Clinical trial NCT04246762
Conditions: Rheumatoid Arthritis
Keywords: moderate Rheumatoid Arthritis severe Rheumatoid Arthritis subcutaneous Olokizumab drug interaction CYP450
Sponsor: R-Pharm International, LLC
Start date: 2021-11-16; Completion date: 2022-10-26
Enrollment: 17 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Olokizumab (OKZ) has been shown to reverse the inhibitory effect of IL-6 on the activity of Cytochrome P450 (CYP450) isozymes CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4/5 in vitro.

The goal of the study was to assess the effect of OKZ on the pharmacokinetics (PK) of the CYP450 probe substrates, caffeine (CYP1A2), S-warfarin (CYP2C9), omeprazole (CYP2C19), and midazolam (CYP3A4) in subjects with rheumatoid arthritis (RA).

Detailed description:
This was a Phase 1, open-label, 3-period, single-sequence, crossover study in subjects with RA with increased C-reactive protein (CRP).

Approximately 15 eligible subjects were planned to be enrolled at approximately 3 study centers to have at least 12 evaluable subjects completing the study. However, if necessary, additional subjects could be dosed to obtain the 12 evaluable subjects required.

There was a 35-day Screening Period, followed by a 29-day study duration: eligible patients were administered a cocktail of 4 substrates alone with following 7 days PK-sampling (Period 1); a single subcutaneous dose of 128 mg OKZ was administered (Period 2) approximately 2 weeks prior to the second administration of the cocktail with following 7-days PK-sampling (Period 3). After completion of the Period 3 patients were followed-up for 19 weeks (133 days) for safety evaluations.

Overall duration of the study was approximately 200 days (6 and a half months).

Arms: arm 1: All subjects have received the following treatment:

Cocktail drugs (Omeprazole + Caffeine + Warfarin (+ vitamin K solution) + Midazolam) orally administered with 240 mL of water on Day 1, single subcutaneous injection of Olokizumab 128 mg administered on Day 8 and second dose of Cocktail drugs (Omeprazole + Caffeine + Warfarin (+ vitamin K solution) + Midazolam) orally administered on Day 22
Interventions: intervention 1: Olokizumab intervention 2: Omeprazole intervention 3: Caffeine intervention 4: Warfarin+ Vitamin K intervention 5: Midazolam
Intervention descriptions: intervention 1: Sterile solution for subcutaneous (SC) injection, 128 mg (0.8 mL injection) intervention 2: Tablets, 20 mg, oral intervention 3: Tablets, 100 mg, oral intervention 4: Warfarin -Tablets 10 mg (containing 5 mg S-warfarin), oral. Vitamin K - solution for intravenous injection, 10 mg/mL ampoule, orally. intervention 5: Syrup, 2 mg/mL, oral

Protocol documents:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
Protocol CL04041026 – Amendment 3 
 
 Page 1 of 115 
 
TITLE PAGE 
 
Protocol Title: 
A Phase 1, Open-label, Study in Subjects with Rheumatoid Arthritis to Evaluate the Effect of a Single 
Dose of Olokizumab on the Pharmacokinetics of Substrates for CYP1A2, CYP2C9, CYP2C19, and 
CYP3A4 
Protocol Number: CL04041026 
Amendment Number: Amendment 3 
Product: Olokizumab 
Study Phase: Phase 1 
Sponsor Name: R-Pharm International 
Legal Registered Address: R-Pharm International,  
19-1, Berzarina Street,  
1st Floor, Premises V, Room 9,  
Moscow,  
Russian Federation,  
123154 
Regulatory Agency Identifying Number: IND 104933 
 
Date of Protocol: 22 September 2021 
 
 


CONFIDENTIAL 
Protocol CL04041026 – Amendment 3 
 
 Page 2 of 115 
Sponsor Signatory: 
I hereby confirm that Protocol CL04041026 “A Phase 1, Open-label Study in Subjects with Rheumatoid 
Arthritis to Evaluate the Effect of a Single Dose of Olokizumab on the Pharmacokinetics of Substrates for 
CYP1A2, CYP2C9, CYP2C19, and CYP3A4” is created in accordance with the ethical principles that 
have their origin in the Declaration of Helsinki, International Council for Harmonisation (ICH) E6 Good 
Clinical Practice (GCP) Consolidated Guideline, current revision and all applicable laws and regulations, 
including, without limitation, data privacy laws, clinical trial disclosure laws, and regulations, as well as 
Order No. 200n dated April 01, 2016 of the Ministry of Health of the Russian Federation on Approval of 
Rules for GCP. 
 
 
Mikhail Samsonov* 
Chief Medical Officer 
R-Pharm 
 
Date 
*Signing the protocol on behalf of R-Pharm International by power of attorney #16 dated 
02 November 2020. 
 
 
 
 
 


CONFIDENTIAL 
Protocol CL04041026 – Amendment 3 
 
 Page 3 of 115 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Table 1 
Document History 
Document 
Date 
Substantial 
Region 
Amendment 3 
22-September-2021 Yes 
Global 
Amendment 2 
11-May-2021 
Yes 
Global 
Amendment 1 
21-Sep-2020 
Yes 
Global 
Original Protocol 
14-Oct-2019 
- 
- 
 
Amendment 3 (22-September-2021) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
The purpose of this amendment (Amendment 3) is to improve enrolment by reducing screen 
failure and possibly enhance further pharmacokinetic analysis. Thus, a maximum age of 
inclusion is increased to 70 years, lower limits of weight are decreased to 55 in males and 45 in 
females; a permission to participate in the study is made for females of childbearing potential 
(with the requirement for highly effective contraception adherence); subjects with the CYP2C9 
*1/*2 and *1/*3 genotypes (which could be considered as intermediate instead of poor 
metabolizers) are considered eligible; subjects are considered eligible with hemoglobin level of 
95 g/L and higher; subjects with positive anti-HBc antibodies test (and negative HBsAg and 
HBV DNA tests) are considered eligible upon hepatologist conclusion that no additional risk is 
suspected; subjects with NYHA Class II heart failure are made eligible (see Table 2 for each 
change implemented rationale description).  
Amendment 2 (11 May-2021) 
This amendment was considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
Previous amendment (Amendment 1) was introduced due to global spread and the severity of 
coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 
2 (SARS-CoV-2). The purpose of this amendment (Amendment 2) was to keep proactive 
measures to exclude subjects with COVID-19 who may be contagious to prevent further 
transmission but to allow inclusion of patients with a history of this condition, vaccine 
administration, as well as increasing the upper age limit for enrollment. These changes are 


CONFIDENTIAL 
Protocol CL04041026 – Amendment 3 
 
 Page 4 of 115 
necessitated due to the changed environmental conditions of COVID-19, including improved 
prophylaxis and treatment. Few changes related to patients’ genotype assessment and analysis of 
the data were included to improve enrolment and possibly enhance further pharmacokinetic 
analysis. 
Amendment 1 (21-September-2020) 
This amendment was considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) was initially detected as a pneumonia of unknown cause in 
Wuhan, China and declared a pandemic due to its global spread and the severity of disease. The 
purpose of this amendment was to implement proactive measures to exclude subjects with 
COVID-19 or a history thereof and to add testing to identify such subjects at the earliest stage of 
infection. Screening tests are intended to identify infected individuals without, or prior to 
development of, symptoms who may be contagious so that measures can be taken to prevent 
further transmission and proper treatment may be implemented as per the local guidelines. 
 
 
 


CONFIDENTIAL 
Protocol CL04041026 – Amendment 3 
 
 Page 5 of 115 
Table 2 
Description of Changes in Amendment 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis: Overall Design 
 
Added physical examination and 
FSH testing as Screening-Stage 1 
procedures. 
In accordance with changes made for SoA 
(Table 3) and Section 4.1. Overall Design.  
1.1 Synopsis: Diagnosis and 
Main Criteria for Inclusion 
Maximum age of inclusion 
updated from 65 to 70 years. 
In accordance with changes made for the 
Section 5.1 Inclusion Criteria.  
 
Lower limits for weight was 
updated from 60 to 55 kg in males 
and from 50 to 45 kg in females. 
In accordance with changes made for the 
Section 5.1 Inclusion Criteria. 
 
Deleted “of nonchildbearing 
potential’ from female subjects 
eligibility description. 
Added contraception requirements 
for male and female subjects in the 
study. 
In accordance with changes made for the 
Section 5.1 Inclusion Criteria.  
1.3 Schedule of Activities – 
Table 3 
An explanation (footnote) for a 
Joint count (DAS28) and Patient 
Global Assessment of Disease 
Activity (Visual Analog Scale – 
Bullet Scale) – was added on Day 
1 and Day 8. 
An explanation (footnote) for a 
physical examination – was added 
on Day 22. 
To establish consistency with the Table 9. 
 
FSH testing was moved to the 
Screening-Stage 1. 
To provide the FSH test results available 
at Screening-Stage 2 so that pregnancy 
test to be made only for WOCBP. 
 
A pregnancy test assessment – 
blood test - for female subjects 
determined as WOCBP was added 
on Screening-Stage 2 with 
applicable footnote. 
In accordance with changes made for the 
Sections 5.1. Inclusion Criteria and 5.2 
Exclusion Criteria - To provide eligibly 
compliance at screening. 
 
A pregnancy test assessment – 
urine test - for female subjects 
determined as WOCBP was added 
on Day (-1), Day 8, Day 21, EOT 
and EOS visits with applicable 
footnote. 
In accordance with changes made for the 
Sections 5.1. Inclusion Criteria and 5.2 
Exclusion Criteria - For pregnancy 
monitoring of female subjects of 
childbearing potential throughout the 
study to avoid pregnancies. 
 
A HBV DNA test was added to the 
viral serology screening procedure 
and applicable footnote was 
corrected accordingly.  
In accordance with changes made for the 
Sections 5.2 Exclusion Criteria – to allow 
inclusion of anti-HBc positive subjects in 
case of HBV DNA test is negative – i.e. 
there is no active infection. 
 
INR only procedure was added on 
Day 5. 
To establish consistency with the Table 9 
and Section 8.1.4 Clinical Safety 
Laboratory Assessments 
 
 
 


CONFIDENTIAL 
Protocol CL04041026 – Amendment 3 
 
 Page 6 of 115 
Section # and Name 
Description of Change 
Brief Rationale 
 
AEs/SAEs recording procedure 
was added on Screening-Stage1. 
To establish consistency with the footnote 
and Section 8.2 Adverse Events as these 
specify that all events are to be reported 
from the signature of the ICF. 
 
A footnote regarding pregnancy 
test performance in the study for 
WOCBP only was added.  
To make procedure performance clear.  
 
Footnote z (previously y) was 
corrected – the excessive 
information was deleted.  
A part of clarification is already provided 
in the footnote x (previously w) and is 
applicable to the entire procedure.  
 
 
 
2.2.2 Clinical Data 
Information regarding completed 
and ongoing clinical studies were 
updated: number of studies, 
designs descriptions, summary of 
PK, safety and efficacy results 
available. 
According to the latest IB edition (ed.12). 
2.3 Benefit/Risk Assessment 
Efficacy conclusion was updated 
with available data from completed 
and ongoing studies. 
In accordance with changes made for 
Section 2.2.2 Clinical Data. 
4.1 Overall Design 
Added physical examination and 
FSH testing as Screening-Stage 1 
procedures. 
To establish consistency with the SoA 
(Table 3). 
4.2 Scientific Rationale for 
Study Design 
Description of female subjects’ 
eligibility was corrected. 
In accordance with changes made for the 
Section 5.1 Inclusion Criteria. 
5.1 Inclusion Criteria 
Maximum age of inclusion 
updated from 65 to 70 years. 
To improve enrollment since the elderly 
age ranges from 60 to 74 (based on the 
WHO data), subjects of 70 years of age 
(inclusively) could be enrolled if the 
investigator considers no safety issues 
based on screening results for such 
subject. 
 
Incl.#2 was updated - WOCBP 
were made eligible for the study. 
To improve enrollment since RA is known 
to be more prevalent in women. 
 
Incl.#3 was added - Contraception 
requirements were added for 
WOCBP in the study (female 
subjects or female partners of male 
subjects). WONCBP to be 
identified as previously described. 
In accordance with changes made for 
Incl.#2 – To avoid pregnancies of 
WOCBP in the study due to the possible 
effects of study drug on the course and 
outcomes of pregnancy, since WOCBP 
were made eligible. 
 
Incl.#4 (prev. #3) was updated – 
lower limits for weight was 
updated from 60 to 55 kg in males 
and from 50 to 45 kg in females. 
To improve enrollment since subjects with 
chronic inflammatory processes (which 
are the desired population of this study) 
have a tendency to lost in weight and to 
acquire cachectic appearance. Thus, such 
subjects could be enrolled if the 
investigator considers no safety issues 


CONFIDENTIAL 
Protocol CL04041026 – Amendment 3 
 
 Page 7 of 115 
Section # and Name 
Description of Change 
Brief Rationale 
based on screening results for such 
subject. 
 
Incl.#8 was added - Female 
subjects of childbearing potential 
must have negative pregnancy test 
at Screening and throughout the 
study until the end of study (EOS, 
Day 161). 
In accordance with changes made for 
Incl.#2 – To avoid pregnancies of 
WOCBP in the study due to the possible 
effects of study drug on the course and 
outcomes of pregnancy, since WOCBP 
were made eligible. 
5.2 Exclusion Criteria 
Excl.#18 was updates - Presence of 
CYP2C9 genotypes *1/*2 and 
*1/*3 were deleted from the 
Exclusion criteria.  
According to the literature data these 
genotypes could be considered as 
intermediate instead of poor metabolizers, 
thus could present evident signs of CYP 
activity alteration after the study drug 
administration and be informative for the 
study assessments.  
 
Excl.#19 was updated with 
clarification that subjects 
previously participated in this or 
other OKZ study should be 
excluded only in case of receiving 
at least one OKZ dose. 
To allow rescreening for subjects 
previously participated in this or other 
OKZ study but excluded from the study 
for some reason before any OKZ 
exposure. 
 
Excl.#20 was corrected – 
hemoglobin level applicable for 
inclusion was changed to 95 g/L 
and higher. 
To improve enrollment – since anemia is a 
common finding for RA subjects, Thus 
such subjects could be enrolled if the 
investigator considers no safety issues 
based on screening results for such 
subject. 
 
Excl,#21 was corrected – a test for 
HBV DNA is added for anti-HBc 
positive subjects only; anti-HBc 
positive (solely or together with 
anti-HBs antibodies) subjects are 
made eligible unless HBsAg or 
HBV DNA positive and upon 
hepatologist consultation with 
documented conclusion no 
additional risk is suspected for the 
subject. 
To improve enrollment - since single-dose 
administration of investigational drug 
(OKZ) is planned only no increase in risks 
is anticipated for the subjects with 
hepatitis in history or latent hepatitis (i.e. 
not active), assuming proper examination 
by hepatologist and his conclusion if the 
subject could participate in the study.  
 
Excl.#27 was corrected – subjects 
with NYHA Class II heart failure 
are made eligible.  
To improve enrollment – since no increase 
in cardiovascular complications risk was 
shown for the investigational drug (OKZ) 
administration in previous phase 3 clinical 
trials (based on the assessment of the 
Cardiovascular Adjudication Committee). 
Thus, such subjects could be enrolled if 
the investigator considers no safety issues 
based on screening results for such 
subject. 


CONFIDENTIAL 
Protocol CL04041026 – Amendment 3 
 
 Page 8 of 115 
Section # and Name 
Description of Change 
Brief Rationale 
 
Excl.#46 was added – pregnant 
and breastfeeding women are not 
eligible for the study. 
In accordance with changes made for 
Incl.#2 – To avoid pregnancies and 
breastfeeding of WOCBP in the study due 
to the possible effects of study drug on the 
course and outcomes of pregnancy and 
breastfeeding, since WOCBP were made 
eligible. 
5.3.3 Contraception 
Requirement to adhere 
contraception in the study is added 
for WOCBP.  
In accordance with changes made for the 
Section 5.1 Inclusion Criteria and 
Appendix 6. 
7.1 Discontinuation of Study 
Treatment 
Permanent Discontinuation of 
Study Treatment is marked as a 
separate section. 
To make Discontinuation of Study 
Treatment criteria clearer.  
 
A clarification was added on 
procedures to be performed in case 
of early treatment discontinuation 
by subject – EOS visit should be 
performed after the EOT and SFU 
visits completion for this subject. 
To make early treatment discontinuation 
process clearer. 
7.1.2 Permanent 
Discontinuation of Study 
Treatment 
Criteria for the permanent 
discontinuation of study treatment 
were corrected. 
To make early treatment discontinuation 
process clearer. 
 
Pregnancy of female subject is 
added as a criteria for subject 
discontinuation from the study 
treatment. 
In accordance with changes in the Section 
5.2 Exclusion Criteria.  
7.2 Subject 
Discontinuation/Withdrawal 
from the Study 
Investigator’s right to stop the 
study is added as a criteria for 
subject discontinuation. 
To establish consistency with the 
Appendix 2. 
 
Other criteria for subject 
discontinuation/withdrawal from 
the study were corrected. 
Since the criteria provided in the new 
version are applicable for the study 
discontinuation only (no other procedures 
to be made for the subjects after study 
discontinuation except EOS visit).  
8.0 Study Assessments – 
Table 9 
AEs/SAEs recording procedure 
was added on Screening-Stage1. 
To establish consistency with the SoA 
(Table 3) and Section 8.2 Adverse Events 
as these specify that all events are to be 
reported from the signature of the ICF. 
 
Moved FSH testing to Screening-
Stage 1. 
In accordance with changes made for the 
Section 4.1 Overall Design and SoA 
(Table 3). 
 
A pregnancy test assessment for 
female subjects of childbearing 
potential was added on Screening-
Stage 2 (blood), urine: Day (-1), 
Day 8, Day 21, EOT and EOS 
visits. 
In accordance with changes made for the 
Section 5.2 Exclusion Criteria and SoA 
(Table 3). 


CONFIDENTIAL 
Protocol CL04041026 – Amendment 3 
 
 Page 9 of 115 
Section # and Name 
Description of Change 
Brief Rationale 
 
COVID-19 RT-PCR testing in 
Period 1 was corrected to be made 
on Day 5 only; excessive 
explanation was deleted. 
To establish consistency with SoA (Table 
3); the test performance clarification is 
already in place within e footnote which is 
applicable to the entire procedure. 
 
Admission procedure is added on 
Day 21 
To make procedures performance on this 
Day clearer. 
8.1.4 Clinical Safety 
Laboratory Assessments 
Added a clarification that RT-PCR 
testing should be comprised of two 
consecutive tests within 
approximately 36 hours. 
To establish consistency with other 
applicable part of the protocol and make 
the procedure performance clearer.  
8.2.6 Reporting and Follow-
up Requirements for 
Pregnancies 
Additional reporting and follow-up 
requirements for pregnancies in 
female subjects (WOCBP) were 
added. 
In accordance with changes made for the 
Section 5.1 Inclusion Criteria – To 
provide proper safety monitoring in case 
of pregnancies since WOCBP were made 
eligible for the study. 
8.6 Genetics  
CYP2C9 genotypes *1/*2 and 
*1/*3 were described as 
intermediate metabolizers. 
In accordance with changes made for the 
Section 5.2 Exclusion Criteria. 
Appendix 3 Clinical 
Laboratory Tests – Table 14 
Added HCG urine test for 
pregnancy exclusion in WOCBP. 
In accordance with changes made for the 
Section 5.2 Exclusion Criteria and SoA 
(Table 3). 
 
A HBV DNA test was added to the 
viral serology screening procedure 
with an applicable footnote. 
In accordance with changes made for the 
Section 5.2 Exclusion Criteria and SoA 
(Table 3). 
Appendix 6 Contraceptive 
Guidance and Collection of 
Pregnancy Information 
Added contraceptive guidance for 
female subjects (WOCBP). 
In accordance with changes made for the 
Section 5.1 Inclusion Criteria – To avoid 
pregnancies of WOCBP in the study due 
to the possible effects of study drug on the 
course and outcomes of pregnancy, since 
WOCBP were made eligible. 
 
Description of collection of 
pregnancy information was 
corrected. 
In accordance with changes made for the 
Section 5.1 Inclusion Criteria and Section 
8.2.6 Reporting and Follow-up 
Requirements for Pregnancies – To 
provide proper safety monitoring in case 
of pregnancies since WOCBP were made 
eligible for the study. 
Throughout document 
Minor editorial updates were 
made. 
To established consistency throughout 
document and compliance with template 
and Style Guide. 
Abbreviations: AE = adverse event; COVID-19 = Coronavirus disease 2019; CYP = cytochrome; EOS = end of 
study; EOT = end of treatment; FSH = follicle-stimulating hormone; HCG = human chorionic gonadotropin; IB 
= investigational brochure; ICF = informed consent form; IgG = Immunoglobulin G; IgM = Immunoglobulin M; 
OKZ = olokizumab; PK = pharmacokinetic; RA = rheumatoid arthritis; RT-PCR = reverse transcription 
polymerase chain reaction; SAE = serious adverse event; SoA = schedule of assessments; WOCBP = woman of 
childbearing potential; WONCBP = woman of nonchildbearing potential. 
 


