigator or study site staff, as appropriate, including the following: 
 
Return of all study data to R-Pharm International 
 
Resolution of data queries 
 
Accountability, reconciliation, and arrangements for unused study treatments 
 
Review of study site, study records for completeness 
 
Review requirements for record retention and audit responsibilities 
11.3 Study Discontinuation 
The study may be discontinued at any time by the IRB/IEC, R-Pharm International, or 
regulatory agencies as part of their duties to ensure that research subjects are protected. 
R-Pharm International reserves the right to temporarily suspend or prematurely discontinue 
this study either at a single study site or at all study sites at any time for reasons including 
safety or ethical issues or severe noncompliance.  If R-Pharm International determines such 
action is needed, R-Pharm International will discuss this with the Investigator (including the 
reasons for taking such action) at that time.  When feasible, R-Pharm International will 
provide advance notification to the Investigator of the impending action prior to its taking 
effect. 
R-Pharm International will promptly inform all other Investigators and/or institutions 
conducting the study if the study is suspended or terminated for safety reasons, and will also 


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inform the regulatory authorities of the suspension or termination of the study and the 
reason(s) for the action.  If required by applicable regulations, the Investigator must inform 
the IRB/IEC promptly and provide the reason for the suspension or termination. 
If the study is prematurely discontinued, all study data must be returned to R-Pharm 
International or its designee.  In addition, arrangements will be made for return of all unused 
study treatments in accordance with R-Pharm International’s applicable procedures for the 
study. 
Financial compensation to Investigators and/or institutions will be in accordance with the 
agreement established between the Investigator and R-Pharm International. 
11.4 Data Handling and Record Keeping 
Information about study subjects will be kept confidential and managed according to the 
regulatory requirements.  It is the Investigator’s responsibility to maintain essential study 
documents (protocol and protocol amendments, completed eCRFs, signed ICFs, relevant 
correspondence, and all other supporting documentation).  The study site should plan on 
retaining such documents for approximately 15 years after study completion.  The study site 
should retain such documents until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years after the formal discontinuation of clinical 
development of the study treatment.  These documents should be retained for a longer period 
if required by the applicable regulatory requirements or the hospital, institution, or private 
practice in which the study is being conducted. 
Subject identification codes (subject names and corresponding study numbers) will be 
retained for this same period of time.  These documents may be transferred to another 
responsible party, acceptable to R-Pharm International, who agrees to abide by the retention 
policies.  Written notification of transfer must be submitted to R-Pharm International.  The 
Investigator must contact R-Pharm International prior to disposing of any study records. 
No records should be disposed of without the written approval of R-Pharm International. 
11.5 Direct Access to Source Data/Documents 
The Investigator will prepare and maintain adequate and accurate source documents to record 
all observations and other pertinent data for each subject randomized into the study. 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical study necessary for the complete reconstruction and evaluation of the 
study.  Source data are contained in source documents.  Examples of these source documents 


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and data records include:  hospital records, clinical and office charts, laboratory notes, 
memoranda, subject’s evaluation checklists, pharmacy dispensing records, recorded data 
from automated instruments, copies or transcriptions certified after verification as being 
accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, 
radiographs, subject’s records, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical study. 
The Investigator will allow the authorized R-Pharm International’s designee and authorized 
regulatory authorities and IRBs/IECs to have direct access to all documents pertaining to the 
study, including individual subject medical records, as appropriate. 
11.6 Investigator Information 
11.6.1 
Investigator Obligations 
The Investigator is responsible for ensuring that all study site staff, including 
sub-Investigators, adhere to all applicable regulations and guidelines, including local laws 
and regulations, regarding clinical studies both during and after study completion. 
The Investigator is responsible for informing the IRB/IEC of the progress of the study, for 
obtaining annual IRB/IEC renewal, and informing the IRB/IEC of completion of the study 
and will provide the IRB/IEC with a summary of the results of the study. 
The study will be conducted in compliance with the protocol, GCP, and the applicable 
regulatory requirements of European Commission Directive (2001/20/EC Apr 2001) and/or 
European Commission Directive (2005/28/EC Apr 2005) and/or the US Food and Drug 
Administration GCP Regulations:  Code of Federal Regulations Title 21, parts 11, 50, 54, 56, 
and 312, and/or other applicable local or regional regulations. 
The Investigator agrees to conduct the clinical study in compliance with this protocol after 
the approval of the protocol by the IRB/IEC in compliance with local regulatory 
requirements.  The Investigator and R-Pharm International will sign the protocol to confirm 
this agreement. 
The Investigator is encouraged to discuss the withdrawal of a subject, from either treatment 
or study, with R-Pharm International or R-Pharm International’s designee, in advance, 
whenever is possible.  In addition, any case when a subject deviated from the dosing 
schedule or missed any scheduled treatment should be reported to R-Pharm International 
and/or R-Pharm International’s designee promptly, for making decision whether the study 
participation should be continued. 