CONFIDENTIAL 
Protocol CL04041026 – Amendment 3 
 
 Page 10 of 115 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ................................3 
TABLE OF CONTENTS ......................................................................................................10 
LIST OF TABLES .................................................................................................................13 
LIST OF FIGURES ...............................................................................................................13 
1.0 
PROTOCOL SUMMARY ........................................................................................14 
1.1 
Synopsis ...........................................................................................................14 
1.2 
Schema .............................................................................................................20 
1.3 
Schedule of Activities ......................................................................................21 
2.0 
INTRODUCTION......................................................................................................29 
2.1 
Study Rationale ................................................................................................29 
2.2 
Background ......................................................................................................29 
2.2.1 
Nonclinical Data ................................................................................30 
2.2.2 
Clinical Data ......................................................................................32 
2.2.3 
Pharmacokinetic Drug Interactions ...................................................37 
2.3 
Benefit/Risk Assessment .................................................................................38 
2.3.1 
Expected Adverse Events and Reference Safety Information ...........39 
2.3.2 
Anticipated Adverse Effects ..............................................................39 
3.0 
OBJECTIVES AND ENDPOINTS ..........................................................................41 
4.0 
STUDY DESIGN ........................................................................................................42 
4.1 
Overall Design .................................................................................................42 
4.2 
Scientific Rationale for Study Design..............................................................44 
4.3 
End of Study Definition (Clinical Part) ...........................................................46 
4.4 
Dose Escalation Criteria ..................................................................................46 
5.0 
STUDY POPULATION ............................................................................................47 
5.1 
Inclusion Criteria .............................................................................................47 
5.2 
Exclusion Criteria ............................................................................................48 
5.3 
Lifestyle Considerations ..................................................................................53 
5.3.1 
Concomitant Medications ..................................................................53 
5.3.2 
Dietary, Caffeine, Alcohol and Tobacco Restrictions .......................54 
5.3.3 
Contraception ....................................................................................54 
5.4 
Screen Failures .................................................................................................54 
6.0 
STUDY TREATMENT .............................................................................................56 
6.1 
Study Treatment(s) Administered ....................................................................56 
6.2 
Preparation/Handling/Storage/Accountability .................................................57 
6.3 
Measures to Minimize Bias: Randomization and Blinding .............................58 
6.4 
Study Treatment Compliance ..........................................................................58 
6.5 
Emergency Treatment Strategy........................................................................58 
6.6 
Concomitant Therapy.......................................................................................59 
6.7 
Dose Modification ...........................................................................................59 
6.8 
Treatment after the End of the Study ...............................................................59 
7.0 
DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ................................................................60 
7.1 
Discontinuation of Study Treatment ................................................................60 
7.1.1 
Temporary Discontinuation of Study Treatment ...............................60 


CONFIDENTIAL 
Protocol CL04041026 – Amendment 3 
 
 Page 11 of 115 
7.1.2 
Permanent Discontinuation of Study Treatment ...............................61 
7.2 
Subject Discontinuation/Withdrawal from the Study ......................................62 
7.3 
Lost to Follow-up .............................................................................................63 
8.0 
STUDY ASSESSMENTS AND PROCEDURES ....................................................64 
8.1 
Safety Assessments ..........................................................................................68 
8.1.1 
Physical Examinations .......................................................................68 
8.1.2 
Vital Signs .........................................................................................68 
8.1.3 
Electrocardiograms ............................................................................68 
8.1.4 
Clinical Safety Laboratory Assessments ...........................................68 
8.1.5 
Tuberculosis Risk Questionnaire .......................................................70 
8.2 
Adverse Events ................................................................................................70 
8.2.1 
Severity ..............................................................................................71 
8.2.2 
Causality Assessment ........................................................................71 
8.2.3 
Eliciting Adverse Event Information .................................................72 
8.2.4 
Serious Adverse Events .....................................................................72 
8.2.5 
Overdose ............................................................................................74 
8.2.6 
Reporting and Follow-up Requirements for Pregnancies .................74 
8.2.7 
Reporting of Adverse Events .............................................................75 
8.2.8 
Reporting of Serious Adverse Events ................................................76 
8.2.9 
Reporting of Serious Adverse Events to Regulatory 
Authorities and Investigators .............................................................76 
8.2.10 
Follow-up of Adverse Events ............................................................77 
8.3 
Disease Activity Assessments..........................................................................77 
8.3.1 
Patient Global Assessment of Disease Activity (Visual 
Analog Scale – Bullet Scale) .............................................................77 
8.3.2 
Disease Activity Score 28-Joint Count (C-Reactive Protein) ...........78 
8.4 
Pharmacokinetics .............................................................................................78 
8.4.1 
Collection of Samples ........................................................................78 
8.4.2 
Determination of Drug Concentration ...............................................78 
8.4.3 
Calculation of Derivation of Pharmacokinetic Variables ..................79 
8.5 
Pharmacodynamics ..........................................................................................79 
8.6 
Genetics............................................................................................................80 
8.7 
Immunogenicity Assessments ..........................................................................80 
8.8 
Health Economics/Medical Resource Utilization and Health 
Economics ........................................................................................................80 
9.0 
STATISTICAL CONSIDERATIONS .....................................................................81 
9.1 
Statistical Hypotheses ......................................................................................81 
9.2 
Sample Size Determination..............................................................................81 
9.3 
Populations for Analyses .................................................................................82 
9.4 
Statistical Analyses ..........................................................................................82 
9.4.1 
Disease Activity Analysis ..................................................................83 
9.4.2 
Pharmacokinetic/Pharmacodynamic Analyses ..................................83 
9.4.3 
Safety Analyses .................................................................................83 
9.4.4 
Other Analyses ..................................................................................84 
9.4.5 
Missing Data ......................................................................................84 
9.5 
Interim Analyses ..............................................................................................85 


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Protocol CL04041026 – Amendment 3 
 
 Page 12 of 115 
10.0 
REFERENCES ...........................................................................................................86 
11.0 
APPENDICES ............................................................................................................89 
Appendix 1 
Abbreviations ....................................................................................90 
Appendix 2 
Regulatory, Ethical, and Study Oversight Considerations ................93 
Regulatory and Ethical Considerations ............................................................93 
Adequate Resources .........................................................................................93 
Financial Disclosure.........................................................................................94 
Insurance ..........................................................................................................94 
Informed Consent Process ...............................................................................94 
Data Protection.................................................................................................94 
Administrative Structure ..................................................................................95 
Medical Monitor ..............................................................................................96 
Dissemination of Clinical Study Data..............................................................96 
Data Quality Assurance ...................................................................................96 
Source Documents ...........................................................................................96 
Study and Study Center Closure ......................................................................97 
Publication Policy ............................................................................................97 
Appendix 3 
Clinical Laboratory Tests ..................................................................98 
Appendix 4 
Concomitant and Excluded Medications/Therapy ..........................101 
Concomitant Medication ................................................................................101 
Restricted and Excluded Medication .............................................................101 
Appendix 5 
Stages of Heart Failure – New York Heart Association 
Classification..................................................................................................105 
Appendix 6 
Contraceptive Guidance and Collection of Pregnancy 
Information ....................................................................................................106 
Definitions......................................................................................................106 
Contraception Guidance.................................................................................106 
Collection of Pregnancy Information.............................................................108 
Appendix 7 
Genetics ...........................................................................................109 
Appendix 8 
Tuberculosis Risk Questionnaire .....................................................110 
Appendix 9 
DAS28 Joint Table ..........................................................................113 
Appendix 10 
Protocol Amendment History ..........................................................114 
Appendix 11 
Signature of Investigator .................................................................115 
 
 
 


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Protocol CL04041026 – Amendment 3 
 
 Page 13 of 115 
LIST OF TABLES 
Table 1 
Document History ..............................................................................................3 
Table 2 
Description of Changes in Amendment .............................................................5 
Table 3 
Schedule of Activities ......................................................................................21 
Table 4 
Times of Blood Collection for the Cocktail Substrates ...................................27 
Table 5 
Times of Blood Collection for OKZ ................................................................28 
Table 6 
Study Objectives and Endpoints ......................................................................41 
Table 7 
Study Treatment Details ..................................................................................56 
Table 8 
Timing of Fluid and Food Intake Around Cocktail Administration ................57 
Table 9 
Tabular Outline of Study Assessments ............................................................65 
Table 10 
CTCAE Grades and Corresponding AE Severity ............................................71 
Table 11 
Plasma Blood Pharmacokinetic Parameters .....................................................79 
Table 12 
Analysis Sets ....................................................................................................82 
Table 13 
Study Administrative Structure........................................................................95 
Table 14 
Protocol-required Safety Laboratory Assessments ..........................................98 
Table 15 
List of Cytochrome P450 Inhibitors and Inducers .........................................103 
Table 16 
List of Endemic TB Countries (Incidence >50/100,000)...............................111 
 
LIST OF FIGURES 
Figure 1 
Study Schema...................................................................................................20 
Figure 2 
Visual Analog Scale – Bullet Style ................................................................113 
 
 


CONFIDENTIAL 
Protocol CL04041026 – Amendment 3 
 
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1.0 PROTOCOL SUMMARY 
1.1 
Synopsis 
Name of Sponsor: 
R-Pharm International 
Name of Finished Product: 
Olokizumab 
Name of Active Ingredient: 
Olokizumab 
Protocol Title: 
A Phase 1, Open-label, Study in Subjects with Rheumatoid Arthritis to Evaluate the Effect of a Single 
Dose of Olokizumab on the Pharmacokinetics of Substrates for CYP1A2, CYP2C9, CYP2C19, and 
CYP3A4 
Protocol Number: 
CL04041026 
Rationale: 
Olokizumab (OKZ) has been shown to reverse the inhibitory effect of IL-6 on the activity of 
Cytochrome P450 (CYP450) isozymes CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4/5 in vitro. 
To support the registration of OKZ, R-Pharm proposes a single-cocktail drug-drug interaction study 
design in subjects with rheumatoid arthritis (RA) to evaluate any potential effects of OKZ on the 
metabolism of substrates selective for specific CYP450 activity. The following probe substrates will be 
studied in the planned cocktail study: caffeine (CYP1A2), S-warfarin (CYP2C9), omeprazole 
(CYP2C19), and midazolam (CYP3A4). 
Objectives and Criteria for Evaluation (Endpoints): 
Objectives 
Criteria for Evaluation (Endpoints) 
Primary 
 
 
To assess the effect of olokizumab (OKZ) on the 
pharmacokinetics (PK) of the Cytochrome P450 
(CYP450) probe substrates, caffeine (CYP1A2), 
S-warfarin (CYP2C9), omeprazole (CYP2C19), 
and midazolam (CYP3A4) in subjects with 
rheumatoid arthritis 
Primary 
 
Area under the plasma concentration-time curve 
(AUC) from time zero to infinity (AUC(0-inf)) for 
caffeine, omeprazole, and midazolam 
 
AUC from time zero to the time “t” of the last 
quantifiable concentration (AUC(0-last)) for 
S-warfarin 
 
Maximum plasma concentration (Cmax) for all 
cocktail substrates 
Secondary 
 
Plasma AUC(0-last) or AUC(0-inf) (if not primary), 
time to maximum plasma concentration (tmax), 
terminal half-life (t1/2), elimination rate constant 
(λz), apparent systemic clearance (CL/F), and 
apparent volume of distribution (Vz/F) for cocktail 
parent compounds (caffeine, S-warfarin, 
omeprazole, and midazolam) 
 
Plasma concentrations for OKZ 


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Protocol CL04041026 – Amendment 3 
 
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Secondary: Safety 
 
 
To assess the safety and tolerability of the cocktail 
substrates when dosed in the presence or absence 
of OKZ 
 
To assess the safety and tolerability of a single 
dose of OKZ in subjects with rheumatoid arthritis 
 
 
Assessment of adverse events (AEs), graded by 
Common Terminology Criteria for Adverse 
Events (CTCAE), physical examination, vital 
signs (blood pressure, pulse rate, and body 
temperature), standard 12-lead electrocardiogram 
(ECG), evaluation of laboratory parameters 
(clinical chemistry, hematology, and coagulation), 
and immunogenicity 
Secondary: Pharmacodynamic 
 
 
To assess the effect of OKZ on inflammatory 
markers (pharmacodynamics [PD]) in subjects 
with rheumatoid arthritis 
 
Interleukin-6 (IL-6) and C-reactive protein (CRP) 
concentrations collected periodically throughout 
the study 
Overall Design: 
This is a Phase 1, open-label, 3-period, single-sequence, crossover study in subjects with RA with 
increased C-reactive protein (CRP) (≥1.2 × upper limit of normal [ULN]). During the study, subjects will 
be administered a cocktail of 4 substrates alone (Period 1) and in the presence of OKZ (Period 3). A 
single dose of 128 mg OKZ will be administered (Period 2) approximately 2 weeks prior to the second 
administration of the cocktail in Period 3. The cocktail comprises 100 mg caffeine (substrate of 
CYP1A2), 10 mg warfarin (containing 5 mg S-warfarin [substrate of CYP2C9]) plus 10 mg vitamin K, 
20 mg omeprazole (substrate of CYP2C19), and 2 mg midazolam (substrate of CYP3A4) and will be 
administered after an overnight fast of at least 10 hours (Turpault et al, 2009). Serial blood samples will 
be collected to determine the PK of the cocktail substrate analytes and OKZ. Blood sampling for the 
measurement of IL-6 and CRP will also be performed. 
Subjects will be screened within 35 days of the first dose administration and eligible subjects will be 
admitted to the study center on Day -1. The study will employ a 2-stage screening process; during the first 
Screening stage, assessments for genotyping, medical history with physical examination and FSH testing 
will be performed, as well as possibly the hepatitis serology and CRP screening assessments, if required 
by the study center. This will be followed approximately 3 weeks later by the second Screening stage, 
where the rest of the assessments will be conducted. 
If a subject has a history of confirmed coronavirus disease 2019 (COVID-19) in the previous 3 months 
before Day 1 (or with sever or critical illness ever) or known exposure to an individual with confirmed 
COVID-19 or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection within the past 2 
weeks and it is revealed at the Screening Visit or prior to cocktail administration on Day 1, the subject 
should not be administered the study treatment, and further COVID-19 related testing is not required. In 
case a patient shows respiratory symptoms or informs the Investigator about contact with a COVID-19 
infected person after OKZ administration, a test for COVID-19 should be performed as soon as possible. 
It is estimated that 15 subjects who meet the study eligibility criteria will need to be dosed in order to 
achieve the required 12 evaluable subjects. However, if necessary, additional subjects may be dosed to 
obtain the 12 evaluable subjects required. 
On the morning of Day 1 after an overnight fast of at least 10 hours, subjects will receive the first 
treatment of the cocktail: 100 mg caffeine, 20 mg omeprazole, 10 mg warfarin, 2 mg midazolam (via 
syringe) followed by 10 mg vitamin K (via syringe [Zhuang et al, 2015]), orally, under the supervision of 
appropriately trained study center staff. The cocktail will be administered with 240 mL of water and all 
4 cocktail substrates as well as the vitamin K should be ingested within 5 minutes (for details regarding 
study treatment administration, see Section 6.1). 


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Protocol CL04041026 – Amendment 3 
 
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Subjects will remain in the study center until Day 2 and will be discharged at the Investigator’s discretion 
(ie, providing there are no safety concerns) after the 30-hour PK sample. Subjects will return to the study 
center on Day 3, Day 4, Day 6, and Day 8 for PK sampling (see Table 4 for PK sampling times). 
On completion of the 7-day PK sampling period for the cocktail substrates on the morning of Day 8, 
subjects will be administered a single subcutaneous (SC) dose of 128 mg OKZ. All subjects will remain 
at the study center for at least 2 hours after the injection to be assessed for any systemic hypersensitivity 
reactions. Blood samples for determination of OKZ concentrations will be collected on Day 8 (predose 
[30-minute window allowed], along with the final PK sample collection for warfarin), Day 9, and Day 15. 
Subjects will attend the study center on an outpatient basis on Day 8, Day 9, and Day 15. 
Subjects will be admitted to the study center on Day 21 and will receive the second administration of the 
cocktail substrates after an overnight fast of at least 10 hours on Day 22 (ie, 14 days after administration 
of OKZ, by which time maximum suppression of CRP is expected). Subjects will remain in the study 
center until the 30-hour PK samples (caffeine) have been taken on Day 23 and will return to the study 
center on Day 24, Day 25, Day 27, and Day 29 (End of Treatment [EOT]) for scheduled PK sampling 
(warfarin) (see Table 4 for PK sampling times). Blood sampling for determination of OKZ concentrations 
will be collected on Day 22 (prior to cocktail administration) and on Day 24 and Day 29 (see Table 5 for 
PK sampling times). 
The IL-6 and CRP levels will be measured at Screening, prior to dose administration with the cocktail 
substrates on Day 1, prior to administration with OKZ on Day 8, and post OKZ administration on Day 9, 
Day 15, Day 22 (prior to dose administration of the cocktail), and Day 29, which will be considered the 
EOT Visit. Safety assessments will be performed at the EOT Visit (Day 29). 
Subjects will be undergoing COVID-19 reverse transcription polymerase chain reaction (RT-PCR) 
testing. Two RT-PCR tests will be conducted, the second RT-PCR test will only be performed if the first 
test results are negative. Only subjects with a negative COVID-19 RT-PCR test result may be included in 
the study. Two consecutive RT-PCR tests will occur at Day -35 (Stage 1) - only if the Investigator 
suspects possible COVID-19 infection, at Day -3, Day 5, Day 19 and Day 29 (EOT) - obligatory. If the 
Investigator suspects possible COVID-19 infection the RT-PCR testing should also occur on Day 43. 
Only subjects with a negative COVID-19 RT-PCR test result may be administered the study drug on 
Day 8. The RT-PCR testing will be performed at local laboratories. 
A rapid test will be conducted for the COVID-19 immunoglobulin G (IgG)/immunoglobulin M (IgM) 
testing at Screening-Stage 1 - only if the Investigator suspects possible COVID-19 infection, prior to first 
inhouse period (Day -2) - obligatory. If the Investigator suspects possible COVID-19 infection, the 
IgG/IgM testing should also be performed prior to dose administration on Day 8 or/and prior to second 
inhouse period (Day 19) or/and Day 43. The serology will be performed onsite. 
The Investigator’s decision on COVID-19 infection should be based on patient’s contacts, travels, 
presence or absence of any complaints, signs and symptoms suspicions for COVID-19 infection, local 
circumstance, or any other conditions if applicable.  
The Safety Follow-up Visit on Day 99 ±7 days is scheduled at approximately 3 × OKZ terminal half-life 
(t1/2). Subjects who discontinue the study early, should be asked to return for an EOT (Day 29) and Safety 
Follow-up Visit (Day 99) - with exception of the cases when it is not possible such as the cases with 
COVID-19 infection when the subject will come to the visit after recovery (subject should not be 
infectious at the time of EOT and follow-up visits). There will be 2 additional telephone follow-up calls, 
with the subject, on Day 130 ±7 days and Day 161 ±10 days (End of Study [EOS]) after the EOT, at 
approximately 4 × OKZ t1/2 and 5 × OKZ t1/2, respectively. 
Number of Investigators and Study Centers: 
Approximately 3 Investigators and study centers are expected to participate in this study. 


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Protocol CL04041026 – Amendment 3 
 
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Number of Subjects: 
Twelve evaluable subjects will be required to complete this study. It is estimated that 15 subjects who 
meet the study eligibility criteria will need be dosed in order to achieve this number. However, if 
necessary, additional subjects may be dosed to obtain the 12 evaluable subjects required. 
Treatment Groups and Duration: 
Subjects with active RA and on a stable dose of methotrexate (MTX), as defined by the inclusion and 
exclusion criteria will be included in a single treatment group. 
There will be a 35-day Screening Period, followed by a 29-day study duration and a 19-week (133-day) 
follow-up period. The duration of the study will be approximately 200 days (approximately 6 and a half 
months). 
Study Treatments Administered: 
 
Olokizumab: Sterile solution for subcutaneous (SC) injection, 128 mg (0.8 mL injection), SC 
injection 
 
Caffeine: Tablet, 100 mg, oral 
 
Warfarin: Warfarin Tablet plus vitamin K solution for intravenous injection, 10 mg and 10 mg/mL 
(vitamin K), oral 
 
Omeprazole: Tablet, 20 mg, oral 
 
Midazolam: Syrup, 2 mg/mL, oral 
Diagnosis and Main Criteria for Inclusion: 
Eligible subjects must be willing and able to give informed consent and sign an Informed Consent Form 
(ICF) to be included in the study and were: male subjects or female subjects aged ≥18 to ≤70 years of age 
with a body mass index of 18 kg/m2 to 29.9 kg/m2, inclusive, and body weight of 55 kg to 110 kg, 
inclusive, if male, and 45 kg to 100 kg, inclusive, if female. Subjects must have a diagnosis of adult onset 
RA classified by the American College of Rheumatology/European League Against Rheumatism 
(ACR/EULAR) 2010 revised classification criteria for RA (Aletaha et al, 2010) for at least 12 weeks prior 
to Screening. If the subject was diagnosed according to ACR 1987 criteria previously, the Investigator 
may classify the subject per ACR 2010 retrospectively, using available source data. Subjects must have 
received MTX, sulfasalazine, or hydroxychloroquine for at least 12 weeks prior to Day 1 and in stable 
dose for at least 6 weeks prior to Day 1 without significant AEs. Stable doses of MTX should be 10 mg to 
25 mg weekly with folic acid (at least 5 mg weekly or equivalent). No significant side effects based on the 
Investigator’s judgment should be observed during treatment by these agents. Male subjects and their 
female partners and female subjects of childbearing potential are to adhere to the contraceptive 
requirements for the study. See Appendix 6 for details regarding contraceptive requirements. 
For details on exclusion criteria see Section 5.2. 
Statistical Methods: 
Calculation of Sample Size: 
No historical data are available for the reduction in S-warfarin area under the plasma concentration-time 
curve from time zero extrapolated to the last quantifiable concentration (AUC(0-last)) following 
administration of OKZ. Hence, the following sample size computation is based on results reported for 
another compound (sirukumab) in the same class of medications as OKZ. Zhuang et al (2015), reported 
an 18% (90% confidence interval [CI]: 0.73 to 0.92), 18% (90% CI: 0.73 to 0.92), and 19% (90% CI: 
0.72 to 0.91) reduction in S-warfarin AUC(0-inf) at 1, 3, and 6 weeks, respectively, following sirukumab 
administration in 12 subjects with RA. Assuming a dropout rate of 20%, approximately 15 subjects who 
meet the study eligibility criteria should be enrolled so that 12 evaluable subjects complete the study. 
However, if necessary, additional subjects may be dosed to obtain the 12 evaluable subjects required. This 
sample size (ie, 12 evaluable subjects) will have over 95% power to determine whether a 90% CI of the 
S-warfarin AUC(0-last) ratio of the geometric mean for some timepoint after the administration of OKZ to 


CONFIDENTIAL 
Protocol CL04041026 – Amendment 3 
 
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that before OKZ administration is within the interval 80% to 125%. The power was calculated assuming a 
13% coefficient of variation (CV) for S-warfarin AUC(0-last). 
Similarly, no historical data are available for the reduction in midazolam and omeprazole AUC(0-inf) 
following administration of OKZ. Based on Zhuang et al (2015), a sample size of 12 subjects with RA 
was sufficient to describe the effect of sirukumab on the model substrates midazolam and omeprazole 
with a reduction in AUC(0-inf) of 30% (90% CI: 0.51 to 0.96) to 35% (90% CI: 0.47 to 0.89) and 37% 
(90% CI: 0.36 to 1.09) to 45% (90% CI: 0.32 to 0.96), respectively, following sirukumab administration 
in 12 subjects with RA. Similarly, the effect of tocilizumab infusion on simvastatin and omeprazole 
exposure was well described with 8 subjects (28% reduction in omeprazole AUC(0-inf)) (Zhou and 
Meibohm, 2013). No statistical powering or formal comparisons are planned for midazolam and 
omeprazole substrates. 
Caffeine is included in this study to further evaluate the effect of CYP450 modulators on this isozyme in 
subjects with RA. Again, no historical data are available for the reduction in caffeine AUC(0-inf) following 
administration of OKZ. As per Zhuang et al (2015), caffeine AUC(0-inf) was increased by 20% (90% 
CI: 0.75 to 1.91) to 34% (90% CI: 0.84 to 2.15) following sirukumab administration in 12 subjects with 
RA. This study is not powered to detect treatment differences in caffeine. 
Analysis Sets: 
The Safety Analysis Set will include all subjects who receive at least 1 dose of study treatment (cocktail 
or OKZ). Subjects will be analyzed according to the treatment they received. 
The Pharmacokinetic (PK) Analysis Set will include all subjects who receive at least 1 dose of study 
treatment (cocktail or OKZ) and have at least 1 quantifiable plasma concentration for any of the cocktail 
substrates or OKZ collected postdose without protocol deviations or events that could affect those 
concentrations. The list of protocol deviations or events that could affect the plasma concentrations will 
be finalized before the database lock from the list of all protocol deviations that occurred during the study. 
The Pharmacodynamic (PD) Analysis Set will include all subjects who receive at least 1 dose of study 
treatment (cocktail or OKZ) and who have at least 1 PD endpoint collected after cocktail or OKZ 
administration without protocol deviations or events that could affect those endpoints. The list of protocol 
deviations or events that could affect the PD endpoints will be finalized before the database lock from the 
list of all protocol deviations that occurred during the study. 
Pharmacokinetic Analysis: 
Concentrations and PK parameters for the cocktail drugs (caffeine, S-warfarin, omeprazole, and 
midazolam), and OKZ (concentration only) in plasma will be summarized using descriptive statistics. 
The natural log transformed PK parameters (maximum concentration [Cmax], AUC(0-inf), and AUC(0-last)) of 
each cocktail substrate will be analyzed using a linear mixed effects model with a fixed effect for 
treatment and a random effect for subject. Estimates of the mean difference between treatments (OKZ + 
cocktail substrate compared to cocktail substrate alone) and its associated 90% CIs will be calculated. The 
mean differences and the CIs will be back transformed to the original scale to obtain estimates of the 
geometric mean ratios and the associated 90% CIs. 
Interpretation of the results will be based on the size of the geometric mean ratios and associated 90% 
CIs. 
Pharmacodynamic Analysis: 
Interleukin-6 (IL-6) and CRP concentrations and their change from baseline (CFB) concentration values 
will be listed and summarized by scheduled collection time. 
Safety Analysis: 
All safety data will be listed and summarized including any AEs, AEs with an outcome of death, serious 
adverse events (SAEs), AEs leading to discontinuation of study treatment, 12-lead electrocardiogram 
(ECG), vital signs, physical examination results, and safety laboratory assessments. Treatment-emergent 


CONFIDENTIAL 
Protocol CL04041026 – Amendment 3 
 
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AEs (TEAEs) will be summarized by the Medical Dictionary for Regulatory Activities (MedDRA) 
Preferred Term (PT) and System Organ Class (SOC). All AEs with an outcome of death, SAEs, and AEs 
leading to discontinuation of study treatment will be summarized similarly. TEAEs will be further 
summarized by relationship to study drug and severity. 
The number and percentage of subjects testing positive for antidrug antibodies (ADAs) will be 
summarized over time. 
Data Monitoring Committee: No 
 
 


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Protocol CL04041026 – Amendment 3 
 
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1.2 
Schema 
Figure 1 
Study Schema 
 
 


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Protocol CL04041026 – Amendment 3 
 
 Page 21 of 115 
1.3 
Schedule of Activities 
Table 3 
Schedule of Activities 
Assessments 
 
 
 
 
 
 
Visit 
Scra 
3 
4 to 7b 
8 
9 
10 
11 
12 
13 to 15b 
16 
17 
18 
19 
20 
Day 
Stage 
1 
(V1) 
Stage 
2  
(V2) 
-3;-2 -1 
1 
2 
3 
4 
5 
6 
8 
9 
15 
19 
21 22 23 24 25 27 
29 
(EOT) 
43 
99 
(SFU)
130 161 
(EOS) 
Visit Window where 
applicable (days) 
-35 to -1 
 
 
 
 
 
 
 
 
 
 
 
 
 
±1 
 
 
 
 
+1 
±3 
±7 
±7 
±10 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inpatient visits 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Outpatient visits 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
X 
 
 
Telephone follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
CYP2C9, CYP2C19 
and VKORC1 
genotyping 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
current medical 
conditions 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Joint count (DAS28) 
and Patient Global 
Assessment of 
Disease Activity 
(Visual Analog Scale 
– Bullet Scale) 
 
 
 
Xc 
 
 
 
 
 
Xc 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
Protocol CL04041026 – Amendment 3 
 
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Assessments 
 
 
 
 
 
 
Visit 
Scra 
3 
4 to 7b 
8 
9 
10 
11 
12 
13 to 15b 
16 
17 
18 
19 
20 
Day 
Stage 
1 
(V1) 
Stage 
2  
(V2) 
-3;-2 -1 
1 
2 
3 
4 
5 
6 
8 
9 
15 
19 
21 22 23 24 25 27 
29 
(EOT) 
43 
99 
(SFU)
130 161 
(EOS) 
Visit Window where 
applicable (days) 
-35 to -1 
 
 
 
 
 
 
 
 
 
 
 
 
 
±1 
 
 
 
 
+1 
±3 
±7 
±7 
±10 
Weight 
 
X 
 
 
Xc 
 
 
 
 
 
Xc 
 
 
 
 
Xc 
 
 
 
 
X 
 
 
 
 
Physical 
examinationd 
X 
X 
X 
X 
 
 
 
 
 
 
Xc 
 
 
X 
 
Xc 
 
 
 
 
X 
X 
X 
 
 
Vital signse 
 
X 
 
X 
 
 
 
 
 
 
Xc 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
12-lead ECG 
 
X 
 
X 
 
 
 
 
 
 
Xc 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
FSHf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
(blood)g 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
(urine)g 
 
 
 
X 
 
 
 
 
 
 
Xc 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
TB risk 
questionnaireh 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest radiographyi 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QuantiFERON-TB 
Gold Plus 
Assessment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV serology 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBsAg, anti-HBs, 
anti-HBc, HBV 
DNA, HCV Abj 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drugs of abuse, 
cotinine, and alcohol 
screen 
 
X 
 
X 
 
 
 
 
 
 
Xc 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
Protocol CL04041026 – Amendment 3 
 
 Page 23 of 115 
Assessments 
 
 
 
 
 
 
Visit 
Scra 
3 
4 to 7b 
8 
9 
10 
11 
12 
13 to 15b 
16 
17 
18 
19 
20 
Day 
Stage 
1 
(V1) 
Stage 
2  
(V2) 
-3;-2 -1 
1 
2 
3 
4 
5 
6 
8 
9 
15 
19 
21 22 23 24 25 27 
29 
(EOT) 
43 
99 
(SFU)
130 161 
(EOS) 
Visit Window where 
applicable (days) 
-35 to -1 
 
 
 
 
 
 
 
 
 
 
 
 
 
±1 
 
 
 
 
+1 
±3 
±7 
±7 
±10 
HbA1c 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologyk 
 
Xl 
 
 
 
 
 
 
 
 
Xc 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
Chemistry panelm 
 
Xl 
 
 
 
 
 
 
 
 
Xc 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
Urinalysis 
 
Xl 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Coagulation paneln 
 
Xl 
 
X 
 
 
 
 
 
 
Xc 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
INR onlyo 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
Blood sampling for 
PGx future testing 
 
 
 
 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer cocktail 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Administer OKZ 
 
 
 
 
 
 
 
 
 
 
Xp,q 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess injection site 
reactionsr 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs/SAEss 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Concomitant and 
prior 
medications/nondrug 
therapy 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
IL-6/CRP samples 
Xt 
X 
 
 
Xc 
 
 
 
 
 
Xc 
X 
X 
 
 
Xc 
 
 
 
 
X 
 
 
 
 
Cocktail PK samplesu 
 
 
 
 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
OKZ PK samplesv 
 
 
 
 
 
 
 
 
 
 
Xc 
X 
X 
 
 
Xc 
 
X 
 
 
X 
 
 
 
 
ADAsw 
 
 
 
 
 
 
 
 
 
 
Xc 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 


CONFIDENTIAL 
Protocol CL04041026 – Amendment 3 
 
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Assessments 
 
 
 
 
 
 
Visit 
Scra 
3 
4 to 7b 
8 
9 
10 
11 
12 
13 to 15b 
16 
17 
18 
19 
20 
Day 
Stage 
1 
(V1) 
Stage 
2  
(V2) 
-3;-2 -1 
1 
2 
3 
4 
5 
6 
8 
9 
15 
19 
21 22 23 24 25 27 
29 
(EOT) 
43 
99 
(SFU)
130 161 
(EOS) 
Visit Window where 
applicable (days) 
-35 to -1 
 
 
 
 
 
 
 
 
 
 
 
 
 
±1 
 
 
 
 
+1 
±3 
±7 
±7 
±10 
COVID-19 RT-PCR 
testingx,y 
Xbb 
 
X 
 
 
 
 
 
Xz 
 
 
 
 
X 
 
 
 
 
 
 
Xaa 
Xbb 
 
 
 
COVID-19 IgM/IgG 
testingcc 
Xbb 
 
X 
 
 
 
 
 
 
 
Xbb 
 
 
Xbb 
 
 
 
 
 
 
 
Xbb 
 
 
 
Abbreviations: Ab = antibody; ADA = antidrug antibody; AE = adverse event; ALT = alanine aminotransferase; anti-HBs = hepatitis B surface antibody; 
anti-HBc = hepatitis B core antibody; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; BP = blood pressure; CK = creatine 
kinase; COVID-19 = Coronavirus disease 2019; CRP = C-reactive protein; CYP = Cytochrome P450; DAS28 = Disease Activity Score 28 joint count; DNA 
= deoxyribonucleic acid; ECG = electrocardiogram; EOS = end of study; EOT = end of treatment; FSH = follicle-stimulating hormone; GGT = gamma 
glutamyl transpeptidase; HbA1c = glycosylated hemoglobin A1c; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV Ab = hepatitis C virus 
antibody; HIV = human immunodeficiency virus; ICF = Informed Consent Form; IgG = Immunoglobulin G; IgM = Immunoglobulin M; IL-6 = interleukin-6; 
INR = international normalized ratio; OKZ = olokizumab; PK = pharmacokinetic; RBC = red blood cells; RT-PCR = reverse transcription polymerase chain 
reaction; SAE = serious adverse event; Scr = screening; SFU = safety follow-up; TB = tuberculosis; V = visit; VKORC1 = Vitamin K epOxide Reductase 
Complex subunit 1; WBC = white blood cells. WOCBP = woman of childbearing potential; WONCBP = woman of nonchildbearing potential. 
a 
The study will employ a 2-stage screening process; during the first Screening stage, assessments for genotyping, medical history with physical examination 
and FSH testing will be taken, followed approximately 3 weeks later by the second Screening stage, when the rest of the assessments will be conducted. 
The second Screening stage should not be initiated until eligibility has been confirmed during the first Screening stage. If needed, assessments can be 
performed on multiple days during the Screening stages. 
b Outpatient visits; optional inpatient stay at the discretion of Investigator and subject. 
c Predose relative to the scheduled treatment. 
d A complete physical examination will be performed at scheduled timepoints, and as needed (see Section 8.1.1). Physical examinations include but are not 
limited to respiratory infection symptoms (acute onset of cough, fever [oral temperature >37.5°C], dyspnea) and asked about contacts with suspected or 
confirmed COVID-19 cases/visiting areas where high frequency of COVID-19 are reported. 
e Vital signs include temperature, pulse rate, and BP. At Screening, BP should be done in triplicate and the mean used to assess for subject eligibility. Vital 
signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 1 BP measurement. In addition, BP and pulse also need to be 
reassessed 1 and 2 hours following OKZ administration on Day 8 (See Section 8.1.2). 
f 
Levels of FSH to be assessed in female subjects presenting as postmenopausal to determine they are of in fact postmenopausal. For inclusion into the study as 
WONCBP the FSH level at Screening should be ≥40 mIU/mL. 


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g Performed for female subjects considered as WOCBP. 
h  The questionnaire “Tuberculosis Risk Questionnaire” (see Appendix 8) should be used as a source document. At the Screening Visit, if question No. 1 (Does 
the subject have currently active TB disease or a history of active TB disease) or question No. 2 (Has the subject been in close contact [ie, sharing the 
same household, or other enclosed environment, such as a social gathering place, workplace, or facility, for extended periods during the day] with an 
individual with active TB within the past 1.5 years) of the questionnaire “Tuberculosis Risk Questionnaire for Screening Visit” is answered “Yes” the 
subject is not allowed to enter the study (see exclusion criterion No. 23, Section 5.2). 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. 
i 
Chest radiography (both posteroanterior and lateral) need not be conducted if performed within 8 weeks prior to the date of Screening and films are available 
for review. Films available at Screening or collected at Screening should be kept as source documents. 
j 
Hepatitis serology testing could be done during first stage of screening if required by the study center. HBV DNA to be tested in anti-HBc positive subjects 
only. 
k Hematology includes RBC, WBC with differential, hemoglobin, hematocrit, and platelet count (see Appendix 3 for details). 
l 
For subjects with abnormal laboratory values at Screening, 1 retest is allowed at the Investigator’s discretion within the 35-day Screening period to assess 
eligibility (see Section 8.1.4). 
m The chemistry panel includes creatinine, fasting glucose, sodium, potassium, total protein, total bilirubin, direct, and indirect bilirubin, ALT, AST, alkaline 
phosphatase, GGT, creatine kinase, albumin, and total cholesterol (see Appendix 3 for details). 
n Samples for the coagulation panel (INR, aPTT, and fibrinogen) should be collected prior to all other blood samples (see Appendix 3). 
o 
INR results should be available within 24 hours (and for the sample taken on Day 21, before cocktail administration on Day 22). 
p 
OKZ should be administered after the final S-warfarin blood sample is obtained on Day 8. Subjects will remain at the study center for at least 2 hours after 
the injection of OKZ to be assessed for onset of any systemic hypersensitivity reactions. 
q 
Only patients with a negative COVID-19 RT-PCR result may be administered the study drug. 
r 
Prior to and following OKZ administration. Additional injection site assessments may be performed at the Investigator’s discretion. 
s 
Serious AEs and AEs are reported from the signature of the ICF. 
t 
The CRP test to assess eligibility can be done during the first stage of Screening and can be repeated once during Screening, provided results arrive prior to 
the admission date. No extensions of the Screening period will be granted for missing laboratory data unless this is due to central laboratory error (after 
Sponsor approval). 
u See Table 4 for times of blood collection for the various cocktail substrates. 
v See Table 5 for times of blood collection for OKZ. 
w Neutralizing antibodies will be tested in samples that were positive for OKZ antibodies. 
x 
COVID-19 RT-PCR testing: two RT-PCR tests should be performed within approximately 36 hours (a second RT-PCR would be performed only if the first 
results are negative). 
y Sample may be taken at the local laboratory or another designated sample collection area. 
z Results for the RT-PCR tests should be available before OKZ is administered on Day 8 (a second RT-PCR would be performed only if the first results are 
negative).  
aa If a subject is withdrawn from the study due to COVID-19 and returns for the EOT Visit after recovery, out of study positive RT-PCR results will be 
acceptable, it is not necessary to repeat a negative RT-PCR test if the subject is considered recovered from COVID-19 by the local guidelines. 


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bb Only if the Investigator suspects possible COVID-19 infection. 
cc Using rapid test.


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Table 4 
Times of Blood Collection for the Cocktail Substrates 
Day 
Day 
Time (hours 
postdose) 
Midazolam 
Omeprazoleb 
Caffeineb 
S-Warfarinb 
1 
22 
Predosea 
1 
1 
1 
1 
1 
22 
0.25 (± 2 min) 
1 
1 
1 
1 
1 
22 
0.5 (± 2 min) 
1 
1 
1 
1 
1 
22 
1 (± 5 min) 
1 
1 
1 
1 
1 
22 
1.5 (± 5 min) 
1 
1 
1 
1 
1 
22 
2 (± 5 min) 
1 
1 
1 
1 
1 
22 
3 (± 5 min) 
1 
1 
1 
1 
1 
22 
4 (± 5 min) 
1 
1 
1 
1 
1 
22 
6 (± 5 min) 
1 
1 
1 
1 
1 
22 
8 (± 5 min) 
1 
1 
1 
1 
1 
22 
12 (± 5 min) 
1 
1 
1 
1 
2 
23 
24 (± 5 min) 
1 
1 
1 
1 
2 
23 
30 (± 5 min) 
 
 
1 
 
3 
24 
48 (± 2 hr) 
 
 
 
1 
4 
25 
72 (± 2 hr) 
 
 
 
1 
6 
27 
120 (± 2 hr) 
 
 
 
1 
8  
29 
168 (+1 day) 
 
 
 
1 
a Predose blood samples for cocktail substrates should be taken within 30-minutes prior to the administration of 
the cocktail substrates. 
b 
A single blood sample or separate samples may be taken at shared timepoints. 
 
 


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Table 5 
Times of Blood Collection for OKZ 
 
Time 
 
Day 
Predose 
Postdose 
OKZ 
8a 
Within 30-minutes 
 
1 
9 
 
Should be clock-matched to the 
sample on Day 8 
1 
15 
 
Should be clock-matched to the 
sample on Day 8 
1 
22 
 
Should be collected prior to the 
administration of the cocktail 
substrates 
1 
24 
 
Should be clock-matched to the 
sample on Day 22 
1 
29b 
 
Should be clock-matched to the 
sample on Day 22 
1 
a Sample collected on Day 8 should be collected within 30 min prior to OKZ administration. 
b 
A window of +1 day is allowed for this visit. 
 


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2.0 INTRODUCTION 
2.1 
Study Rationale 
Olokizumab (OKZ) is being developed by R-Pharm International for the treatment of moderately 
to severely active rheumatoid arthritis (RA). Olokizumab is a humanized (complementarity 
determining region [CDR] grafted) monoclonal antibody (mAb) of immunoglobulin (Ig) 
G4/kappa isotype, developed as an antagonist of interleukin-6 (IL-6) that is anticipated to have 
utility in a wide range of autoimmune/inflammatory conditions. 
As a consequence of co-morbidities, patients with RA, may require treatment with many 
medications which undergo metabolism through Cytochrome P450 (CYP450) enzymes and due 
to ongoing inflammation, they often have elevated cytokine levels including IL-6 in synovial 
fluid (Arend et al, 1990) and in the systemic circulation. In in vitro models, IL-6 has been found 
to suppress the activity of CYP450 enzymes (such as CYP3A, CYP2C19, CYP2C9, and 
CYP1A2) (Abdel Razzak et al, 1993) leading to reduced metabolism and therefore higher 
exposure to CYP450 substrates (Lee et al, 2010). 
It is hypothesized that drugs such as OKZ, which reduce levels of cytokines or inhibit cytokine 
signaling pathways, may reverse cytokine mediated suppression of CYP450s in patients with 
RA, resulting in normalization of CYP450 substrate plasma levels. For example the anti-IL-6 
mAb tocilizumab has been shown to normalize IL-6 induced suppression of CYP450s in vitro 
(Tocilizumab SPC, 2016) and to reduce the plasma levels of omeprazole and simvastatin 
(CYP2C19 and CYP3A substrates, respectively) in patients with RA compared to values prior to 
tocilizumab treatment. Similarly, the anti-IL-6 mAb sirukumab, reversed IL-6 mediated 
suppression of CYP3A, CYP2C19 and CYP2C9 in a cocktail study performed in patients with 
RA (Zhuang et al, 2015). 
The primary objective of the current study is to evaluate the effects of a single subcutaneous 
(SC) 128 mg injection of OKZ on the pharmacokinetics (PK) of the probe CYP450 substrates 
midazolam (CYP3A), omeprazole (CYP2C19), S-warfarin (CYP2C9) and caffeine (CYP1A2), 
in subjects with active RA. 
The subjects to be included in this study must have raised CRP levels (≥1.2 × upper limit of 
normal [ULN]) indicating active inflammation, which is necessary for the adequate 
characterization of the drug-drug interaction potential of OKZ. 
2.2 
Background 
Rheumatoid arthritis is an 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 lead to significant morbidity, and accelerated mortality (Jacobsson et al, 2007). Moderate to 


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severe RA is often treated with disease modifying antirheumatic drugs (DMARDs), with 
methotrexate (MTX) being the most commonly used. For patients with an inadequate response to 
conventional DMARDs, biologic agents which inhibit tumor necrosis factor alpha (TNF-α), 
especially in combination with MTX, are indicated (Smolen et al, 2014). Nonetheless, a 
substantial proportion of patients receiving biologics (ie, approximately 40% to 50% of those 
receiving TNF-α inhibitor [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. 
The inflammation as well as the emergence of disease-specific autoantibodies, and the 
characteristic acute phase response in RA may be explained, at least in part, by observed 
sustained IL-6 overproduction (Yoshizaki et al, 1998). Tocilizumab (TCZ), known as 
RoActemra® or Actemra®, a recombinant humanized mAb that acts as an IL-6R antagonist, has 
been approved for the treatment of moderate to severe RA (Tocilizumab SPC, 2016). 
According to the Actemra prescribing information, the following warnings exist, and precautions 
should be taken: 
 Serious Infections – do not administer Actemra during an active infection, including 
localized infections. If a serious infection develops, interrupt Actemra until the infection is 
controlled. 
 Gastrointestinal (GI) perforation – use with caution in patients who may be at increased risk. 
 Laboratory monitoring – recommended due to potential consequences of treatment-related 
changes in neutrophils, platelets, lipids, and liver function tests. 
 Hypersensitivity reactions, including anaphylaxis, and death have occurred. 
 Live vaccines – Avoid use with Actemra. 
Targeting the IL-6 pathway, either via IL-6R, or the cytokine itself, may provide a favorable 
risk-benefit profile for the treatment of a potential number of other human diseases besides RA. 
Anti-IL-6 agents offer the possibility of broad-spectrum activity across the immune mediated 
disease spectrum. Within the class of therapeutic antibodies targeting the IL-6 pathway, OKZ is 
anticipated to be potentially more potent because of its high affinity for IL-6 and its axis of 
intervention (inhibiting the interaction between IL-6 and signal transducing receptor gp130). 
Also, as OKZ is of the IgG4 isotype, it would not be expected to mediate significant levels of 
antibody-mediated complement fixation or cell-mediated cytotoxicity. 
2.2.1 
Nonclinical Data 
Olokizumab has been shown to have a high affinity for human IL-6 as determined by BIAcore 
analysis, with a corresponding dissociation constant of approximately 10 pM. Additionally, in 
vitro whole blood and cell line assays were also performed to assess the effect of OKZ on IL-6 


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signaling. Results showed that OKZ potently neutralizes IL-6-mediated effects in vitro, and no 
evidence was found that OKZ could mediate activation of the IL-6 signaling pathway. 
The PK of OKZ has been investigated in the cynomolgus monkey following either a single 
intravenous (IV) (1 and 10 mg/kg) or single SC (10 mg/kg) administration. Peak plasma levels of 
OKZ after an IV administration, infused over 2 minutes, occurred after 5 minutes and for SC 
administration, it occurred after 2 to 4 days. Plasma levels of OKZ decreased slowly after dose 
administration with a t1/2 of approximately 10 to 11 days. The bioavailability of OKZ after SC 
administration was shown to be approximately 80% compared to IV administration. 
Antibodies to OKZ were detected in monkeys after a single dose of 1 mg/kg IV or 10 mg/kg SC. 
However, no detectable levels of antibodies to OKZ were found in any plasma samples from 
animals receiving >10 mg/kg IV or 50 mg/kg SC. As the presence of OKZ in all postdose 
samples could have interfered with detection of antibodies, these results should be interpreted 
with caution. 
The pharmacodynamic (PD) properties of OKZ were assessed in both mice and cynomolgus 
monkeys. In mice, an acute phase response (measured as release of serum amyloid A [SAA]) 
induced by injection of human IL-6 was inhibited by OKZ in a dose-related manner with 
maximal inhibition noted at 0.3 mg/kg (p <0.001). 
General toxicology studies have shown that inhibition of IL-6 signaling does not result in any 
adverse effects either in animal models or formal toxicology studies. Olokizumab is well 
tolerated in the cynomolgus monkey. No target organ toxicity was noted, however, decreases in 
haptoglobin and fibrinogen levels were observed consistently for animals treated with OKZ. 
These are considered to be pharmacologically related since both haptoglobin and fibrinogen are 
acute phase proteins under the control of IL-6 (Akira et al, 1993). Despite very high doses of 
OKZ, far above those required for full target neutralization, the decrease in fibrinogen levels 
plateaued and did not interfere with coagulation and did not result in bleeding events. Decreases 
are also expected in humans, although to a lower extent and are not expected to interfere with 
coagulation. 
No deaths or early termination of OKZ-treated animals were noted in the 13/26-week toxicity 
study (doses of 20 to 200 mg/kg/week SC). Olokizumab-related effects were limited to slight 
reductions in haptoglobin and fibrinogen, slightly lower numbers of immune cells, evidence of 
decreased/delayed antibody production in response to antigen challenge, and higher thymus 
weight, all of which could be related to the pharmacology of IL-6. These changes were not 
associated with an increased rate of infection or impaired coagulation/apparent bleeding events. 
Full reversibility was not observed for all parameters by the end of the 26-week treatment-free 
period, possibly due to remaining plasma OKZ. 
In the prenatal and postnatal development in the cynomolgus monkey, the animals were well 
exposed, the treatment was well tolerated during pregnancy, and had no abortifacient effect. 