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Medical Monitor should be contacted before restarting the study treatment after any 
interruption of study tretatement. Medical Monitor should be contacted in case of potential 
hepatotoxicity events that fulfill any of the criteria of seriousness to investigate all potential 
causes of liver toxicity (see Section 7.4.3.4). 
11.6.2 
Protocol Signatures 
After reading the protocol, each Investigator will sign the protocol signature page and send a 
copy of the signed page to R-Pharm International or its designee.  By signing the protocol, 
the Investigator confirms in writing that he/she has read, understands, and will strictly adhere 
to the study protocol and will conduct the study in accordance with the ICH Tripartite 
Guidelines for GCP and applicable regulatory requirements.  The study will not be able to 
start at any study site where the Investigator has not signed the protocol. 
11.6.3 
Publication Policy 
R-Pharm International shall retain the title and the right to publish all documentation, 
records, raw data, specimens or other work product generated pertaining to the study (“data”) 
conducted by the study site (study site includes the Investigator and the institution) as defined 
in the applicable protocol or study plan or study agreement.  The study site shall maintain 
confidentiality and not disclose or divulge such “data” to any third party.  However, the study 
site may seek permission to publish such “data” for limited purpose and such “data” may be 
published by the study site only upon receipt of prior written approval from R-Pharm 
International. 
11.7 Financing and Insurance 
R-Pharm International is the Sponsor of the study.  R-Pharm International will provide 
insurance in accordance with local guidelines and requirements as a minimum for the 
subjects participating in this study.  The terms of the insurance will be kept in the study files. 
R-Pharm International has obtained liability insurance, which covers this study as required 
by local law and/or national regulations and/or ICH guidelines, whichever is applicable.  The 
terms of the insurance will be kept in the study files. 


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12. 
REFERENCES 
Bykerk VP, Östör AJK, Alvaro-Gracia J, Pavelka K, Ivorra JAR, Graninger W, et al.  
Tocilizumab in patients with active rheumatoid arthritis and inadequate responses to 
DMARDs and/or TNF inhibitors: a large, open-label study close to clinical practice.  Ann 
Rheum Dis 2012;71:1950-1954. 
Cohen SB, Cohen MD, Cush JJ, Fleischmann RM, Mease PJ, Schiff MH, et al.  Unresolved 
issues in identifying and overcoming inadequate response in rheumatoid arthritis: weighing 
the evidence.  J Rheumatol Suppl 2008;81:4-30. 
Furst DE, Gaylis N, Bray V, Olech E, Yocum D, Ritter J, et al.  Open-label, pilot protocol of 
patients with rheumatoid arthritis who switch to infliximab after an incomplete response to 
etanercept: the opposite study.  Ann Rheum Dis 2007;66:893-899. 
Humira® (adalimumab) Prescribing Information, 2015 
http://www.rxabbvie.com/pdf/humira.pdf  
Jacobsson LT, Turesson C, Nilsson JA, Petersson IF, Lindqvist E, Saxne T, et al.  Treatment 
with TNF blockers and mortality risk in patients with rheumatoid arthritis.  Ann Rheum Dis 
2007;66:670-675. 
Marchesoni A, Zaccara E, Gorla R, Bazzani C, Sarzi-Puttini P, Atzeni F, et al.  TNF-alpha 
antagonist survival rate in a cohort of rheumatoid arthritis patients observed under conditions 
of standard clinical practice.  Ann N Y Acad Sci 2009;1173:837-846. 
Nelson WB.  Recurrent events data analysis for product repairs, disease recurrences, and 
other applications.  SIAM, 2003. 
Rubbert-Roth A, Finckh A.  Treatment options in patients with rheumatoid arthritis failing 
initial TNF inhibitor therapy: a critical review.  Arthritis Res Ther 2009;11(Suppl 1):S1. 
Sahai H, Khurshid A.  Confidence intervals for the mean of a Poisson distribution: a review.  
Biometrical J 1993;35(7):857-867. 
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al.  
Second symposium on the definition and management of anaphylaxis: summary 
report--Second National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network symposium.  J Allergy Clin Immunol 2006 Feb;117(2):391-397. 
Schiff M, Pritchard C, Huffstutter JE, Rodriguez-Valverde V, Durez P, Zhou X, et al.  The 
6-month safety and efficacy of abatacept in patients with rheumatoid arthritis who underwent 


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a washout after anti-tumour necrosis factor therapy or were directly switched to abatacept: 
the ARRIVE trial.  Ann Rheum Dis 2009;68:1708-1714. 
Siddiqui O.  Statistical methods to analyze adverse events data of randomized clinical trials.  
J Biopharm Stat 2009;19(5):889-899. 
Smolen JS, Landewé R, Breedveld FC, Buch M, Burmester G, Dougados M, et al.  EULAR 
recommendations for the management of rheumatoid arthritis with synthetic and biological 
disease-modifying antirheumatic drugs:  2013 updated.  Ann Rheum Dis 2014;73:492-509. 
Wollenhaupt J, Silverfield J, Lee EB, Curtis JR, Wood SP, Soma K, et al.  Safety and 
efficacy of tofacitinib, an oral janus kinase inhibitor, for the treatment of rheumatoid arthritis 
in open-label, longterm extension studies.  J Rheumatol 2014;41(5):837-852. 
World Health Organization.  Global Tuberculosis Report 2015.  Accessed on 
14 December 2015.  Available from: http://www.who.int/tb/publications/global_report/en/ 


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13. 
APPENDICES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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13.1 Appendix 1:  Methotrexate Dose Reduction Guidelines 
ALT and/or AST 
Total Bilirubin 
Repeat Laboratory  
MTX 
Study Treatment 
1× to ≤2× ULN 
NA 
No need 
No change 
No change 
>2× to ≤3× ULN  
NA  
Within 1 week 
No change or can consider reduction 
in dose 
No change 
If repeat >2× to ≤3× ULN   
NA 
Within 1 week 
Reduce dosage and follow LFTs 
No change 
>3× to <8× ULN 
(without the appearance of 
fatigue, nausea, vomiting, right 
upper quadrant pain or 
tenderness, fever, rash, and/or 
eosinophilia [>5%]) 
≤2× ULN 
Within 72 hours of initial finding, 
and then at least weekly after last 
finding until resolution, 
stabilization, or return to baseline 
values 
Hold MTX until LFTs normalize or 
return to baseline and consider 
restarting at lower dose 
No change 
If repeat >3× to <8× ULN 
(without the appearance of 
fatigue, nausea, vomiting, right 
upper quadrant pain or 
tenderness, fever, rash, and/or 
eosinophilia [>5%]) 
≤2× ULN 
Within 72 hours of initial finding, 
and then at least weekly after last 
finding until resolution, 
stabilization, or return to baseline 
values 
Hold MTX until LFTs normalize or 
return to baseline and consider 
restarting at lower dose 
Hold and consider 
restarting after discussion 
with the R-Pharm 
International Medical 
Advisor or designee  
>3× ULN accompanied by 
symptoms which, as determined 
by the Investigator, are the result 
of hepatic injury (e.g., fatigue, 
nausea, vomiting, right upper 
quadrant pain or tenderness, 
fever, rash, eosinophilia (>5%) 
≤2× ULN 
Within 72 hours of initial finding, 
and then at least weekly after last 
finding until resolution, 
stabilization, or return to baseline 
values 
Hold MTX.  Follow local Standard 
of Care. 
Permanently discontinue 
study treatment 
>3× ULN 
>2× ULN 
Within 72 hours of initial finding, 
and then at least weekly after last 
finding until resolution, 
stabilization, or return to baseline 
values 
Hold MTX.  Follow local Standard 
of Care. 
Permanently discontinue 
study treatment 


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ALT and/or AST 
Total Bilirubin 
Repeat Laboratory  
MTX 
Study Treatment 
>5× ULN for for 
≥2 consecutive weeks 
≤2× ULN 
Within 72 hours of initial finding, 
and then at least weekly after last 
finding until resolution, 
stabilization, or return to baseline 
values 
Hold MTX.  Follow local Standard 
of Care. 
Permanently discontinue 
study treatment 
>8× ULN 
≤2× ULN 
Within 72 hours of initial finding, 
and then at least weekly after last 
finding until resolution, 
stabilization, or return to baseline 
values 
Hold MTX.  Follow local Standard 
of Care. 
Permanently discontinue 
study treatment 
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; MTX = methotrexate; LFTs = liver function tests; NA = not applicable; ULN = upper limit of 
normal. 