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Mortality was observed at delivery in some OKZ-treated maternal animals, without premonitory 
signs, and in some infants of OKZ-treated animals. 
The local tolerance after IV and SC administrations of OKZ was also assessed as part of the 
repeat-dose studies in the cynomolgus monkey. No macroscopic or histological changes were 
observed at the infusion or injection sites. An acute SC local tolerance study in rats comparing 
4 formulations at 2 dose levels was conducted and all injections were well tolerated. 
Olokizumab is not expected to induce drug-drug interactions. Nevertheless, as IL-6 has been 
shown to downregulate the expression and to decrease the activity of some CYP450 enzymes 
involved in the metabolism of drugs, the possibility cannot be ruled out that treatment with OKZ 
may change the metabolism rate of CYP450-metabolized drugs to levels observed in control 
conditions. A study has been conducted to evaluate the effects of OKZ on CYP450 enzymes in 
vitro (Study Number NCD2107). Data indicate that, in cryopreserved human hepatocytes, IL-6 
treatment for 48 hours resulted in a down-regulation of the activity of CYP1A1/2, CYP2B6, 
CYP2C9, CYP3A4/5, and CYP2C19 and the activity of sodium/taurocholate cotransporting 
polypeptide (NTCP). The activity of CYP2D6, organic cation transporting polypeptides (OCTPs) 
and organic anion transporting polypeptides (OATPs) was not affected. Olokizumab had no 
effects on the activity of CYP450 enzymes or the transporters NTCP, OCTPs, or OATPs. In 
contrast, OKZ reverses the inhibitory effect of IL-6 on the activity of CYP1A1/2, CYP2B6, 
CYP2C9, CYP3A4/5, and CYP2C19, and on the activity of NTCP. 
Taken together, the nonclinical data were deemed sufficient to support the clinical development 
of OKZ in humans for the treatment of moderate to severe RA, other autoimmune inflammatory 
diseases, and oncological diseases with IL-6 pathophysiology. 
2.2.2 
Clinical Data 
Eleven clinical studies with OKZ have been completed and include: 
 two Phase 1 studies (Study RA0001 in 67 male healthy volunteers [Kretsos et al 2014] and 
RA0074 in 20 male Japanese healthy volunteers); 
 a Phase 1/2a study (Study RA0010) in 40 subjects (7 males and 33 females) with RA and 
relatively low disease activity on stable doses of MTX; 
 a Phase 2 study (Study RA0056 [Genovese et al, 2014]) in 221 subjects (33 males and 186 
females) with active RA who had previously failed TNFi therapy; 
 a Phase 2b open-label extension (OLE) study to Study RA0056 (Study RA0057) in 
190 subjects (29 males and 161 females); 
 a Phase 2 study (Study RA0083 [Takeuchi et al, 2016]) in 119 Asian subjects (16 males and 
103 females) with active RA who had previously failed TNFi therapy; and 


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 a Phase 2 OLE study to Study RA0083 (Study RA0089) in 103 subjects (15 males and 
88 females); 
 a Phase 3 study (Study CL04041022) in 428 subjects (74 males and 354 females) with 
moderate to severe active RA inadequately controlled by MTX therapy (randomized to 
receive OKZ in two regimens or placebo);  
 a Phase 3 study (Study CL04041023) in 1648 subjects (365 males and 1283 females) with 
moderate to severe active RA inadequately controlled by MTX therapy (randomized to 
receive OKZ in two regimens, adalimumab or placebo);  
 a Phase 3 study (Study CL04041025) in 368 subjects with moderate to severe active RA 
inadequately controlled by TNFi therapy;  
 a Phase 2/3 study (CL04041078) in subjects with severe SARS-CoV-2 virus infection 
(COVID-19).  
Pharmacokinetic bioavailability of OKZ via SC administration was estimated to be 63% across 
the 3 studies evaluated (Studies RA0056, RA0001, and RA0010). The estimated t1/2 in Study 
RA0001 and Study RA0010 was 31 days (median). Similar PK was observed in Study RA0056. 
In CL04041022, a steady state was reached by Week 16 and Week 14 for 64 mg OKZ 
administered once every 4 weeks (q4w) and once every 2 weeks (q2w), respectively. 
Accumulation based on the geometric means ratio for AUC(0-tau) was 2.94-fold for q4w dosing 
and 3.52-fold for q2w dosing, consistent with the anticipated 1 month OKZ elimination half-life. 
Overall, across treatment groups, comparing average OKZ trough levels following q4w 
administration were approximately half those observed after q2w dosing. In CL04041023, mean 
OKZ trough concentrations, compared to the OKZ 64 mg q4w regimen, were 2.3- to 2.5-fold 
higher when OKZ was dosed q2w. In CL02021025, mean OKZ trough concentrations compared 
to the q4w regimen were 2.6- to 2.9-fold higher when OKZ 64 mg was dosed q2w. On graphical 
assessment for both CL04041023 and CL04041025 studies, steady-state appeared to be reached 
by 20 weeks post first dose in both treatment regimens. In study CL04041023, mean trough 
concentrations were up to 64% and 25% lower in the presence of ADAs for the q4w and q2w 
dosing regimens, respectively. In study CL04041025, mean trough concentrations were up to 
21% and 32% lower in the presence of ADAs assessed across timepoints for the q4w and q2w 
dosing regimens, respectively.  
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 serious adverse events (SAEs) (exacerbation of RA 
and Bowen’s disease) in Study RA0010. One subject in Study RA0010, prematurely 
discontinued the study due to an AE (exacerbation of RA symptoms), but no subjects withdrew 
from Studies RA0001 or RA0074 due to treatment-emergent AEs (TEAEs).  


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In Study RA0056, OKZ was tolerated at doses of up to 240 mg every 2 weeks (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 prematurely discontinued from the study due to 
TEAEs (10 subjects in the OKZ groups and 1 subject in the placebo group). 
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 1 subject each 
in the 60 mg (3.1%) and 240 mg (3.8%) OKZ groups. Overall, 2 subjects in the placebo group 
and 5 subjects in the OKZ groups reported a total of 9 TEAEs leading to premature 
discontinuation from the study. 
The Phase 2 open-label extension studies (Studies RA0057 and RA0089) collected additional 
data on the safety of OKZ in subjects with RA over a 48-week treatment period. In Study 
RA0057, SAEs were reported by 50 subjects (26.3%). Overall, 33 subjects reported a total of 
321 TEAEs leading to discontinuation. Three additional subjects reported AEs leading to 
permanent discontinuation of OKZ (bladder cancer, palmar pustular dermatitis, and cholecystis 
chronic). There were 2 deaths in this study (road traffic accident; necrotizing fasciitis (NF), acute 
renal failure, multi-system organ failure, and sepsis). In Study RA0089, SAEs were reported by 
14 subjects (13.6%). Overall, 7 subjects reported a total of 33 TEAEs leading to discontinuation. 
There were no deaths in this study. 
In CL04041022, OKZ was well tolerated at 64 mg q4w and 64 mg q2w doses. There was 1 death 
in this study (toxic shock syndrome) in OKZ q2w group. Less than 5% of subjects reported a 
SAE (mainly ALT increased, AST increased, rheumatoid arthritis, and subcutaneous abscess). 
Overall, 13 subjects (3.0%) reported at least 1 TEAE leading to discontinuation of study 
treatment; and 9 subjects (2.1%) reported at least 1 TEAE leading to withdrawal from the study.  
In CL04041023, OKZ was well tolerated at 64 mg q4w and 64 mg q2w doses. A total of 80 
(4.9%) subjects reported at least one treatment-emergent SAEs, with similar proportions of 
subjects with SAEs reported for the OKZ, adalimumab and placebo treatment groups. The most 
frequently reported SAEs were pneumonia (8 subjects [0.5%]), alanine aminotransferase 
increased (4 subjects [0.2%]), sepsis and urosepsis (4 subjects [0.2%]), and transaminases 
increased and hepatotoxicity (3 subjects [0.2%]). Seven subjects (0.4%) had a TEAE leading to 
death, and the incidences of death were comparable for the OKZ and placebo treatment groups. 
A total of 86 subjects (5.2%) reported at least 1 TEAE leading to discontinuation of study 
treatment; the most frequently reported TEAEs leading to withdrawal of study treatment were 
alanine aminotransferase increased, overall and transferases increased. Of the adverse events of 
special interest, Infections were reported for 534 subjects (32.5% of the safety population) 
overall, with similar proportions in each of the treatment groups. 
In CL04041025, OKZ was well tolerated at 64 mg q2w and 64 mg q4w doses. A total of 18 
subjects (4.9%) reported at least 1 treatment-emergent SAE and no TEAEs leading to death were 


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reported. Treatment emergent SAEs were reported for 6 subjects (3.2%) in the any OKZ q4w 
group, 12 subjects (7.0%) in the any OKZ q2w group, and no subjects (0.0%) in the placebo 
group. The frequency and type of SAE reported for the OKZ treatment groups were consistent 
with the SAEs reported for other OKZ clinical studies. A total of 18 subjects (4.9%) reported 
TEAEs leading to discontinuation of the study treatment. Overall, 15 subjects (4.1%) reported 
TEAEs leading to discontinuation from the study. The most frequently reported TEAEs leading 
to withdrawal of study treatment by SOC were Infections and infestations, reported for 6 subjects 
(1.6%) overall and Investigations, reported for 6 subjects (1.6%) overall. 
In CL04041078, OKZ was well tolerated; the observed OKZ safety profile was consistent with 
the profile established in previous clinical studies and there were no new findings regarding the 
safety profile of OKZ. The occurrence of TEAEs was 35.5% in the OKZ group. Among them, 
8.1% events were Grade 4 and 5. TEAEs related to the study drug were reported in 14.5% 
subjects in the OKZ group. TEAEs leading to discontinuation from the study were reported in 10 
subjects (8.1%) in the OKZ group. At least 1 treatment-emergent SAE occurred in 8.1% subjects 
in the OKZ group in this study. Among them, 8.1% events in the OKZ group were Grade 4 and 
5. Treatment emergent SAEs leading to death were reported in 7.3% subjects in the OKZ group. 
Preliminary efficacy data in terms of 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, ie, 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.  
In Study RA0056, a greater improvement in least squares (LS) mean DAS28 (CRP) from 
baseline at Week 12 was observed across all OKZ dose 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, every 4 weeks [q4w] and q2w dosing frequencies) was highly 
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. 
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 240 mg OKZ 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 dose group versus placebo 
(p <0.0001 for each dose group). The comparisons of dosing frequency (120 mg OKZ group 
[60 mg q2w versus 120 mg q4w] and 240 mg OKZ [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. 


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The Phase 2 open-label extension study to Study RA0056 (Study RA0057) collected additional 
data on the efficacy of OKZ with respect to signs and symptoms of RA. All treatment groups 
from Study RA0056 were transferred to a single treatment group of 120 mg q2w in Study 
RA0057, and efficacy was assessed at Week 12, Week 24, and Week 48. Relative to Study 
RA0057 baseline, all treatment groups (with the exception of OKZ 60 mg q4w at Week 12), 
showed a decrease in DAS28 (CRP) at Week 12, Week 24, and Week 48. Subjects switching 
from the placebo group showed a marked improvement in DAS28 (CRP), similar to the 
improvement shown by subjects in the OKZ groups in the parent RA0056 study. 
The Phase 2 open-label extension study to Study RA0083 (Study RA0089) in Japan, the 
Republic of Korea, and Taiwan collected additional data on efficacy in subjects with active RA. 
All treatment groups from Study RA0083 were transferred to a single treatment group of 120 mg 
q2w in Study RA0089, and efficacy was assessed at Week 12, Week 24, and Week 48. Relative 
to Week 0 of RA0083, there was a notable decrease in DAS28 (CRP) at Week 12, Week 24, and 
Week 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. 
Confirmatory efficacy data were obtained in CL04041022 in subjects with moderately to 
severely active RA inadequately controlled by MTX. The ACR20 response was achieved at 
Week 12 by 191 subjects (100 subjects [70.4%] in the OKZ q4w group and 91 subjects [63.6%] 
in the OKZ q2w group) in OKZ group and 37 subjects (25.9%) in the placebo group. The 
secondary efficacy endpoint of DAS28 (CRP) < 3.2 response was achieved at Week 12 by 103 
subjects (55 subjects [38.7%] in the OKZ q4w group and 48 subjects [33.6%] in the OKZ q2w 
group) in OKZ group and 5 subjects (3.5%) in placebo group.  
In CL04041023 study in subjects with moderately to severely active RA inadequately controlled 
by MTX the ACR20 response was achieved at Week 12 by 342 subjects (71.4%) of 479 subjects 
in the OKZ q4w group, 326 subjects (70.6%) of 464 subjects in the OKZ q2w group and 108 
subjects (44.4%) of 243 subjects in the placebo group. The DAS28 (CRP) < 3.2 score was 
achieved at Week 12 by 219 subjects (45.7%) in the OKZ q4w group, 210 subjects (45.3%) in 
the OKZ q2w group and 31 subjects (12.8%) in the placebo group.  
In CL04041025 study in subjects with moderately to severely active RA inadequately controlled 
by TNF-α inhibitory therapy the ACR20 response was achieved at Week 12 by 96 subjects 
(59.6%) of 161 subjects in the OKZ q4w group, 84 subjects (60.9%) of 138 subjects in the OKZ 
q2w group, and 28 subjects (40.6%) of 69 subjects in the placebo group. The DAS28 (CRP) < 
3.2 score was reported at Week 12 for 45 subjects (28.0%) in the olokizumab q4w group, 55 
subjects (39.9%) in the olokizumab q2w group, and 8 subjects (11.6%) in the placebo group.  
In CL04041078 in subjects with severe COVID-19 infection, primary efficacy results did not 
find the significant difference between treatment groups: there were 98 subjects (79.0%) of 
124 subjects in the OKZ group classified as responders. The OKZ/placebo RR was 1.125 (one-


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sided 97.5% CI: 0.989; ∞) (adjusted p=0.073). Analysis of secondary endpoints as well as 
exploratory endpoints also did not show the clinically significant difference in term of clinical 
outcomes and biomarkers levels. Mortality by Day 29 was 7.3% subjects in the OKZ group and 
4.8% subjects in the placebo group. Relative risk for mortality: OKZ group/placebo group – 1.50 
(two-sided 95% CI: 0.55; 4.09). Based on the study results it was concluded that OKZ does not 
contribute to improving the clinical status (relative to the respiratory system function) or 
mortality rates in patients with severe COVID-19, however, the potential benefit in relation to 
other clinical outcomes requires elucidation in further clinical studies. 
A Phase 3 OLE study (Study CL04041024) in subjects with active RA previously completed 
CL04041022, CL04041023 or CL04041025 study are currently ongoing. According to the 
interim analysis of this study data OKZ is well tolerated at 64 mg q4w and 64 mg q2w doses. As 
of interim data cut-off date, there were 11 subjects (0.6%) that had a TEAE leading to death. The 
incidence rate was similar in all treatment sequence groups: 6 receiving the OKZ 64 mg q4w 
regimen and 5 receiving the OKZ 64 mg q2w regimen. One subject had a TEAE leading to death 
(completed suicide) that was assessed as related to study treatment by the Investigator; this 
subject had received adalimumab during the CL04041023 study followed by OLE OKZ 64 mg 
q4w. A total of 149 subjects (8.3%) reported at least 1 treatment-emergent SAE; 75 subjects 
(8.6%) in the OKZ q4w OLE group and 74 subjects (8.1%) in the OKZq2w OLE group. The 
most frequently reported SAEs by preferred term were ALT increased, reported for 9 subjects 
(0.5%), pneumonia reported for 8 subjects (0.4%), and cellulitis reported for 7 subjects (0.4%), 
and osteoarthritis reported for 6 subjects (0.3%). Confirmatory efficacy data derived by interim 
analysis shows the ACR20 response achievement at Week 52 by 341 subjects (148 subjects 
[16.7%] of 887 subjects in the OKZ q4w group and 193 subjects [21.5%] of 898 subjects in the 
OKZ q2w group) of total 1785 subjects in OKZ group. The DAS28 (CRP) < 3.2 response was 
achieved at Week 52 by 1153 subjects (575 subjects [64.8%] of 887 subjects in the OKZ q4w 
group and 578 subjects [64.4%] of 898 subjects in the OKZ q2w group) of total 1785 subjects in 
olokizumab group.  
One more Phase 3 open-label randomized, comparative, parallel group, active controlled study in 
patients with moderate coronavirus infection (CL040401094) are currently ongoing. 
The Phase 3 studies program includes efficacy and safety evaluations designed to demonstrate 
that OKZ can be used in a wide range of autoimmune/inflammatory conditions and to support 
marketing approval. 
2.2.3 
Pharmacokinetic Drug Interactions 
Drug interactions with OKZ have not been investigated in clinical studies. 
Hepatic CYP450 enzyme expression is known to be suppressed by IL-6 overproduction in 
subjects with inflammatory conditions (Aitken and Morgan, 2007; Carcillo et al, 2003; Frye et 
al, 2002). In vitro studies demonstrated that OKZ dose-dependently reversed IL-6-induced 


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suppression of the activities of the assayed CYP450 enzymes (ie, CYP1A1/2, CYP2B6, 
CYP2C9, CYP2C19, and CYP3A4/5) and of the bile acid transporter NTCP (see Section 5.2.4 of 
the IB). These findings suggest OKZ, via antagonism of IL-6, may restore the normal 
constitutive expression (and activity) of CYP450s and NTCP which had been previously 
suppressed in subjects with RA. As such, OKZ treatment may lead to a change in the systemic 
concentration and/or effect of coadministered drugs which are metabolized via the CYP450 
enzymes and/or NTCP. These drugs include, but are not limited to, certain ‘statins’ (ie, 
3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors), calcium channel blockers, oral 
contraceptives, benzodiazepines, as well as theophylline, warfarin, phenytoin, and cyclosporine. 
Accordingly, while a subject is on OKZ treatment, close attention should be paid to the 
effectiveness or toxicity of their coadministered medication(s) known to be 
metabolized/eliminated by CYP1A1/2, CYP2B6, CYP2C9, CYP2C19, CYP3A4/5, and NTCP, 
and dose adjustments of concomitant medication(s) might be needed. Given the long elimination 
t1/2 of OKZ, any such effects of OKZ on the expression of metabolizing enzymes and NTCP may 
persist for up to 4 months after the last administration of OKZ or until IL-6 concentrations 
become elevated. 
This Phase 1, open-label drug-drug interaction study is planned to assess the effect of OKZ on 
the PK of substrates for CYP1A2, CYP2C9, CYP2C19, and CYP3A4 in subjects with RA. 
2.3 
Benefit/Risk Assessment 
Olokizumab has undergone extensive nonclinical testing, and 11 clinical studies have been 
completed. In the difficult-to-treat population of subjects with RA who previously failed TNFi 
therapy, OKZ has demonstrated efficacy in 2 Phase 2 studies (Study RA0056 [extended with 
Study RA0057] in 221 subjects and Study RA0083 [extended with Study RA0089] in 119 Asian 
subjects). The efficacy of OKZ was further confirmed in subject population with moderate to 
severe active RA inadequately controlled by MTX therapy in CL04041022 (428 subjects) and 
CL04041023 (1648 subjects) studies as well as in 368 subjects with moderate to severe active 
RA inadequately controlled by TNFi therapy in the CL04041025 study. In the ongoing 
CL04041024 OLE study the long-term efficacy is shown preliminary by interim analysis results.  
The completed clinical studies to date suggested that OKZ is effective in reducing disease 
symptoms in subjects with RA, compared with placebo, and that it is generally well tolerated (for 
further efficacy and safety information, refer to the most recent version of the IB). The safety 
profile of OKZ is consistent with the known effects of IL-6 blockers. Overall, the benefit/risk 
profile for subjects in this proposed study is favorable. 
The design of this study contains adequate measures to mitigate risk factors and adequate safety 
monitoring to protect the subjects. 
Taking the nonclinical and clinical data for OKZ into consideration, subjects should be 
monitored during clinical studies for potential AEs of infections and decreases in fibrinogen. In 