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13.2 Appendix 2:  Tuberculosis Risk Questionnaire 
The following questions are to be asked to every subject for evaluation of signs and 
symptoms of tuberculosis (TB).  Responses to each question must be documented on this 
source document. 
Question 
Response 
1) Does the subject have a new diagnosis of TB disease? 
     Yes        No 
2) Has the subject been in close contact (i.e., 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 since the last scheduled visit? 
     Yes        No 
3) Has the subject become an employee at a TB hospital, forensic medical 
examiner, or morgue since the last scheduled visit? 
     Yes        No 
4) Has the subject started work or has the subject stayed in long-stay 
institutions (e.g., homes for elderly or disabled, prisons, etc) since the last 
scheduled visit? 
     Yes        No 
5) Does the subject reside in or is the subject frequently travelling to a TB 
endemic region (as defined in Table 5)? (only applicable for subjects not 
living in an endemic region) 
     Yes        No 
   Not applicable 
6) Has the subject been in frequent contact with underprivileged 
populations (homeless people or other people needing social assistance) 
since the last scheduled visit? 
     Yes        No 
7) Does the subject have a new cough lasting more than 14 days or a 
change in a chronic cough? 
     Yes        No 
8) Does the subject have night sweats? 
     Yes        No 
9) Does the subject have a persistent fever? 
     Yes        No 
10) Does the subject have unintentional weight loss (more than 10% of 
body weight) in the past 3 months? 
     Yes        No 
11) Does the subject appear malnourished? 
     Yes        No 
12) Has the subject had an abnormal chest X-ray since the last 
evaluation? 
     Yes        No 
 
Physician’s signature:  


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Table 5 
List of Endemic TB Countries (Incidence >50/100,000) 
Country 
Incidencea 
Country 
Incidencea 
Country 
Incidencea 
Afghanistan 
189 (167–212) 
Greenland 
197 (173–223) 
Nigeria 
322 (189–488) 
Algeria 
78 (64–94) 
Guatemala 
57 (51–64) 
Northern 
Mariana Islands 
61 (53–69) 
Angola 
370 (240–529) 
Guinea 
177 (156–199) 
Pakistan 
270 (201–350) 
Azerbaijan 
77 (68–86) 
Guinea-Bissau 
369 (261–495) 
Papua New 
Guinea 
417 (304–547) 
Bangladesh 
227 (200–256) 
Guyana 
103 (91–116) 
Peru 
120 (98–145) 
Belarus 
58 (50–67) 
Haiti 
200 (177–225) 
Philippines 
288 (254–324) 
Benin 
61 (50–74) 
India 
167 (156–179) 
Romania 
81 (71–91) 
Bhutan 
164 (148–181) 
Indonesia 
399 (274–546) 
Russia 
84 (76–93) 
Bolivia 
120 (106–135) 
Ivory Coast 
165 (150–179) 
Rwanda 
63 (54–72) 
Botswana 
385 (361–410) 
Kazakhstan 
99 (64–141) 
Sao Tome and 
Principe 
97 (85–109) 
Brunei 
62 (54–70) 
Kenya 
246 (240–252) 
Senegal 
138 (122–154) 
Burkina Faso 
54 (48–59) 
Kiribati 
497 (406–597) 
Sierra Leone 
310 (235–394) 
Burundi 
126 (116–136) 
Kyrgyzstan 
142 (126–160) 
Solomon 
Islands 
86 (71–102) 
Cabo Verde 
138 (122–156) 
Laos 
189 (141–244) 
Somalia 
274 (242–308) 
Cambodia 
390 (353–428) 
Lesotho 
852 (612–1130) 
South Africa 
834 (737–936) 
Cameroon 
220 (195–247) 
Liberia 
308 (273–346) 
South Korea 
86 (81–91) 
Central African 
Republic 
375 (333–420) 
Lithuania 
62 (57–68) 
South Sudan 
146 (121–173) 
Chad 
159 (141–179) 
Madagascar 
235 (207–264) 
 
Sri Lanka 
65 (57–73) 
China 
68 (63–73) 
Malawi 
227 (122–365) 
Sudan 
94 (52–148) 
China, Hong 
Kong 
74 (65–84) 
Malaysia 
103 (83–124) 
Swaziland 
733 (533–963) 
China, Macao  
82 (72–93) 
Mali 
58 (56–59) 
Tanzania 
327 (155–561) 
Congo 
381 (335–430) 
Marshall Islands 
335 (274–402) 
Tajikistan 
91 (80–103) 
Democratic 
Republic of 
325 (295–356) 
Mauritania 
111 (79–148) 
Thailand 
171 (90–276) 