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addition, based on the mechanism of action of OKZ, subjects should be observed for events of 
dyslipidemia, increased liver transaminases and bilirubin, and decreases in neutrophils, which 
may be possible class effects (see Section 7.4.6.3 of the IB). 
2.3.1 
Expected Adverse Events and Reference Safety Information 
From the safety data available to date, the following AEs are considered expected: 
 Liver function test abnormalities (Medical Dictionary for Regulatory Activities [MedDRA] 
Preferred Terms [PTs] included alanine aminotransferase [ALT] increased, aspartate 
aminotransferase [AST] increased, and liver function tests [LFT] abnormal); 
 Elevations in total cholesterol, low-density lipoproteins (LDL), and triglycerides (MedDRA 
PTs included blood cholesterol increased, blood triglycerides increased, and 
hypertriglyceridemia); 
 Reductions in neutrophil count (MedDRA PTs included neutropenia, neutrophil count 
decreased, leukopenia, and white blood cell count decreased); 
 Increased incidence of infection (MedDRA PTs included influenza, nasopharyngitis, upper 
respiratory tract infections, and urinary tract infection); and 
 Injection site reactions (MedDRA PTs included injection site erythema, injection site 
hematoma, injection site pruritus, and injection site reaction). 
2.3.2 
Anticipated Adverse Effects 
Drug-class-related and disease-related events will be reported according to the Final Rule for 
Investigational New Drug Safety Reporting Requirements for Human Drug and Biological 
Products and Safety Reporting Requirements for Bioavailability and Bioequivalence Studies in 
Humans (21 CFR Parts 312 and 320, 2011). 
Drug Class-related Effects 
Subjects treated with an IL-6 inhibitor should be aware that they may be at increased risk of 
experiencing the following events, which are PTs (unless otherwise specified) listed by System 
Organ Class (SOC): 
1. Gastrointestinal disorders 
a) Diverticular perforation 
2. Hepatobiliary disorders 
a) Any liver enzyme increase (medical judgment, not per MedDRA) 
3. Immune system disorders 
a) Anaphylactic reaction 
b) Hypersensitivity 
c) Drug hypersensitivity 
4. Infections and infestations 
a) Any infection (including serious infection) is anticipated, including, but not limited to: 


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i) Pneumonia, cellulitis, herpes zoster, urinary tract infection, sepsis, gastroenteritis, 
upper respiratory tract infections, tuberculosis; 
ii) Opportunistic infections (eg, candidiasis, listeriosis, histoplasmosis, 
coccidioidomycosis, paracoccidioidomycosis, pneumocystis, nontuberculous 
mycobacteria, blastomycosis, or aspergillosis); and 
iii) Necrotizing fasciitis. 
5. Investigations 
a) Neutrophil count decreased 
b) Platelet count decreased 
c) Any PT suggesting an elevation of blood lipid (medical judgment, not per MedDRA) 
6. Vascular disorders 
a) Vascular hypertensive disorders (high-level term) not elsewhere classified (NEC) 
The administration of products that contain protein may be associated with immunologic/allergic 
or nonimmunologic drug hypersensitivity reactions that could be severe. These reactions can 
occur as acute infusion, allergic, or delayed-type hypersensitivity reactions. Therefore, 
Investigators should only administer OKZ where medication and equipment for management of 
anaphylactic or anaphylactoid reactions are available. While injection site reactions have 
occurred, there have been no serious or severe systemic hypersensitivity reactions observed in 
the completed clinical studies to date. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of OKZ may be found in the IB. Details on the rationale for the study design, 
including dose selection, study-specific restriction such as food restrictions and selection of the 
study population is discussed in Section 4.2. 
The Sponsor will immediately notify the Principal Investigator if any additional safety or 
toxicology information becomes available during the study. 
This study will be performed in compliance with the protocol, International Council for 
Harmonisation (ICH) Good Clinical Practice (GCP) and applicable regulatory requirements. 
Aspects of the study concerned with the investigational medicinal product(s) will meet the 
requirements of European Union – Good Manufacturing Practice (EU GMP), ICH E6 GCP, 
Consolidated Guideline, current revision and all applicable laws and regulations, including, 
without limitation, data privacy laws, clinical trial disclosure laws, and regulations, as well as 
Order No. 200n dated April 01, 2016 of the Ministry of Health of the Russian Federation on 
Approval of Rules for GCP. 


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3.0 OBJECTIVES AND ENDPOINTS 
Table 6 
Study Objectives and Endpoints 
Objectives 
Criteria for Evaluation (Endpoints) 
Primary 
 
 
To assess the effect of olokizumab (OKZ) on the 
pharmacokinetics (PK) of the Cytochrome P450 
(CYP450) probe substrates, caffeine (CYP1A2), 
S-warfarin (CYP2C9), omeprazole (CYP2C19), 
and midazolam (CYP3A4) in subjects with 
rheumatoid arthritis 
Primary 
 
Area under the plasma concentration-time curve 
(AUC) from time zero to infinity (AUC(0-inf)) for 
caffeine, omeprazole, and midazolam 
 
AUC from time zero to the time “t” of the last 
quantifiable concentration (AUC(0-last)) for 
S-warfarin 
 
Maximum plasma concentration (Cmax) for all 
cocktail substrates 
Secondary 
 
Plasma AUC(0-last) or AUC(0-inf) (if not primary), 
time to maximum plasma concentration (tmax), 
terminal half-life (t1/2), elimination rate constant 
(λz), apparent systemic clearance (CL/F), and 
apparent volume of distribution (Vz/F) for cocktail 
parent compounds (caffeine, S-warfarin, 
omeprazole, and midazolam) 
 
Plasma concentrations for OKZ 
Secondary: Safety 
 
 
To assess the safety and tolerability of the cocktail 
substrates when dosed in the presence or absence 
of OKZ 
 
To assess the safety and tolerability of a single 
dose of OKZ in subjects with rheumatoid arthritis 
 
 
Assessment of adverse events (AEs), graded by 
Common Terminology Criteria for Adverse 
Events (CTCAE), physical examination, vital 
signs (blood pressure, pulse rate, and body 
temperature), standard 12-lead electrocardiogram 
(ECG), evaluation of laboratory parameters 
(clinical chemistry, hematology, and coagulation), 
and immunogenicity 
Secondary: Pharmacodynamic 
 
 
To assess the effect of OKZ on inflammatory 
markers (pharmacodynamics [PD]) in subjects 
with rheumatoid arthritis 
 
Interleukin-6 (IL-6) and C-reactive protein (CRP) 
concentrations collected periodically throughout 
the study 
 
 
 


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4.0 STUDY DESIGN 
4.1 
Overall Design 
This is a Phase 1, open-label, 3-period, single-sequence, crossover study in subjects with RA 
with increased C-reactive protein (CRP) (≥1.2 × upper limit of normal [ULN]). During the study, 
subjects will be administered a cocktail of 4 substrates alone (Period 1) and in the presence of 
OKZ (Period 3). A single dose of 128 mg OKZ will be administered (Period 2) approximately 
2 weeks prior to the second administration of the cocktail in Period 3. The cocktail comprises 
100 mg caffeine (substrate of CYP1A2), 10 mg warfarin (containing 5 mg S-warfarin [substrate 
of CYP2C9]) plus 10 mg vitamin K, 20 mg omeprazole (substrate of CYP2C19), and 2 mg 
midazolam (substrate of CYP3A4) and will be administered after an overnight fast of at least 
10 hours (Turpault et al, 2009). Serial blood samples will be collected to determine the PK of the 
cocktail substrate analytes and OKZ. Blood sampling for the measurement of IL-6 and CRP will 
also be performed. 
Subjects will be screened within 35 days of the first dose administration and eligible subjects 
will be admitted to the study center on Day -1. The study will employ a 2-stage screening 
process; during the first Screening stage, assessments for genotyping, medical history with 
physical examination and FSH testing will be performed, as well as possibly the hepatitis 
serology and CRP screening assessments, if required by the study center. This will be followed 
approximately 3 weeks later by the second Screening stage, where the rest of the assessments 
will be conducted. 
If a subject has a history of confirmed coronavirus disease 2019 (COVID-19) in the previous 3 
months before Day 1 (or with sever or critical illness ever) or known exposure to an individual 
with confirmed COVID-19 or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
infection within the past 2 weeks and it is revealed at the Screening Visit or prior to cocktail 
administration on Day 1, the subject should not be administered the study treatment, and further 
testing for COVID-19 is not required. In case a patient shows respiratory symptoms or informs 
the Investigator about contact with a COVID-19 infected person after drug administration the 
test for COVID-19 should be performed as soon as possible. Out of study positive RT-PCR 
results will be acceptable as well as following negative results, it is not necessary to repeat RT-
PCR test in the site if the subject is considered recovered from COVID-19 by the local 
guidelines. If the Investigator suspects that a subject has contracted COVID-19, the Investigator 
should request feedback from the medical monitor and discuss this with the Sponsor. 
Subjects whom tests positive for COVID-19 during the treatment period but before OKZ is 
administered (Day 8) will not be administered with OKZ and will be discontinued from the 
study. These subjects will however attend the End of Treatment (EOT) Visit after their recovery 
and the Safety Follow-up Visit. Subjects whom are dosed with OKZ (Day 8) and then tests 
positive for COVID-19 should attend the EOT Visit (Day 29) as well as the Safety Follow-up 


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Visit based on local guidelines for COVID-19 on Day 99 - with exception of the cases when it is 
not possible such as the cases with COVID-19 infection when the subject will come to the visit 
after recovery (subject should not be infectious at the time of EOT and follow-up visits) - and 
afterwards telephonic follow-up visits until 5 × OKZ t1/2. 
It is estimated that 15 subjects who meet the study eligibility criteria will need to be dosed in 
order to achieve the required 12 evaluable subjects. However, if necessary, additional subjects 
may be dosed to obtain the 12 evaluable subjects required. 
On the morning of Day 1 after an overnight fast of at least 10 hours, subjects will receive the first 
treatment of the cocktail: 100 mg caffeine, 20 mg omeprazole, 10 mg warfarin, 2 mg midazolam 
(via syringe) followed by 10 mg vitamin K (via syringe [Zhuang et al, 2015]), orally, under the 
supervision of appropriately trained study center staff. The cocktail will be administered with 
240 mL of water and all 4 cocktail substrates as well as the vitamin K should be ingested within 
5 minutes (for details regarding study treatment administration, see Section 6.1). 
Subjects will remain in the study center until Day 2 and will be discharged at the Investigator’s 
discretion (ie, providing there are no safety concerns) after the 30-hour PK sample. Subjects will 
return to the study center on Day 3, Day 4, Day 6, and Day 8 for PK sampling (see Table 4 for 
PK sampling times). 
On completion of the 7-day PK sampling period for the cocktail substrates on the morning of 
Day 8, subjects will be administered a single subcutaneous (SC) dose of 128 mg OKZ. All 
subjects will remain at the study center for at least 2 hours after the injection to be assessed for 
any systemic hypersensitivity reactions. Blood samples for determination of OKZ concentrations 
will be collected on Day 8 (predose [30-minute window allowed], along with the final PK 
sample collection for warfarin), Day 9, and Day 15. Subjects will attend the study center on an 
outpatient basis on Day 8, Day 9, and Day 15. 
Subjects will be admitted to the study center on Day 21 and will receive the second 
administration of the cocktail substrates after an overnight fast of at least 10 hours on Day 22 (ie, 
14 days after administration of OKZ, by which time maximum suppression of CRP is expected). 
Subjects will remain in the study center until the 30-hour PK samples (caffeine) have been taken 
on Day 23 and will return to the study center on Day 24, Day 25, Day 27, and Day 29 (EOT) for 
scheduled PK sampling (warfarin) (see Table 4 for PK sampling times). Blood sampling for 
determination of OKZ concentrations will be collected on Day 22 (prior to cocktail 
administration) and on Day 24 and Day 29 (see Table 5 for PK sampling times). 
The IL-6 and CRP levels will be measured at Screening, prior to dose administration with the 
cocktail substrates on Day 1, prior to administration with OKZ on Day 8, and post OKZ 
administration on Day 9, Day 15, Day 22 (prior to dose administration of the cocktail), and 
Day 29, which will be considered the EOT Visit. Safety assessments will be performed at the 
EOT Visit (Day 29). 


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Subjects will be undergoing COVID-19 reverse transcription polymerase chain reaction 
(RT-PCR) testing. Two RT-PCR tests will be conducted, the second RT-PCR test will only be 
performed if the first test results are negative. Only subjects with a negative COVID-19 RT-PCR 
test result may be included in the study. Two consecutive RT-PCR tests will occur at Day -35 
(Stage 1) - only if the Investigator suspects possible COVID-19 infection, at Day -3, Day 5, Day 
19 and Day 29 (EOT) - obligatory. If the Investigator suspects possible COVID-19 infection, the 
RT-PCR tests should also be performed on Day 43. Only subjects with a negative COVID-19 
RT-PCR test result may be administered the study drug on Day 8. The RT-PCR testing will be 
performed at local laboratories. 
A rapid test will be conducted for the COVID-19 immunoglobulin G (IgG)/immunoglobulin M 
(IgM) testing at Screening–Stage 1 - only if the Investigator suspects possible COVID-19 
infection, and prior to first inhouse period (Day -2) - obligatory. If the Investigator suspects 
possible COVID-19 infection, the IgG/IgM testing should also be performed prior to dose 
administration on Day 8 or/and prior to second inhouse period (Day 19) or/and Day 43. The 
serology will be performed onsite. 
The Investigator’s decision on COVID-19 infection should be based on patient’s contacts, 
travels, presence or absence of any complaints, signs and symptoms suspicions for COVID-19 
infection, local circumstance, or any other conditions if applicable. 
The Safety Follow-up Visit on Day 99 ±7 days is scheduled at approximately 3 × OKZ terminal 
half-life (t1/2). Subjects who discontinue the study early, should be asked to return for an EOT 
and Safety Follow-up Visit - with exception of the cases when it is not possible such as the cases 
with COVID-19 infection when the subject will come to the visit after recovery (subject should 
not be infectious at the time of EOT and follow-up visits). There will be 2 additional telephone 
follow-up calls, with the subject, on Day 130 ±7 days and Day 161 ±10 days after the EOT, at 
approximately 4 × OKZ t1/2 and 5 × OKZ t1/2, respectively. 
4.2 
Scientific Rationale for Study Design 
Olokizumab has been shown to reverse the inhibitory effect of IL-6 on the activity of CYP450 
isozymes CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4/5, and on the activity of NTCP 
in vitro (Study NCD2107). 
To support the registration of OKZ, R-Pharm proposes a single-cocktail drug-drug interaction 
study design in subjects with RA to evaluate any potential effects of OKZ on the metabolism of 
substrates selective for specific CYP450 activity. The following probe substrates will be studied 
in the planned cocktail study: caffeine (CYP1A2), S-warfarin (CYP2C9), omeprazole 
(CYP2C19), and midazolam (CYP3A4). The planned substrates are specific for the indicated 
CYP450 isozymes, and a previous study has shown that there were no interactions between the 
individual substrates when administered in combination as cocktail (Turpault et al, 2009). 


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Currently, there are no plans to study CYP2B6 or NTCP. Study NCD2107 showed in vitro that 
the effect of OKZ on recombinant human IL-6-mediated suppression of CYP2B6 activity was 
similar to that of CYP2C19 and CYP3A4 activity, and less effect compared with CYP2C9 
activity. Therefore, results from the planned cocktail study for CYP1A2, CYP2C19, CYP2C9, 
and CYP3A4 are expected to be representative for the spectrum of potential reversal of the 
inhibitory effect of IL-6 on CYP450 activity. 
The fasting restrictions are based on those typically used for healthy volunteer studies and are in 
general based on the FDA Guidance for Bioavailability and Bioequivalence Studies (FDA 
Guidance for Bioavailability and Bioequivalence Studies). 
The proposed study will be conducted in subjects with RA as it is not possible to assess the 
reversal of IL-6-induced suppression in healthy subjects with normal IL-6 levels. As there is an 
inverse correlation between IL-6 or CRP levels and CYP450-metabolized drug clearance 
(Rivory et al, 2002; Frye et al, 2002; Machavaram et al, 2013), a threshold CRP (ie, ≥1.2 × ULN) 
will be utilized as an inclusion criterion. This will ensure that the selected RA population is 
sufficiently sensitive to any potential cytokine-modulating activity of OKZ. 
A single dose of 128 mg OKZ has been selected. This design limits the exposure of subjects with 
RA to a single dose treatment, where there is no prospect of direct therapeutic benefit. 
Given similar human and cynomolgus monkey physiology during pregnancy, and the observed 
increased risk of dystocia and hemorrhage at delivery, inhibition of IL-6 signaling during 
pregnancy is not recommended. Therefore, female subjects of childbearing are eligible to 
participate in this study only if they continue to have negative pregnancy test and agree to use a 
highly effective contraception methods (see Appendix 6) during the study starting from the 
screening (signed ICF) and for 6 months after OKZ dosing (irrespectively if the subject 
continues the study till end of study (EOS) visit per protocol or not). 
Justification for Dose 
It has been previously demonstrated that a single dose of a cytokine modulator can reverse IL-6 
mediated suppression of CYP450 activity (Schmitt et al, 2011; Zhuang et al, 2015; 
Zhou & Meibohm, 2013). Administration of a SC dose of OKZ at 1 mg/kg was associated with 
maximum CRP suppression (Study RA0010) obtained at 14 days postdose. At this dose, a 
maximum reduction in IL-6 was observed on Day 28 (first postdose IL-6 sample collection in 
Study RA0010), and suppression was maintained through the final IL-6 sample collection on 
Day 84. Olokizumab Cmax following a dose of 1 mg/kg SC ranged from 3.19 to 12.5 μg/mL 
(geometric mean: 6.29 μg/mL) and occurred at a median time to Cmax (tmax) of 313 hours (range: 
48.0 to 648 hours). Olokizumab concentrations will be measured periodically throughout the 
study. 


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Due to an increase in the concentration of the formulation, it should be noted that the volume 
used in this Phase 1 study (0.8 mL) results in a dose of 128 mg rather than 120 mg. This change 
will allow the objectives of the study to be met and it was not expected that there should be an 
impact on safety of the subjects. 
The planned single dose of 128 mg OKZ exceeds the OKZ dose which previously elicited full 
CRP and IL-6 suppression. Olokizumab was well tolerated at repeat SC doses of up to 240 mg 
q2w over a maximum dosing period of 12 weeks, or 120 mg q2w over a maximum dosing period 
of 48 weeks. Olokizumab doses in the Phase 3 program were 64 mg q4w and 64 mg q2w (ie, 
64 and 128 mg/month). Based on an approximate half-life of 31 days, an approximately 2.1-fold 
to 3.7-fold OKZ accumulation is anticipated for the q4w and q2w regimens, respectively; hence 
exposure following a single dose of 128 mg approximates that of the lower 64 mg q4w dose. 
Because maximum IL-6 suppression is anticipated at the 128 mg OKZ dose, it is considered 
sufficiently high to adequately characterize potential cytokine modulating activity by OKZ. 
Assessment of the potential reversal of IL-6-mediated down-regulation of CYP450 activity by 
OKZ will be evaluated once, 14 days after OKZ administration. This schedule coincides with full 
CRP suppression (Study RA0010). The scheduled cocktail coadministration is close to the 
median tmax observed following 1 mg/kg SC OKZ but is later than the median tmax observed 
following 3 g/kg SC OKZ (171 hours [range: 144 to 478 hours]). Cocktail administration 14 days 
after the OKZ dose has been selected to ensure that the maximum effect of OKZ on CYP450 
activity is evaluated, based on CRP and IL-6 suppression, and to allow time for CYP450 
upregulation, especially for CYP3A4. R-Pharm considers a single timepoint comparison to be 
sufficient. It is anticipated that OKZ reversal of CYP450 activity suppression will be maintained 
for at least 3 to 4 × the half-life of OKZ. Any evaluation of the duration of the effect of OKZ on 
CYP450 activity would pose an undue burden on the subjects dosed in this study. 
4.3 
End of Study Definition (Clinical Part) 
The end of the study is defined as the date of the last scheduled procedure, ie, telephonic 
follow-up on Day 161 ±10 days, shown in the Schedule of Activities (SoA) (see Table 3) for the 
last subject in the study globally. 
4.4 
Dose Escalation Criteria 
Not applicable. 
 


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5.0 STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
a protocol waiver or exemption, is not permitted. 
Approximately 15 eligible subjects will be enrolled at approximately 3 study centers to have at 
least 12 evaluable subjects completing the study. However, if necessary, additional subjects may 
be dosed to obtain the 12 evaluable subjects required. Participating subjects should have a 
diagnosis of RA and be on a stable dose of MTX (see inclusion criterion #5). 
5.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
1. Subjects willing and able to give voluntary informed consent and sign an Informed 
Consent Form (ICF). 
2. Male or female subjects aged ≥18 to ≤70 years of age. 
3. Male subjects and their female partners and female subjects of childbearing potential* 
must agree to adhere to the contraceptive requirements for the study (see Appendix 6).  
*Female subjects of nonchildbearing potential must be: 
a. Surgically sterile (ie, documented bilateral tubal ligation or removal of both 
ovaries and/or uterus at least 6 months prior to first dosing), or 
b. Naturally postmenopausal (spontaneous cessation of menses) for at least 
24 consecutive months prior to first dosing, with a follicle-stimulating hormone 
level at Screening of ≥40 mIU/mL. 
4. Body mass index of 18 kg/m2 to 29.9 kg/m2, inclusive, and body weight of 55 kg to 
110 kg, inclusive, if male, and 45 kg to 100 kg, inclusive, if female. 
5. Subjects must have a diagnosis of adult onset RA classified by the American College of 
Rheumatology/European League Against Rheumatism (ACR/EULAR) 2010 revised 
classification criteria for RA (Aletaha et al, 2010) for at least 12 weeks prior to 
Screening. If the subject was previously diagnosed according to ACR 1987 criteria, the 
Investigator may classify the subject per ACR 2010 retrospectively, based on medical 
history, and using available source data. 
6. Subjects must have received MTX, sulfasalazine, or hydroxychloroquine for at least 
12 weeks prior to Day 1 and in stable dose for at least 6 weeks prior to Day 1 without 
significant AEs. Stable doses of MTX should be 10 mg to 25 mg weekly with folic acid 
(at least 5 mg weekly or equivalent). No significant side effects based on the 


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Investigator’s judgment should be observed during treatment by these agents. The 
maximum allowed doses of sulfasalazine and hydroxychloroquine are: 
a. Sulfasalazine: 3 g per day 
b. Hydroxychloroquine: 400 mg per day 
Note: The doses should remain stable and not be changed from the time of signing the 
ICF until the end of the treatment period (EOT, Day 29). 
7. Subjects must have an increased CRP at Screening (of ≥1.2 × ULN). 
8. Female subjects of childbearing potential must have negative pregnancy test at Screening 
and throughout the study until the end of study (EOS, Day 161). 
5.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
1. Diagnosis of any other inflammatory arthritis or systemic inflammatory disease (eg, gout, 
psoriatic or reactive arthritis, Crohn’s disease, Lyme disease, juvenile idiopathic arthritis, 
or systemic lupus erythematosus). Osteoarthritis is classified as a degenerative disease 
rather than an inflammatory disease. 
2. Subjects with Steinbrocker Class III or IV functional capacity (incapacitated, largely, or 
wholly bed ridden, or confined to a wheelchair, with little, or no self-care). 
3. Prior exposure to any licensed or investigational compound directly or indirectly 
targeting IL-6 or IL-6R within 12 months of Day 1. 
4. Treatment with DMARDs other than MTX, hydroxychloroquine, or sulfasalazine. 
Treatment with the following DMARDs are not allowed within the specified time period 
prior to Day 1: 
a. 4 weeks for azathioprine, cyclosporine, chloroquine, gold, penicillamine, 
minocycline, or doxycycline. 
b. 12 weeks for leflunomide unless the subject has completed the following 
elimination procedure at least 4 weeks prior to Day 1: Cholestyramine at a dosage 
of 8 grams 3 times daily for at least 24 hours or activated charcoal at a dosage of 
50 grams 4 times a day for at least 24 hours. 
c. 24 weeks for cyclophosphamide. 
5. Treatment with any cell-depleting therapies including anticluster of differentiation 
(CD)20 or investigational agents (eg, CAMPATH®, anti-CD4, anti-CD5, anti-CD3, and 


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anti-CD19) with the exception of rituximab. Treatment with rituximab is not allowed 
within 6 months of Day 1. 
6. Treatment with TNFi (including investigational proposed or licensed biosimilars) or any 
other biologic therapy for the treatment of RA within 12 weeks of Day 1. 
7. Use of parenteral or intra-articular glucocorticoids within 4 weeks prior to Day 1. 
8. Use of oral glucocorticoids greater than 10 mg/day prednisone (or equivalent) or change 
in dosage within 4 weeks prior to Day 1. 
9. Use of indomethacin and ketorolac; other nonsteroidal anti-inflammatory drugs 
(NSAIDs) (with the exception of aspirin, see below) must be taken at a stable dose and 
route of administration for at least 2 weeks prior to Day 1. 
10. Female subjects of nonchildbearing potential taking hormone replacement therapy within 
4 weeks prior to Day 1. 
11. Vaccination with live vaccines in the 6 weeks prior to Day 1 or planned vaccination with 
live vaccines during the study. 
12. Participation in any other investigational drug study within 30 days or 5 times the t1/2 of 
the investigational drug, whichever is longer, prior to Day 1. 
13. Use of aspirin or other antiplatelet agents and anticoagulants including warfarin in the 
4 weeks prior to Day 1. 
14. Has received any prescription or nonprescription drugs or other products (eg, herbal 
preparations, food products) known to be inhibitors/inducers of CYP3A4, CYP2C9, 
CYP2C19, or CYP1A2 within 4 weeks prior to Day 1 and for the duration of the study up 
to the EOT (Day 29) Visit. See Appendix 4 for a list of inhibitors and inducers. The use 
of MTX, as described in inclusion criterion #5, is permitted. 
15. Use of any herbal preparations (including foods or beverages containing herbal 
preparations), dietary supplements, or natural medications within 14 days of Day 1. 
16. Has received midazolam and/or omeprazole (or esomeprazole) within 14 days of Day 1. 
17. Excessive intake of caffeine (more than 5 cups of coffee or equivalent per day) and the 
inability to abstain from caffeine-containing drinks and foods from 2 days prior to each 
cocktail administration and while inpatient (Day -1 to Day 2 and Day 21 to Day 23, 
respectively). 
18. Poor metabolizers of CYP2C9 (genotype *2/*2, *2/*3, *3/*3) or CYP2C19 (genotype 
*2/*2, *2/*3, *3/*3), ultra-rapid metabolizers of CYP2C19 (*17/*17), or high sensitivity 
to warfarin (VKORCI genotype AA). 


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19. Previous participation (enrolled) in this study or another study of OKZ in case of 
receiving at least one OKZ dose. 
20. Abnormal laboratory values as defined below. If, in the opinion of the Investigator, 
exclusionary results are due to laboratory error or a transient condition, these tests may be 
repeated once during Screening. 
a. Creatinine level ≥1.5 mg/dL (132 µmol/L) for females or ≥2.0 mg/dL 
(177 µmol/L) for males. 
b. ALT or AST level ≥1.5 × ULN. 
c. Platelets <150 × 109/L (<150,000/mm3). 
d. White blood cell count <3.0 × 109/L. 
e. Neutrophil count <2.0 × 109/L (<2,000 mm3). 
f. Hemoglobin level ≤95 g/L. 
g. Glycosylated hemoglobin (HbA1c) level ≥8%. 
h. International normalized ratio above the ULN (Normal range: 0.80 or 0.90 to 
1.20, males and females of all ages). 
21. Subjects with concurrent viral hepatitis B or C infection as detected by blood tests at 
Screening (eg, positive for hepatitis B surface antigen [HBsAg], hepatitis B DNA [HBV 
DNA] or hepatitis C virus antibody [HCV Ab]). 
a. HBV DNA to be tested only in anti-hepatitis B core antigen [anti-HBc] positive 
subjects.  
b. Subject who is positive for hepatitis B surface antibody (anti-HBs) and total anti-
HBc but negative for HBsAg and HBV DNA, will be eligible upon qualified 
specialist (i.e. hepatologist) consultation with documented conclusion no 
additional risk is suspected for the subject.  
c. Subject who is positive for hepatitis B surface antibody (anti-HBs) but negative 
for HBsAg and total anti-HBc, will be eligible with no additional consultation. 
22. Subjects with human immunodeficiency virus (HIV) infection. 
23. Subjects with: 
a. Suspected or confirmed current active tuberculosis (TB) disease or a history of 
active TB disease. 


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b. Close contact (ie, sharing the same household or other enclosed environment, 
such as a social gathering place, workplace or facility, for extended periods during 
the day) with an individual with active TB within 1.5 years prior to Screening. 
c. History of untreated latent TB infection (LTBI), regardless of QuantiFERON-TB 
Gold Plus interferon-gamma release assay (IGRA) result at Screening. 
d. Positive IGRA result at Screening. If indeterminate, the IGRA can be repeated 
once during Screening. If there is a second indeterminate result, the subject will 
be excluded. 
24. Concurrent malignancy or a history of malignancy within the last 5 years (with the 
exception of successfully treated carcinoma of the cervix in situ or successfully treated 
basal cell carcinoma or squamous cell carcinoma not less than 1 year prior to Screening 
[and no more than 3 excised nonmelanoma skin cancers within the last 5 years prior to 
Screening]). 
25. Subjects with a history of major bleeding, bleeding tendencies (such as any prior 
gastrointestinal bleeding and recent ulceration of gastrointestinal track, congenital and 
acquired disorders by hemostasis), or other clinically significant predisposition to 
bleeding according to the physician's judgment. 
26. Subjects with a history or presence of severe cardiovascular conditions such as stroke, 
transient ischemic attack, or myocardial infarction in medical history. 
27. Uncompensated congestive heart failure, or Class III, or IV heart failure defined by the 
New York Heart Association classification (see Appendix 5). 
28. Untreated, uncontrolled, or resistant arterial hypertension Grade 2 to 3 (systolic blood 
pressure [BP] >160 mm Hg and/or diastolic BP >100 mm Hg, based on the mean of 
3 readings). If hypertension is not controlled, subjects should be excluded, and not 
allowed for rescreening. 
29. Uncontrolled diabetes mellitus (based on the Investigator’s judgment). 
30. Subjects with a history or presence of any other cardiovascular, respiratory, hepatic, 
renal, gastrointestinal, endocrinological, dermatological, neurological, psychiatric, 
hematological, or immunologic/immunodeficiency disorder(s) or any other concurrent 
severe and/or uncontrolled medical condition that would, in the Investigator’s judgment, 
contraindicate subject participation in the clinical study, or clinically significant enough 
in the opinion of the Investigator to alter the disposition of the study treatment, or 
constitute a possible confounding factor for assessment of safety of the study treatment. 


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31. Subjects with gastrointestinal (GI) resection (eg, partial or total gastrectomy) likely to 
interfere with absorption of study treatment. 
32. Subjects with any infection requiring any anti-infective therapy (eg, antibiotic, antiviral, 
or antifungal therapy) in the 4 weeks prior to Day 1, or serious or recurrent infection with 
history of hospitalization in the 6 months prior to Day 1 or active infection on Day 1.  
33. Subjects with evidence of disseminated herpes zoster infection, zoster encephalitis, 
meningitis, or other nonself-limited herpes zoster infections in the 6 months prior to 
Day 1. 
34. Subjects with planned surgery during the study (up to and including the EOT Visit, 
[Day 29]) or surgery ≤4 weeks prior to Screening and from which the subject has not 
fully recovered, as judged by the Investigator. 
35. Subjects with diverticulitis or other symptomatic GI conditions that might predispose the 
subject to perforations, including subjects with a history of such predisposing conditions 
(eg, diverticulitis, GI perforation, or ulcerative colitis). 
36. History of chronic alcohol or drug abuse or consumption of more than 21 units (male 
subjects) or 14 units (female subjects) of alcohol a week (unit = 1 glass of wine [125 mL] 
= 1 measure of spirits = ½ pint of beer) as judged by the Investigator. 
37. Current smokers or those who have smoked or used nicotine products within the previous 
3 months prior to Screening. 
38. Subjects with a known hypersensitivity or contraindication to any component of the 
cocktail drugs or OKZ. 
39. History of severe allergic or anaphylactic reactions to human, humanized, or murine 
monoclonal antibodies. 
40. Any self-reported symptoms of influenza-like or COVID-19 like illness in the 14 days 
preceding Screening OR Day 1 as per the Investigators assessment. Symptoms related to 
COVID-19 include, but are not limited to: 
a. Respiratory symptoms (eg, sore throat, nasal congestion, post-nasal discharge, 
wheezing, cough, dyspnea, and bronchial breath sounds); 
b. Non-respiratory symptoms, such as gastrointestinal symptoms (eg, nausea, 
vomiting, and diarrhea), neurologic symptoms (eg, anosmia, ageusia, headache), 
myalgia or fatigue. 
41. Active SARS-CoV-2 infection as confirmed by RT-PCR or/and positive serology at 
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42. Known exposure to an individual with confirmed COVID-19 or SARS-CoV-2 infection 
within 2 weeks before Screening OR Day 1. 
43. History of COVID-19 infection in the previous 3 months before Day 1 or with sever or 
critical illness ever. 
Note: The subject can be enrolled if all of the following criteria are fulfill: 
1) had non-sever or non-critical COVID-19 infection more than 3 months before 
Day 1;  
2) fully recovered as per official medical records which should be documented as a 
source document (mild sequalae of the previous infection such as dry cough, weakness 
should be resolved by the time of Screening);  
3) there are no any concerns that the subject is infections to others;  
4) there are no any other local guidelines/requirements with regards of this group of 
subjects. 
44. Those subjects who have been at high risk of exposure before Screening, including but 
not limited to: Close contacts of confirmed COVID-19 cases, anyone who had to 
self-isolate as a result of a symptomatic household member, frontline healthcare 
professionals working in accident and emergency (A&E), ICU and other higher risk 
areas. 
45. Individuals currently working with high risk of exposure to SARS-CoV-2 (eg, active 
healthcare workers or emergency response personnel having direct interactions with or 
providing direct care to patients). 
46. Pregnancy and breastfeeding. 
47. Other medical or psychiatric conditions or laboratory abnormalities that may increase 
potential risk associated with study participation and administration of study treatment, or 
that may affect study results interpretation and, as per the Investigator's judgment. 
48. Subject's unwillingness or inability to follow the procedures outlined in the protocol. 
49. Employees or relatives of the Sponsor, Contract Research Organization, or the study 
center personnel. 
5.3 
Lifestyle Considerations 
5.3.1 
Concomitant Medications 
1. Subjects must avoid concomitant medications, herbal preparations, and/or ingestion of foods 
with known inducer/inhibitory effects on CYP1A2, CYP2C19, CYP2C9, and CYP3A4 
through Day 29 (See Appendix 4 for a list of these). 


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2. Subjects must not take medication that could adversely affect GI motility or transit (eg, 
diphenoxylate, loperamide, metoclopramide, cisapride, tegaserod, erythromycin) from 7 days 
prior to each administration of the cocktail drugs (Day 1 and Day 22) through the 48 hours 
following each cocktail administration. 
5.3.2 
Dietary, Caffeine, Alcohol and Tobacco Restrictions 
1. Subjects are to abstain from taking caffeine-containing drinks or foods (eg, coffee, tea, 
cocoa, chocolate, and cola) from 48 hours prior to each cocktail administration and while 
inpatient (Day -1 to Day 2 and Day 21 to Day 23, respectively). During the outpatient period 
Days 2 to 20 subjects are to avoid high caffeine-containing energy drinks (eg, Red Bull) and 
will be provided with decaffeinated tea and coffee by the study center. 
2. Subjects are to refrain from intake of alcohol within the 48 hours prior to Day 1 until the final 
warfarin PK sample on Day 8 and within 48 hours of Day 22 until the final warfarin PK 
sample on Day 29 (EOT). During the outpatient period Day 8 to Day 20, alcohol 
consumption should be limited to no more than 2 units per day. 
3. Subjects are to maintain their normal diet throughout the study and not implement any 
changes. 
4. The cocktail will be administered with 240 mL water after an overnight fast of at least 
10 hours. See Table 9 for detailed requirements regarding fasting at study assessment visits. 
5. Subjects are to attempt to avoid passive (secondhand) smoking from 2 weeks prior to the first 
dose of cocktail administration until after the last PK sample is collected on Day 29 (EOT) of 
the study. 
6. Subjects are not to consume any grapefruit, grapefruit juice, Seville oranges, Seville orange 
marmalade, or other products containing grapefruit or Seville oranges from at least 1 week 
prior to the first dose of cocktail administration (Day 1) until after the last PK sample (EOT, 
Day 29). 
5.3.3 
Contraception 
Male subjects and their female partners and female subjects of childbearing potential are to 
adhere to the contraceptive requirements for the study. See Appendix 6 for details regarding 
contraceptive requirements. 
5.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently enrolled in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure subjects to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
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Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once if the reason for the screen failure no longer exists (with exception of the 
subjects with arterial hypertension in case hypertension is not controlled). Rescreened subjects 
should not be assigned the same subject number as for the initial screening. 


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6.0 STUDY TREATMENT 
Study treatment is defined as any investigational treatment(s), and marketed product(s) intended 
to be administered to a subject according to the study protocol. 
6.1 
Study Treatment(s) Administered 
The details of the study treatment(s) administered are presented in Table 7. 
Table 7 
Study Treatment Details 
 
Study 
Treatment 
Cocktail 
Study Treatment 
Name: 
Olokizumab 
Caffeine 
Warfarin 
Omeprazole 
Midazolam  
Dosage 
Formulation: 
 
Sterile solution 
for 
subcutaneous 
(SC) injection 
Tablet 
Warfarin Tablet 
plus vitamin K- 
solution for 
intravenous 
injection to be 
taken orally 
Tablet 
Syrup to be 
taken orally 
Unit Dose 
Strength(s)/Dosage 
Level(s): 
128 mg 
(0.8 mL 
injection) 
100 mg 
10 mg 
10 mg/mL 
20 mg 
2 mg/mL  
Route of 
Administration:  
SC injection 
Oral 
Oral 
Oral 
Oral 
Dosing 
Instructions: 
 
Subjects will 
receive a single 
dose of OKZ 
128 mg via SC 
injection 
(0.8 mL) by 
study center 
staff on Day 8 
Subjects will receive an oral administration of a cocktail of substrates 
(100 mg caffeine, 20 mg omeprazole, 10 mg warfarin, 2 mg midazolam 
[via syringe] followed by 10 mg vitamin K [via syringe], on 
2 occasions, on the morning of Day 1 and Day 22 (±1). 
The cocktail will be administered with 240 mL water after a 10 hour 
overnight fast. The interval in which all 4 cocktail substrates and 
vitamin K are administered and ingested should be within 5 minutes. 
Subjects will continue to fast until 4 hours postdose. 
All doses will be administered under the supervision of a suitably 
qualified study center staff member. 
Immediately after tablet administration, visual inspection of the oral 
cavity will be performed for each subject. 
The midazolam solution will be administered directly into the subject’s 
mouth by syringe by a study center staff member and then immediately 
washed down with water. 
The vitamin K solution will be administered directly into the subject’s 
mouth by syringe and then immediately washed down with water 
(Zhuang et al, 2015) 
In total each subject will drink 240 mL water with the cocktail 
medications. 
Packaging and 
Labeling: 
Study treatment will be provided in commercially available secondary packages for the 
cocktail and in cartons for OKZ. Each package or carton will be labeled as per country 
requirements. Each subject will receive their own package and sharing is not permitted. 


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Manufacturer: 
R-Pharm 
International 
Purchased by a 3rd party and distributed to study centers from a central 
depot 
 
For the cocktail administration, the timings of food and fluid intake up to 24 hours postdose are 
detailed in Table 8: 
Table 8 
Timing of Fluid and Food Intake Around Cocktail Administration 
Time 
Food and fluid details 
Evening of previous day 
Evening meal 
From 22:00 on previous day 
Fast from food and fluids except water 
From 1-hour predose (9 hours after the last meal) 
No fluids allowed including water 
At dosing (10 hours after the last meal) 
240 mL water administered with the cocktail medications  
From 2 hours postdose 
Free access to water 
Approximately 4.5 hours postdose 
Lunch 
Approximately 7.5 hours postdose 
Afternoon snack 
Approximately 11 hours postdose 
Evening meal 
After 24 hours postdose assessments 
Breakfast 
Reference = FDA Guidance for Bioavailability and Bioequivalence Studies (FDA Guidance for Bioavailability and 
Bioequivalence Studies) 
 
The study pharmacist or designee will prepare the OKZ syringes for SC injection. The solution 
may remain in the syringe for a maximum of 4 hours prior to its injection. The SC syringes 
should be warmed at room temperature prior to handing to the study center staff for SC injection. 
Qualified study center staff will administer a single SC injection (0.8 mL of OKZ) on Day 8 in 
either the abdomen or the thigh. All subjects will remain at the study center for at least 2 hours 
following the administration of OKZ to be assessed for onset of any systemic injection reactions. 
The date, time, and location of the SC injection should be recorded in the electronic Case Report 
Form (eCRF). The Investigator should also record in the eCRF whether or not the full dose was 
injected. 
Further detailed instructions on study treatment preparation and handling are provided in the 
Pharmacy Manual. 
6.2 
Preparation/Handling/Storage/Accountability 
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment. 


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2. Only subjects enrolled in the study may receive study treatment and only authorized study 
center staff may supply or administer study treatment. All study treatments must be stored in 
a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the Investigator and 
authorized study center staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study treatment are 
provided in the Study Reference Manual. 
The Investigator, a member of the study center staff, or a hospital pharmacist must maintain an 
adequate record of the receipt and distribution of all study medication using the Drug 
Accountability Form. These forms must be available for inspection at any time. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label, nonrandomized study, therefore no randomization of subjects will occur. 
No blinding procedures are applicable. 
6.4 
Study Treatment Compliance 
The prescribed dosage, timing, and mode of administration may not be changed. All dates and 
times of study treatment administration and any departures from the intended regimen must be 
recorded on the eCRFs. 
All study treatment administrations will be performed in the study center under the supervision 
of appropriately trained staff. A mouth check will be performed following oral administration. A 
monitor will review the pharmacy records at each study center including the drug dispensing 
records or drug accountability forms. The pharmacist (or designee) should record all study 
treatment dispensed to subjects on the eCRFs. 
6.5 
Emergency Treatment Strategy 
The study center staff is responsible for the ongoing safety and wellbeing of the subjects while 
they are in the study center. There is a paging system to alert the staff to any area in the center 
where a subject may need medical attention. In the case of an emergency, equipment and 
emergency drugs are available to treat common medical emergencies that might occur in a 
Phase 1 study. If necessary, the clinical staff can contact on-call physicians or public 
emergencies services in the event of a serious medical event. 


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6.6 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the subject is receiving at the time of enrollment or receives 
during the study must be recorded on the eCRF along with: 
 Reason for use; 
 Dates of administration including start and end dates; 
 Dosage information including dose and frequency; and 
 Mode of administration. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
A list of excluded medications/therapy is provided in Appendix 4. 
Paracetamol/acetaminophen, at doses of 2 gram/day, is permitted for use any time during the 
study with the exception of within 24 hours prior to joint assessment. Other concomitant 
medication may be considered on a case-by-case basis by the Investigator in consultation with 
the Medical Monitor, if required. 
6.7 
Dose Modification 
Dose modifications are not planned or allowed in this study. 
6.8 
Treatment after the End of the Study 
The Sponsor will not provide any care to subjects after they leave the study because subjects will 
be on their standard RA maintenance care. 


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7.0 DISCONTINUATION OF STUDY TREATMENT AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Treatment 
If a subject who does not meet enrollment criteria is inadvertently enrolled, the Sponsor or 
Sponsor designee must be contacted, and that subject must be discontinued from study treatment 
after confirmation with the PK specialist and Sponsor. 
Study treatment administration for any individual subject will be stopped if the subject 
experiences an SAE or a clinically significant possibly drug-related AE, which in the opinion of 
the Principal Investigator, or Sponsor’s medical representative, warrants discontinuation of the 
study and/or study treatment for that subject’s wellbeing. 
Subject who discontinue the study treatment early, should be asked to return for an End of 
Treatment (EOT) (Day 29) and Safety Follow-up Visit (Day 99) - with exception of the cases 
when it is not possible such as the cases with COVID-19 infection when the subject will come to 
the visit after recovery (subject should not be infectious at the time of EOT and follow-up visits). 
After that an End of Study (EOS) visit should be performed. See the SoA (Table 3) for data to be 
collected at the time of EOT, Safety Follow-up and EOS Visit and for any further evaluations 
needed to be completed. 
7.1.1 
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. 
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; or 
 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 (eg, 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 judgment or 
other clinically significant newly diagnosed comorbidity that requires additional assessments for 


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clarification of the diagnosis, and the severity of which could worsen if study treatment is 
continued). 
7.1.2 
Permanent Discontinuation of Study Treatment 
In addition to the above, study treatment will be discontinued permanently 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 laboratory value, the 
study treatment is to be discontinued, appropriate measures are to be taken, and the Sponsor 
or designee is to be notified. 
 Subject presents with any of the following elevated liver function tests (LFTs): 
 ALT or AST elevations >8 × ULN at any time, regardless of total bilirubin or 
accompanying symptoms. 
 ALT or AST >5 × ULN for ≥2 weeks regardless of total bilirubin or accompanying 
symptoms. 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 study treatment 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 (eg, 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 
baseline 
 Creatinine value >2 × ULN 
 If the subject tests positive for COVID-19 or SARS-CoV-2 (RT-PCR testing or IgM testing). 
 Subject has a GI perforation. 
 Subject diagnosed with diverticulitis. 
 Subject has a confirmed active TB. 
 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. 
 Pregnancy of female subject. 