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Country 
Incidencea 
Country 
Incidencea 
Country 
Incidencea 
Congo 
Djibouti 
619 (547–696) 
Micronesia 
195 (87–347) 
Timor-Leste 
498 (411–594) 
Dominican 
Republic 
60 (53–68) 
Moldova 
153 (135–172) 
Togo 
58 (47–70) 
Ecuador 
54 (39–71) 
Mongolia 
170 (149–193) 
Turkmenistan 
64 (52–78) 
Equatorial 
Guinea 
162 (142–184) 
Morocco 
106 (97–115) 
Tuvalu 
190 (154–228) 
Eritrea 
78 (57–103) 
Mozambique 
551 (435–680) 
Uganda 
161 (141–183) 
Ethiopia 
207 (168–250) 
Myanmar 
369 (334–406) 
Ukraine 
94 (83–106) 
Fiji 
67 (55–81) 
Namibia 
561 (492–635) 
Uzbekistan 
82 (61–107) 
Gabon 
444 (393–497) 
Nauru 
73 (64–83) 
Vanuatu 
63 (52–74) 
Gambia 
174 (145–206) 
Nepal 
158 (139–178) 
Vietnam 
140 (116–167) 
Georgia 
106 (99–114) 
Nicaragua 
58 (53–63) 
Yemen 
48 (42–54) 
Ghana 
165 (80–281) 
Niger 
98 (87–110) 
Zambia 
406 (279–557) 
 
Zimbabwe 
278 (193–379) 
Abbreviation:  HIV = human immunodeficiency virus; TB = tuberculosis; WHO = World Health Organization. 
a.  Rate per 100,000 population 
Note:  ranges represent uncertainty intervals. 
Note:  The 30 WHO TB high burden countries are as follows:  Angola, Bangladesh, Brazil, Cambodia, China, Congo, 
Central African Republic, Democratic Republic of Congo, Ethiopia, India, Indonesia, Kenya, Lesotho, Liberia, 
Mozambique, Myanmar, Namibia, Nigeria, Pakistan, Papua New Guinea, Philippines, Russian Federation, Sierra Leone, 
South Africa, South Korea, Thailand, the United Republic of Tanzania, Viet Nam, Zambia, and Zimbabwe. 
Source: WHO Global Tuberculosis Report 2015. 


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13.3 Appendix 3:  Clinical Criteria for Diagnosing Anaphylaxis 
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen 
lips-tongue-uvula) AND AT LEAST 1 OF THE FOLLOWING 
a. 
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia) 
b. 
Reduced BP or associated symptoms of end-organ dysfunction (e.g., hypotonia 
[collapse], syncope, incontinence) 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours): 
a. 
Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen 
lips-tongue-uvula) 
b. 
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia) 
c. 
Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence) 
d. 
Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours): 
a. 
Infants and children:  low systolic BP (age specific) or greater than 30% decrease 
in systolic BPa 
b. 
Adults:  systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline 
Abbreviations:  BP = blood pressure; PEF = peak expiratory flow. 
a.  Low systolic BP for children is defined as less than 70 mm Hg from 1 month to 1 year, less than (70 mm Hg + [2× age]) 
from 1 to 10 years, and less than 90 mm Hg from 11 to 17 years. 
Source:  Reproduced from Sampson HA, et al.  J Allergy Clin Immunol. 2006.  Feb;117(2):391-7. 
 


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13.4 Appendix 4:  Recommendations for Management of Latent 
Tuberculosis Infection 
Recommendations for management of latent tuberculosis infection (LTBI) are provided 
below.  If the known source of a subject’s LTBI is an individual with drug-resistant TB, these 
recommended treatments must be modified after consultation with a certified TB specialist or 
pulmonologist who is familiar with treating TB, as acceptable per local practice. 
Adapted CDC Recommendations for Management of Latent TB 
Drug(s) 
Duration 
Interval 
Comments 
Isoniazid 
9 months 
Daily 
 
 
 
Twice weeklya 
 
 
 
 
 
Isoniazid 
6 months 
Daily 
This regimen is not preferred for TB prophylaxis 
and should not be used in this study. 
 
 
Twice weeklya 
 
 
 
 
 
Isoniazid and 
Rifapentine 
3 months 
Once weeklya 
 
 
 
 
 
Rifampin 
4 months 
Daily 
 
 
 
 
 
Abbreviations:  CDC = Centers for Disease Control and Prevention; TB = tuberculosis. 
a.  Use Directly Observed Therapy (DOT). 
 
 


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13.5 Appendix 5:  Protocol Amendment 2 Summary of Changes