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7.2 
Subject Discontinuation/Withdrawal from the Study 
The criteria for enrollment are to be followed explicitly. 
If a subject who does not meet enrollment criteria is inadvertently enrolled, the Sponsor or 
designee must be informed immediately, and the subject may be discontinued from the study. 
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, 
the Sponsor or designee must be informed as soon as it can be possible, and the case will be 
reviewed by the Sponsor on a case-by-case basis and the noncompliant subject can be 
discontinued from the study. 
A subject should be discontinued from the study in the following circumstances: 
 Subject is unwilling to continue the study participation (informed consent withdrawal). If the 
subject discontinues from the study, the Investigator should inquire about the reason for 
discontinuing. 
 Subject is lost to follow-up (see section 7.3). 
 Death of subject. 
 The Sponsor, Investigator, a regulatory agency, or an ethical committee stops the study for 
any reason (see Appendix 2). 
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. Appropriate standard of care, at 
the discretion of the Investigator, will be initiated. 
If the study is discontinued the End of Study (EOS) Visit should be completed.  
Should a subject request or decide to withdraw from the study, all efforts must be made to 
complete and report the observations as thoroughly as possible up to the date of withdrawal. 
Subjects withdrawing due to an AE should be followed up according to the section 8.2.10. 
Subjects who voluntarily withdraw are termed dropouts. Dropouts and subjects withdrawn due to 
protocol violations will not be replaced. 
Additional subjects may be dosed to obtain the 12 fully eligible subjects. 
 


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7.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study center. 
The following actions must be taken if a subject fails to return to the study center for a required 
study visit: 
 The study center must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in the 
study. 
 Before a subject is deemed lost to follow-up, the Investigator or designee must make every 
effort to regain contact with the subject (where possible, 3 telephone calls and, if necessary, a 
certified letter to the subject’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the subject’s medical record. 
 Should the subject continue to be unreachable, he/she will be considered to have withdrawn 
from the study. 


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8.0 STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SoA (see Table 3). 
Protocol waivers or exemptions are not allowed (See Section 5.0). 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the subject should continue or discontinue study treatment. 
Adherence to the study design requirements, including those specified in the SoA (see Table 3) is 
essential, and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
subjects screened and to confirm eligibility or record reasons for screening failure, as applicable. 
The maximum amount of blood collected from each subject over the duration of the study, 
including any extra assessments that may be required, will not exceed the normal amount of 
blood (450 mL) collected during such studies. Repeat or unscheduled samples may be taken for 
safety reasons or for technical issues with the samples. 
Unscheduled Visits will be allowed at the Investigator’s discretion if deemed necessary for the 
subject’s safety and wellbeing. At this visit, any of the assessments from the SoA (see Table 3) 
may be performed dependent on the presenting reason. The Sponsor or Sponsor’s designee 
should be informed of these incidents in a timely fashion. 
A tabular representation of the study assessments per visit is presented in Table 9. 
 


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Table 9 
Tabular Outline of Study Assessments 
Study period 
Study Window 
Day 
Assessments to be performeda 
Screening 
Stage 1 
Day -35 to 
Day -14 
 
Informed consent, inclusion/exclusion, physical examination, genotyping, medical history, FSH, 
hepatitis serologyb, AEs/SAEs, CRPc, and, only if the Investigator suspects possible COVID-19 
infection - COVID-19 RT-PCR testinge and COVID-19 IgM/IgG testing (using rapid testing) 
Screening 
Stage 2 
Day -14d to 
Day -1 
 
Inclusion/exclusion, demography, height and weight, physical examination, vital signs, ECG, blood 
pregnancy test for WOCBP, TB risk questionnaire, chest radiography, QuantiFERON-TB Gold Plus, 
HIV serology, hepatitis serologyb, drugs of abuse, HbA1c, hematology, chemistry panel, urinalysis, 
coagulation panel, AEs/SAEs, concomitant medication, IL-6, and CRPc samples 
Day -3 to 
Day -2 
 
Physical examination, COVID-19 RT-PCR testinge and COVID-19 IgM/IgG testing (using rapid 
testing) 
Day -1 
Day -1 
Admission, medical history, inclusion/exclusion, physical examination, vital signs, ECG, urine 
pregnancy test for WOCBP, drugs of abuse, cotinine and alcohol screen, coagulation panel, AEs/SAEs, 
concomitant medication 
Period 1 
Day 1 to Day 6 
Day 1 
Predose: weight, DAS28 assessment, and IL-6/CRP samples, additional blood sampling for future 
genotype testing 
Cocktail PK samples (predose - see Table 4 for details) 
Administer cocktail after 10-hour overnight fast. See Table 8 for details 
Cocktail administration (see Table 7 for details) 
Cocktail PK samples (postdose - see Table 4 for details), AEs/SAEs, concomitant medication 
Day 2 to 
Day 6 
Cocktail PK samples (see Table 4 for details), INR onlyf, AEs/SAEs, concomitant medication, and 
COVID-19 RT-PCR testinge (Day 5 only). Results for the RT-PCR tests should be available before 
OKZ are administered on Day 8  
Period 2 
Day 8 to 
Day 21 
Day 8 
Predose: COVID-19 IgM/IgG testing (using rapid testing) - only if the Investigator suspects possible 
COVID-19 infection, collect final warfarin PK sample, DAS28 assessment, weight, physical 
examination, vital signs, ECG, urine pregnancy test for WOCBP, IL-6/CRP samples, hematology, 
chemistry panel, coagulation panel, drugs of abuse, cotinine and alcohol screen, AEs/SAEs, concomitant 
medication, assess injection site reactions, cocktail and OKZ PK samples (predose – see Table 4 and 
Table 5 for details), and ADAsg 
Administer OKZ, assess injection site reactions, cocktail and OKZ PK samples (postdose – see Table 4 
and Table 5 for details), AEs/SAEs, concomitant medication 


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Study period 
Study Window 
Day 
Assessments to be performeda 
Day 9 
Assess injection site reactions, OKZ PK samples (see Table 5 for details), AEs/SAEs, concomitant 
medication, IL-6/CRP samples 
Day 15 
OKZ PK samples (see Table 5 for details), AEs/SAEs, concomitant medication, IL-6/CRP samples 
Day 19 
Physical examination, COVID-19 RT-PCR testinge, and, only if the Investigator suspects possible 
COVID-19 infection - COVID-19 IgM/IgG testing (using rapid testing) 
Day 21 
Admission, urine pregnancy test for WOCBP, drugs of abuse, cotinine and alcohol screen, INR onlyf, 
AEs/SAEs, concomitant medication 
Period 3 
Day 22 to 
Day 29 
Day 22 
Predose: weight, physical examination, OKZ PK samples (see Table 5 for details), AEs/SAEs, 
concomitant medication, and IL-6/CRP samples 
Cocktail PK samples (see Table 4 for details for details) 
Administer cocktail after 10-hour overnight fast. See Table 8 for details 
Cocktail administration (see Table 7 for details), cocktail PK samples (see Table 4 for details) 
Day 23  
Cocktail PK samples (see Table 4 for details), INR onlyf, AEs/SAEs, and concomitant medication 
Day 24 
Cocktail PK samples (see Table 4 for details), OKZ PK samples (see Table 5 for details), INR onlyf, 
AEs/SAEs, concomitant medication 
Day 25 
Cocktail PK samples (see Table 4 for details), INR onlyf, AEs/SAEs, concomitant medication 
Day 27 
Cocktail PK samples (see Table 4 for details), INR onlyf, AEs/SAEs, concomitant medication 
Day 29 
(EOT): DAS28 assessment, weight, physical examination, vital signs, ECG, urine pregnancy test for 
WOCBP, OKZ PK samples (see Table 5 for details), Cocktail PK samples (see Table 4 for details), 
hematology, chemistry panel, urinalysis, coagulation panel, AEs/SAEs, concomitant medication, IL-6 
and CRP samples, ADAsg, and COVID-19 RT-PCR testinge  
Safety 
Follow-up 
Day 30 to 
Day 161 
Day 43 
(Telephonic): Physical examination, COVID-19 RT-PCR testinge (only if the Investigator suspects 
possible COVID-19 infection), and, only if the Investigator suspects possible COVID-19 infection - 
COVID-19 IgM/IgG testing (using rapid testing)h 
Day 99 
(SFU): Physical examination, vital signs, urine pregnancy test for WOCBP, hematology, chemistry 
panel, AEs/SAEs, concomitant medication, ADAsg 
Day 130 
(Telephonic): AEs/SAEs, concomitant medication 
Day 161 
(Telephonic, EOS): AEs/SAEs, concomitant medication 


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Abbreviations: ADA = antidrug antibody; AE = adverse event; COVID-19 = Coronavirus disease 2019; CRP = C-reactive protein; DAS28 = Disease Activity 
Score 28 joint count; ECG = electrocardiogram; EOS = end of study; EOT = end of treatment; FSH = follicle-stimulating hormone; HbA1c = glycosylated 
hemoglobin A1c; HIV = human immunodeficiency virus; IgG = Immunoglobulin G; IgM = Immunoglobulin M; IL-6 = interleukin-6; INR = international 
normalized ratio; OKZ = olokizumab; PK = pharmacokinetic; RT-PCR = reverse transcription polymerase chain reaction; SAE = serious adverse event; 
SFU = safety follow-up; TB = tuberculosis; WOCBP = woman of childbearing potential. 
a Food restriction: none, except as indicated in inclusion/exclusion and restrictions, with the exception of an overnight fast ahead of cocktail administration. 
b Hepatitis serology and CRP screening assessments could be performed during Screening Stage 1, if required by the study center. 
c The CRP test to assess eligibility can be done during the first stage of Screening and can be repeated once during Screening, provided results arrive prior to 
the admission date. No extensions of the Screening period will be granted for missing laboratory data unless this is due to central laboratory error (after 
Sponsor approval). 
d If genotype screening results are available earlier, Screening Stage 2 can start before Day -14. 
e 
COVID-19 RT-PCR testing: two PCR tests should be performed within approximately 36 hours (a second PCR would be performed only if the first results 
are negative). 
f 
INR results should be available within 24 hours (and for the sample taken on Day 21, before cocktail administration on Day 22). 
g Neutralizing antibodies will be tested in samples that were positive for OKZ antibodies. 
h Sample may be taken at the local laboratory or another designated sample collection area. 
 
 


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8.1 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA (see Table 3). 
8.1.1 
Physical Examinations 
 A complete physical examination will include the evaluation of general appearance, skin, 
head, eyes, ears, nose, and throat, lymph nodes, respiratory, cardiovascular (CV), 
gastrointestinal (GI) including hepatobiliary assessment, musculoskeletal, endocrine system, 
neurological systems, and urogenital system. 
 Physical examinations include but are not limited to respiratory infection symptoms (acute 
onset of cough, fever [oral temperature >37.5°C], dyspnea) and asked about contacts with 
suspected or confirmed COVID-19 cases/visiting areas where high frequency of COVID-19 
are reported. 
 All significant findings present at Screening must be reported in the relevant medical 
history/current medical conditions eCRF. Significant findings made after enrollment meeting 
the definition of an AE must be recorded in the AEs eCRF. 
8.1.2 
Vital Signs 
 Body temperature, pulse rate, BP, and respiratory rate will be assessed. 
 Blood pressure and pulse measurements will be assessed in the semi-supine position with a 
completely automated device. Manual techniques will only be used if an automated device is 
not available. 
 Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for 
the subject in a quiet setting without distractions (eg, television, cell phones). 
 At Screening, BP should be done in triplicate and the mean used to assess for subject 
eligibility. 
 Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse 
and 1 BP measurement. 
8.1.3 
Electrocardiograms 
 Single 12-lead ECG will be obtained as outlined in the SoA (see Table 3) using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTcF 
intervals after the subject had been resting for at least 5 minutes in the semi-supine position 
and recorded in the eCRF. 
8.1.4 
Clinical Safety Laboratory Assessments 
 The central laboratory will be used in this study to analyze routine blood samples. See 
Appendix 3 for the list of clinical laboratory tests to be performed and the SoA (see Table 3) 
for the timing and frequency. 


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 Results from the INR samples taken as safety assessments for warfarin (Days 2, 3, 4, 5, and 
6, as well as Day 21, and Days 23, 24, 25, and 27) should be available within 24 hours (and 
for the sample taken on Day 21, before cocktail administration on Day 22). 
 Subjects will be undergoing COVID-19 reverse transcription polymerase chain reaction 
(RT-PCR) testing. Two consecutive RT-PCR tests to be conducted within approximately 36 
hours, the second RT-PCR test will only be performed if the first test results are negative. 
Only subjects with a negative COVID-19 RT-PCR test result may be included in the study. 
Two consecutive RT-PCR tests will occur at Day -35 (Stage 1) - only if the Investigator 
suspects possible COVID-19 infection, at Day -3, Day 5, Day 19 and Day 29 (EOT) - 
obligatory. If the Investigator suspects possible COVID-19 infection - on Day 43. Only 
subjects with a negative COVID-19 RT-PCR test result may be administered the study 
treatment on Day 8. The RT-PCR testing will be performed at local laboratories. 
 A rapid test will be conducted for the COVID-19 IgG/IgM testing at Screening–Stage 1 - 
only if the Investigator suspects possible COVID-19 infection, prior to first inhouse period 
(Day -2) - obligatory. If the Investigator suspects possible COVID-19 infection - prior to 
dose administration on Day 8 or/and prior to second inhouse period (Day 19) or/and Day 43. 
The serology will be performed onsite. 
 COVID-19 (SARS-CoV-2 infections) will be regarded as AEs and summarized as such. 
 The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF and 
classify according to Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those that are not associated with the underlying 
disease/subject’s health status, unless judged by the Investigator to be more severe than 
expected for the subject’s condition. 
 All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 77 days after the last dose of study treatment (Day 99 
Safety Follow-up Visit) should be repeated until the values return to normal or baseline or 
are no longer considered clinically significant by the Investigator or Medical Monitor, ie, 
until 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. 
 If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, and the Sponsor 
notified. 
 All protocol-required laboratory assessments, as defined in Appendix 3, must be 
conducted in accordance with the Laboratory Manual and the SoA (Table 3). 


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 If laboratory values from nonprotocol-specified laboratory assessments require a 
change in subject management or are considered clinically significant by the 
Investigator (eg, SAE or AE), then the results must be recorded in the eCRF. 
8.1.5 
Tuberculosis Risk Questionnaire 
The questionnaire “Tuberculosis Risk Questionnaire” (see Appendix 8) should be used as a 
source document. The questionnaire will be completed at Screening as noted in Table 3. 
At the Screening Visit, if question No. 1 (Does the subject have currently active TB disease or a 
history of active TB disease) or question No. 2 (Has the subject been in close contact [ie, sharing 
the same household, or other enclosed environment, such as a social gathering place, workplace, 
or facility, for extended periods during the day] with an individual with active TB within the past 
1.5 years) of the questionnaire “Tuberculosis Risk Questionnaire for Screening Visit” is 
answered “Yes” the subject is not allowed to enter the study (see exclusion criterion # 23, 
Section 5.2). 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. 
8.2 
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). 


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The Investigator is responsible for recording all AEs and SAEs from the signing of the ICF until 
the final EOS telephonic follow-up visit (Day 161 ±10 days) at the timepoints specified in the 
SoA (see Table 3). The Investigator is responsible for the appropriate medical care of the 
subjects during the entire study. 
Each AE is to be evaluated for duration, severity, seriousness, and causal relationship to the 
study treatment (cocktail, OKZ and OKZ + cocktail). 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. The detailed analysis plan for COVID-19 can be included in the Statistical 
Analysis Plan (SAP). 
8.2.1 
Severity 
The severity of AEs will be characterized according to the CTCAE grades and definitions 
summarized in Table 10. 
Table 10 
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. 
 
8.2.2 
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. 


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 Known association of the event with the study treatment, or with similar treatments. 
 Known association of the event with the disease under study. 
 Presence of risk factors in the subject or use of concomitant medications known to increase 
the occurrence of the event. 
 Presence of nontreatment-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 center staff is responsible for obtaining any missing information. 
8.2.3 
Eliciting Adverse Event Information 
A consistent methodology of nondirective questioning should be adopted for eliciting AE 
information at all subject evaluation timepoints. 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?” 
8.2.4 
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 (eg, 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: 
 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 


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the level decreases for some time within 2 weeks, subject permanent 
discontinuation is not mandated, but left under Investigator discretion. 
Resuming the study treatment 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 (eg, 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 the Sponsor’s designee through the end of the Safety Follow-Up period (ie, for a 
period of approximately 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 
immediately reported to the Sponsor or their 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 


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unexpected cardiac death and not within 30 days of an acute myocardial infarction (MI) within 
scenarios: 
 Death witnessed and occurring without new or worsening symptoms. 
 Death witnessed within 60 min of the onset of new or worsening cardiac symptoms unless 
the symptoms suggest acute MI. 
 Death witnessed and attributed to an identified arrhythmia (eg, captured on an 
electrocardiographic recording, witnessed on a monitor, or unwitnessed but found on 
implantable cardioverter-defibrillator (ICD) review). 
 Death after unsuccessful resuscitation from cardiac arrest (eg, ICD unresponsive sudden 
cardiac death, pulseless electrical activity arrest). 
 Death after successful resuscitation from cardiac arrest and without identification of a 
specific cardiac or non-cardiac etiology. 
 Unwitnessed death in a subject seen alive and clinically stable ≤24 h before being found dead 
without any evidence supporting a specific non- cardiovascular cause of death (information 
about the patient’s clinical status preceding death should be provided if available).  
Unless additional information suggests an alternate specific cause of death (e.g., Death due to 
Other Cardiovascular Causes), if a patient is seen alive ≤24 h before being found dead, sudden 
cardiac death should be recorded. 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 (eg, after 
autopsy), “unexplained death” should be replaced by the established cause of death. 
8.2.5 
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. 
8.2.6 
Reporting and Follow-up Requirements for Pregnancies 
Pregnancy per se is not an AE except for the cases when it is reasonable to suppose that 
administration of the study product reduced efficacy of contraceptive methods. Congenital 
abnormalities or birth defects in children of study subjects are considered to be SAEs. Elective 
abortions, abortions for medical reasons, with sequelae as well as any serious pregnancy 
complications (including spontaneous abortions) should be recorded as SAEs. Planned abortions 
without sequelae are not AEs. 


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Pregnancy of the female subjects and partners of male subjects exposed to the study treatment 
will be recorded since the first study drug administration until the last study-related procedure. 
All pregnancy cases reported during the study (including pregnancies of female partners of the 
study subjects) should be duly recorded.  
Female subjects of childbearing potential will be instructed through the ICF to immediately 
inform the Investigator if they become pregnant during the study and up to 6 months after the 
OKZ dosing. The same, male subjects will be instructed through the ICF to immediately inform 
the Investigator if their partner becomes pregnant during the study and up to 6 months after the 
OKZ dosing.  
If a pregnancy is reported, the female subject must be immediately discontinued from the study 
and followed-up as described in the Section 7.2.  
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 6.  
8.2.7 
Reporting of Adverse Events 
Study center 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. All AEs, whether reported by the subject or noted by study center 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, 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 the Sponsor’s designee their assessment of the 
potential relatedness of each AE to protocol procedure and/or study treatment via the eCRF. 
Study center 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 the Sponsor’s designee via eCRF, electronic data capture 
(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 (eg, 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 (ie, any procedure required by 
the study protocol). The action taken, and the outcome must also be recorded in the AE page of 
the eCRF. 
8.2.8 
Reporting of Serious Adverse Events 
All SAEs that occur at or after Visit 1, regardless of the Investigator’s assessment on causality, 
must be recorded on the relevant pages of the eCRF and reported to the Sponsor 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, and the 
timelines and procedure for follow-up reports are the same as those for the initial report. The 
Sponsor’s designee is responsible for managing the safety database. 
The Sponsor 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 received the last dose 
of study treatment will be collected and reported to the Sponsor’s designee through the end of the 
Safety Follow-Up period (ie, 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. 
8.2.9 
Reporting of Serious Adverse Events to Regulatory Authorities and 
Investigators 
The Sponsor’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 


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study is conducted. Relative to the first awareness of the event by/or further provision to the 
Sponsor’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. The 
Sponsor’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 center 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. 
8.2.10 
Follow-up of Adverse Events 
Any AEs that occur at or after Visit 1 until the end of the Safety Follow-Up period (ie, 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, the Sponsor or its designee must concur 
with the Investigator’s assessment. 
For SAEs, nonserious AESIs, and pregnancies, the Sponsor’s designee may follow-up by 
telephone, fax, electronic mail, and/or a monitoring visit to obtain additional case details and 
outcome information (eg, from hospital discharge summaries, consultant reports, or autopsy 
reports) in order to perform an independent medical assessment of the reported case. 
8.3 
Disease Activity Assessments 
The disease activity will be assessed by Patient Global Assessment of Disease Activity (Visual 
Analog Scale – Bullet Scale) and Disease Activity Score 28-Joint Count (C-Reactive Protein) – 
DAS28 (CRP). 
8.3.1 
Patient Global Assessment of Disease Activity (Visual Analog Scale – Bullet 
Scale) 
Subjects will assess their overall disease activity using a visual analog scale (VAS) bullet scale 
of 21 circles in 0.5-unit increments, numbered below each circle, where 0 is “very well” and 10 
is “very poorly”, 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. 
See Appendix 9 for more details. 


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8.3.2 
Disease Activity Score 28-Joint Count (C-Reactive Protein) 
The DAS28 (CRP) will be calculated using the Swollen Joint Count (SJC) (28 joints), Tender 
Joint Count (TJC) (28 joints), CRP level (mg/dL), and the Patient Global Assessment of Disease 
Activity (VAS) according to the following formula: 
DAS28 (CRP) = 0.56 × √(TJC) + 0.28 × √(SJC) + 0.36 × lognat (CRP + 1) + 0.14 × Patient 
Global Assessment of Disease Activity (VAS) + 0.96 
The 28 joints evaluated for the SJC and TJC are as follows: 
 Shoulders, elbows, wrists, and knees, and for each hand: interphalangeal joint (IP) on digit 1, 
proximal interphalangeal joints (PIP) on digits 2 to 5, and metacarpophalangeal joints (MCP) 
on digits 1 to 5 (See Appendix 9 for more details). 
8.4 
Pharmacokinetics 
8.4.1 
Collection of Samples 
 Venous blood samples (main and back-up) will be collected for measurement of plasma 
concentrations of study treatment and cocktail substrates at times as specified in the SoA (see 
Table 3, Table 4, and Table 5). Blood samples will be taken either by direct venipuncture or 
an indwelling cannula inserted in a forearm vein. The actual date and time (24-hour clock 
time) of each sample will be recorded in the source documents. The time and date of study 
treatment administration will also be recorded in the source documents. Samples will be 
collected, labeled, stored, and shipped as detailed in the Laboratory Manual. 
 Predose samples may be collected within 30 minutes before dose administration. A 2-minute 
window will be allowed for samples taken up to 30 minutes postdose; a 5-minute window 
will be allowed for samples taken at 1 to 30 hours postdose; a 2-hour window for samples 
taken at 48 hours to 120 hours postdose; and a +1-calendar day window is allowed for the 
168-hour postdose sample. 
8.4.2 
Determination of Drug Concentration 
 Samples for the determination of study treatment and cocktail substrates in plasma will be 
analyzed using appropriate validated bioanalytical methods. Full details of the bioanalytical 
methods will be described in a separate Bioanalytical Report. 
 All samples still within the known stability of the analyte of interest at the time of receipt by 
the bioanalytical laboratory will be analyzed. 
 Remaining plasma samples may be subjected to further analysis by the Sponsor or designee 
for the purpose of the development of additional bioanalytical assays. Samples collected for 
analyses of study treatment and cocktail substrates plasma concentration may also be used to 
evaluate safety or efficacy aspects related to concerns arising during or after the study. 


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 A single blood sample or separate samples may be taken at shared timepoints as described in 
the Laboratory Manual. 
8.4.3 
Calculation of Derivation of Pharmacokinetic Variables 
Pharmacokinetic parameters will be derived using noncompartmental methods with Phoenix® 
WinNonlin® Version 8.0 or higher (Certara, L.P. Princeton, New Jersey, United States of 
America [USA]) and/or SAS® Version 9.4 or higher (SAS Institute, Inc., Cary, North Carolina, 
USA). Actual elapsed time from dosing will be used for the final plasma PK parameter 
calculations. 
Plasma Blood Pharmacokinetic Parameters 
The PK parameters in Table 11 will be determined for the cocktail substrates, when possible. 
Table 11 
Plasma Blood Pharmacokinetic Parameters 
Pharmacokinetic Parameter 
Definition 
Cmax 
Maximum concentration obtained directly from the observed concentration 
versus time data 
tmax 
Time to Cmax 
AUC(0-inf) 
Area under the plasma concentration-time curve from time zero extrapolated 
to infinity, calculated by linear up/log down trapezoidal summation 
AUC(0-last) 
Area under the plasma concentration-time curve from time zero to the time of 
the last quantifiable concentration, calculated by linear up/log down 
trapezoidal summation 
CL/F 
Apparent oral plasma clearance  
Vz/F 
Apparent volume of distribution 
t1/2 
Terminal half-life; a minimum of 3 points will be used for estimation 
λz 
Terminal rate constant 
 
Additional plasma parameters may be calculated if deemed appropriate. 
8.5 
Pharmacodynamics 
Venous blood samples will be collected for measurement of IL-6 and CRP at the timepoints 
specified below. 
Blood sampling for the measurement of IL-6 and CRP will be performed. IL-6 and CRP levels 
will be measured at Screening, prior to dosing with the cocktail on Day 1, prior to dose 
administration with OKZ on Day 8, and post OKZ dose administration on Day 9, Day 15, 
Day 22 (prior to dose administration of the cocktail on Day 22), and Day 29, which will be 
considered the EOT Visit. 


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8.6 
Genetics 
Blood samples for DNA isolation will be collected from subjects who have consented to the 
study to identify intermediate metabolizers of CYP2C9 (genotype *1/*2,*1/*3), poor 
metabolizers of CYP2C9 (genotype *2/*2, 2/*3,*3/*3) or CYP2C19 (genotype *2/*2,*2/*3, 
*3/*3), ultra-rapid metabolizers of CYP2C19 (*17/*17), or high sensitivity to warfarin 
(VKORCI genotype AG and AA). Additional blood sampling for future genotype testing to 
identify any genotypes that could have significant impact on CYP metabolism but not listed 
above will also be performed. 
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the subject. Signed informed consent will be required to obtain a replacement sample 
unless it was included in the original consent. 
See Appendix 7 for Information regarding genetic research. Details on processes for collection 
and shipment and destruction of these samples can be found in the Study Reference Manual. 
8.7 
Immunogenicity Assessments 
Antibodies to OKZ will be evaluated in plasma samples collected from all subjects according to 
the SoA. Additionally, plasma samples should also be collected at the final visit from subjects 
who discontinued study treatment or were withdrawn from the study. These samples will be 
tested by the Sponsor or Sponsor's designee. 
Plasma samples will be screened for antibodies binding to OKZ and the titer of confirmed 
positive samples will be reported. Other analyses may be performed to verify the stability of 
antibodies to OKZ and/or further characterize the immunogenicity of OKZ. Neutralizing 
antibodies will be tested in samples that were positive for OKZ antibodies. 
The detection and characterization of antibodies to OKZ will be performed using a validated 
assay method by or under the supervision of the Sponsor. All samples collected for detection of 
antibodies to OKZ will also be evaluated for OKZ plasma concentration to enable interpretation 
of the antibody data. Samples may be stored for a maximum of 5 years (or according to local 
regulations) following the last subject’s last visit for the study at a facility selected by the 
Sponsor to enable further analysis of immune responses to OKZ. 
8.8 
Health Economics/Medical Resource Utilization and Health Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 


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9.0 STATISTICAL CONSIDERATIONS 
All statistical analyses will be performed using SAS® Version 9.4 or later. 
9.1 
Statistical Hypotheses 
The assessment of the effect of OKZ on the PK of the probe substrates, caffeine, S-warfarin, 
omeprazole, and midazolam will be undertaken using descriptive statistics of the PK parameters 
listed in Table 11 at each of the relevant timepoints listed in Table 4. Additionally, estimates of 
the change after administration of OKZ in Cmax, AUC(0-inf), and AUC(0-last) for each of these 
substrates will be analyzed. 
9.2 
Sample Size Determination 
No historical data are available for the reduction in S-warfarin AUC(0-last) following 
administration of OKZ. Hence, the following sample size computation is based on results 
reported for another compound (sirukumab) in the same class of medications as OKZ. Zhuang et 
al, 2015, reported an 18% (90% confidence interval [CI]: 0.73 to 0.92), 18% (90% CI: 
0.73 to 0.92), and 19% (90% CI: 0.72 to 0.91) reduction in S-warfarin AUC(0-inf) at 1, 3, and 
6 weeks, respectively, following sirukumab administration in 12 subjects with RA. Assuming a 
dropout rate of 20%, approximately 15 subjects who meet the study eligibility criteria should be 
enrolled so that 12 evaluable subjects complete the study. However, if necessary, additional 
subjects may be dosed to obtain the 12 evaluable subjects required. This sample size (ie, 
12 evaluable subjects) will have over 95% power to determine whether a 90% CI of the 
S-warfarin AUC(0-last) ratio of the geometric mean for some timepoint after the administration of 
OKZ to that before OKZ administration is within the interval 80% to 125%. The power was 
calculated assuming a 13% coefficient of variation (CV) for S-warfarin AUC(0-last). 
Similarly, no historical data are available for the reduction in midazolam and omeprazole 
AUC(0-inf) following administration of OKZ. Based on Zhuang et al, 2015, a sample size of 
12 subjects with RA was sufficient to describe the effect of sirukumab on the model substrates 
midazolam and omeprazole with a reduction in AUC(0-inf) of 30% (90% CI: 0.51 to 0.96) to 35% 
(90% CI: 0.47 to 0.89) and 37% (90% CI: 0.36 to 1.09) to 45% (90% CI: 0.32 to 0.96), 
respectively following sirukumab administration in 12 subjects with RA. Similarly, the effect of 
tocilizumab infusion on simvastatin and omeprazole exposure was well described with 8 subjects 
(28% reduction in omeprazole AUC(0-inf)) (Zhou and Meibohm, 2013). No statistical powering or 
formal comparisons are planned for midazolam and omeprazole substrates. 
Caffeine is included in this study to further evaluate the effect of CYP450 modulators on this 
isozyme in subjects with RA. Again, no historical data are available for the reduction in caffeine 
AUC(0-inf) following administration of OKZ. As per Zhuang et al (2015) (Zhuang et al, 2015), 
caffeine AUC(0-inf) was increased by 20% (90% CI: 0.75 to 1.91) to 34% (90% CI: 0.84 to 2.15) 


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following sirukumab administration in 12 subjects with RA. This study is not powered to detect 
treatment differences in caffeine. 
9.3 
Populations for Analyses 
For purposes of analysis, the analysis sets in Table 12 are defined. 
Table 12 
Analysis Sets 
Analysis Set 
Description 
Screened Analysis Set 
All subjects who sign the Informed Consent Form (ICF). 
Enrolled Analysis Set 
All subjects who signed the ICF and were deemed as meeting all eligibility 
criteria by the Investigator prior to their first dose of study treatment. 
Safety Analysis Set 
The Safety population will include all subjects who receive at least 1 dose of 
study treatment (CYP450 probe cocktail or olokizumab [OKZ]). Subjects 
will be analyzed according to the treatment they received. 
Pharmacokinetic (PK) Analysis 
Set 
The PK population will include all subjects who receive at least 1 dose of 
study treatment (cocktail or OKZ) and who have at least 1 quantifiable 
plasma concentration for any of the cocktail drugs or OKZ collected 
postdose without protocol deviations or events that could affect those 
concentrations. The list of protocol deviations or events that could affect the 
plasma concentrations will be finalized before the database lock from the list 
of all protocol deviations that occurred during the study. 
Pharmacodynamic (PD) Analysis 
Set 
The PD population will include all subjects who receive at least 1 dose of 
study treatment (cocktail or OKZ) and who have at least 1 PD endpoint 
collected after cocktail or OKZ administration without protocol deviations 
or events that could affect those endpoints. The list of protocol deviations or 
events that could affect the PD endpoints will be finalized before the 
database lock from the list of all protocol deviations that will occurred 
during the study. 
9.4 
Statistical Analyses 
The SAP will be developed and finalized before database lock and will describe the subject 
analysis sets to be included in the analyses, and procedures for accounting for missing, unused, 
and spurious data. 
The following descriptive statistics will be used as applicable to summarize the study data unless 
otherwise specified: 
 Continuous variables: sample size [n], mean, standard deviation [SD], median, minimum 
[min], and maximum [max]; 
 Categorical variables: frequencies and percentages. 
Individual subject data will be presented in listings. 


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9.4.1 
Disease Activity Analysis 
Descriptive statistics for change from baseline in Disease Activity Score 28 joint count (DAS28) 
and Patient Global Assessment of Disease Activity (Bullet Scale) will be presented. 
9.4.2 
Pharmacokinetic/Pharmacodynamic Analyses 
9.4.2.1 
Pharmacokinetic Analyses 
The PK analyses will be based on the Pharmacokinetic Analysis Set. 
Concentrations and PK parameters for the cocktail drugs (caffeine, S-warfarin, omeprazole, and 
midazolam), and OKZ (concentration only) in plasma will be summarized using descriptive 
statistics. Geometric mean and CV will also be provided. 
The natural log transformed PK parameters (Cmax, AUC(0-inf), and AUC(0-last)) of each cocktail 
substrate will be analyzed using a linear mixed effects model with a fixed effect for treatment 
and a random effect for subject. Estimates of the mean difference between treatments (OKZ + 
cocktail substrate compared to cocktail substrate alone) and its corresponding 90% CIs will be 
calculated. The mean differences and the CIs will be back transformed to the original scale to 
obtain estimates of the geometric mean ratios and the associated 90% CIs. 
Interpretation of the results will be based on the size of the estimated geometric mean ratios and 
90% CIs. 
PK parameters can be calculated for part/all patients preliminary that will be documented 
accordingly in analysis plan. 
9.4.2.2 
Pharmacodynamic Analyses 
Descriptive statistic of IL-6 and CRP concentrations and their change from baseline (CFB) 
concentration values will be listed and summarized by scheduled collection time. Line plots of 
mean concentrations over time will also be presented. 
Interleukin-6 (IL-6) and CRP concentrations descriptive statistics will be presented by the visits 
at which they are scheduled to be collected as shown in the SoA. By-subject listings showing 
each subject’s observed values in order by Study Day will also be provided. 
9.4.3 
Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set. 
All safety data including any AEs, AEs with an outcome of death, SAEs, AEs leading to 
discontinuation of study treatment, 12-lead ECG, vital signs, physical examination results and 
laboratory assessments will be listed by subject and within subject by start date or where relevant 
assessment date. 


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All AEs will be mapped to SOC and PT using MedDRA Version 20.0 or higher. 
The number and percentage of subjects with TEAEs, SAEs and TEAs leading to study 
discontinuation will be summarized separately by MedDRA SOC and PT without regard to 
severity or relationship to study treatment. 
A table summarizing TEAE by severity will be produced. The table will display the number and 
percentage of subjects with TEAEs summarized by MedDRA SOC, PT, and maximum severity. 
A table summarizing TEAE by relationship to OKZ will be produced. This table will display the 
number and percentage of subjects with TEAEs summarized by MedDRA SOC, PT, and 
maximum relationship to study drug. A similar table summarizing TEAEs by maximum 
relationship to the cocktail will be produced. 
For Period 1, assessment of relationship will automatically be between the cocktail and AE. For 
Period 2, assessment of relationship will automatically be between the OKZ and AE. For 
Period 3, assessment of relationship between study treatment and AE should be done separately 
for OKZ and the cocktail (2 questions in the eCRF: 1 for the relationship to OKZ and 1 for the 
relationship to the cocktail). 
All weight, BMI and vital signs measurements, 12-lead ECG results, and laboratory test results 
will be summarized using descriptive statistics at each visit for raw numbers and change from 
baseline. The incidence of treatment-emergent abnormal laboratory, vital sign, and ECG values 
will also be summarized using descriptive statistics 
The number and percentage of subjects testing positive for ADAs will be summarized over time. 
A listing will be presented for COVID-19 positive cases reported. The detailed analysis plan for 
COVID-19 can be included in the SAP. 
9.4.4 
Other Analyses 
A table showing the number and percentage of subjects who had each medical history condition 
coded to MedDRA Version 20.0 or higher SOC and PT and a by-subject data listing with each 
subject’s conditions in order by start date will be presented. 
Descriptive statistics and a by-subject listings will also be presented for demographic 
characteristics, subject disposition, analysis set, prior, and concomitant medications, disease 
history, and exposure to each study treatment. 
9.4.5 
Missing Data 
Missing study treatment data will not be imputed. Rules for imputing missing dates will be 
described in the SAP. 


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9.5 
Interim Analyses 
Interim analysis of the data collected after the last End of treatment visit of the last patient in the 
study can be conducted. 


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10.0 REFERENCES 
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cytochrome P450 enzymes in adult hepatocytes in primary culture. Mol Pharmacol. 
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Actemra Prescribing Information, Genentech, CA, 2014 
Aitken AE, Morgan ET. Gene-specific effects of inflammatory cytokines on Cytochrome P450 
2C, 2B6 and 3A4 mRNA levels in human hepatocytes. DMD. 2007;35:1687-93. 
Akira S, Tage T, Kishimoto T. Interleukin-6 in Biology and Medicine. Advances in Immunology 
1993;54:1-78. 
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010 
Rheumatoid Arthritis Classification Criteria: an American College of Rheumatology/European 
League Against Rheumatism Collaborative Initiative. Ann Rheum Dis. 2010;69(9):1580-8. 
Arend WP, Dayer GM. Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. 
Arthritis Rheum. 1990;33(3):305-315. 
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mediated drug metabolism is reduced in children with sepsis-induced multiple organ failure. 
Intensive Care Medicine. 2003;29:980-4. 
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 
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Frye RF, Schneider VM, Frye CS, Feldman AM. Plasma levels of TNF-α and IL-6 are inversely 
related to cytochrome P450-dependent drug metabolism in patients with congestive heart failure. 
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Genovese MC, Fleischmann R, Furst D, Janssen N, Carter J, Dasgupta B, et al. Efficacy and 
safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF 
inhibitor therapy: outcomes of a randomised Phase IIb study. Ann Rheum Dis. 2014;73(9):1607-
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Jacobsson LTH, Turesson C, Nilsson J-A, Petersson IF, Lindqvist E, Saxne T, et al. Treatment 
with TNF blockers and mortality risk in patients with rheumatoid arthritis. Ann Rheum Dis. 
2007;66:670-75. 
Kretsos K, Golor G, Jullion A, Hickling M, McCabe S, Shaw S, et al. Safety and 
pharmacokinetics of olokizumab, an anti-IL-6 monoclonal antibody, administered to healthy 
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Lee JI, Zhang L, Men Ay, Kenna LA, Huang SM. CYP-mediated therapeutic protein 
interactions: clinical findings, proposed mechanisms and regulatory implications. Clin 
Pharmacokinet. 2010;49(5):1116-23. 
Machavaram KK, Almond LM, Rostami-Hodjegan A, Gardner I, Jamei M, Tay S, Wong S, Joshi 
A, Kenny JR. A physiologically based pharmacokinetic modeling approach to predict disease–
drug interactions: Suppression of CYP3A by IL-6. Clin Pharmacol Ther. 2013;94(2):260 268. 
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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. 
Rivory LP, Slaviero, KA, Clarke SJ. Hepatic cytochrome P450 3A drug metabolism is reduced 
in cancer patients who have an acute-phase response. Br J Cancer. 2002;87:277 280. 
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TNF inhibitor therapy: a critical review. Arthritis Res Ther. 2009;11(Suppl 1):S1. 
Schmitt C, Kuhn B, Zhang X, Kivitz AJ, Grange S. Disease–drug–drug interaction involving 
tocilizumab and simvastatin in patients with rheumatoid arthritis. Clin Pharmacol Ther. 
2011;89(5):735 740. 
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. 
Takeuchi T, Tanaka Y, Yamanaka H, Amano K, Nagamine R, Park W, et al. Efficacy and safety 
of olokizumab in Asian patients with moderate-to-severe rheumatoid arthritis, previously 
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Tocilizumab (summary of product characteristics). Welyn Garden City: Roche. 2016. 
Turpault S, Brian W, Van Horn R, Santoni A, Poitiers F, Donaz-zolo Y et al. Pharmacokinetic 
assessment of a five-probe cocktail for CYPs 1A2,2C9,2C19,2D6 and 3A. Br J Clin Pharmacol. 
2009;68(6):928-35. 
U.S. Department of Health and Human Services Food and Drug Administration Center for Drugs 
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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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IL-6 signal transduction with a humanized anti-IL-6 receptor antibody. Springer Semin 
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Zang X, Schmitt C, Grange S, et al. Disease-Drug Interaction studies of Tocilizumab with 
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2015;55(12):1386-94. 


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11.0 APPENDICES 


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Appendix 1 
Abbreviations 
Abbreviation 
Definition 
λz 
Terminal rate constant 
ACR 
American College of Rheumatology 
ADA 
Antidrug antibody(ies) 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
AUC(0-inf) 
Area under the plasma concentration-time curve from time zero 
extrapolated to infinity, calculated by linear up/log down 
trapezoidal summation 
AUC(0-last) 
Area under the plasma concentration-time curve from time zero 
to the time of the last quantifiable concentration, calculated by 
linear up/log down trapezoidal summation 
BP 
Blood pressure 
CDAI 
Clinical Disease Activity Index 
CI 
Confidence interval 
CL/F 
Apparent oral plasma clearance 
Cmax 
Maximum concentration obtained directly from the observed 
concentration versus time data 
COVID-19 
Coronavirus disease 2019 
CRP 
C-reactive protein 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 isozyme 
DAS28 
Disease Activity Score 28 joint count 
DMARDs 
Disease modifying anti-rheumatic drugs 
DNA 
Deoxyribonucleic acid 
ECD 
Electronic data capture 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EOS 
End of study 
EOT 
End of treatment 
FSH 
Follicle-stimulating hormone 


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Abbreviation 
Definition 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transpeptidase 
GI 
Gastrointestinal 
HB 
Hepatitis B virus 
HCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HRT 
Hormonal replacement therapy 
IB 
Investigator’s Brochure 
ICD 
Implantable Cardioverter-Defibrillator 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committees 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IGRA 
Interferon-gamma release assay 
IL-6 
Interleukin-6 
IRB 
Institutional Review Board 
mAb 
Monoclonal atibody 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial Infarction 
Min 
Minimum 
MTX 
Methotrexate 
NTCP 
Sodium/taurocholate cotransporting polypeptide 
OKZ 
Olokizumab 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
q2w 
Every 2 weeks 
q4w 
Every 4 weeks 
RT-PCR 
Reverse transcription polymerase chain reaction 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 


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Abbreviation 
Definition 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SDAI 
Simplified Disease Activity Index 
SFU 
Safety Follow-up 
SoA 
Schedule of Activities 
TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
TNF-α 
Tumor necrosis factor alpha 
TNFi 
TNF-α inhibitor 
t1/2 
Terminal half-life 
tmax 
Time to Cmax 
ULN 
Upper limit of normal 
Vz/F 
Apparent volume of distribution 
VKORC1 
Vitamin K epOxide Reductase Complex subunit 1 
WOCBP 
Woman of childbearing potential 
 


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Appendix 2 
Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
 This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
 Applicable ICH Good Clinical Practice (GCP) Guidelines Revision 2. 
 Applicable laws and regulations. 
 Order No. 200n dated April 01, 2016 of the Ministry of Health of the Russian 
Federation on Approval of Rules for Good Clinical Practice. 
 The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
 Any amendments to the protocol will require IRB/IEC and regulatory authority approval, 
when applicable, before implementation of changes made to the study design, except for 
changes necessary to eliminate an immediate hazard to subjects. 
 The Investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
 Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
 Providing oversight of the conduct of the study at the study center and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations. 
 After reading the protocol, each Investigator will sign the protocol signature page and send a 
copy of the signed page to the Sponsor or representative (Appendix 11). The study will not 
start at any study center at which the Investigator has not signed the protocol. 
Adequate Resources 
The Investigator is responsible for supervising any individual or party to whom the Investigator 
delegates study-related duties and functions conducted at the study center. 
If the Investigator/institution retains the services of any individual or party to perform 
study-related duties and functions, the Investigator/institution should ensure this individual or 
party is qualified to perform those study-related duties and functions and should implement 


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procedures to ensure the integrity of the study-related duties and functions performed and any 
data generated. 
Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
Insurance 
The Sponsor 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. 
Informed Consent Process 
 The Investigator or his/her representative will explain the nature of the study to the subject or 
his/her legally authorized representative and answer all questions regarding the study. 
 Subjects must be informed that their participation is voluntary. Subjects or their legally 
authorized representative will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the 
IRB/IEC or study center. 
 The medical record must include a statement that written informed consent was obtained 
before the subject was entered in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
 Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
 A copy of the ICF(s) must be provided to the subject or the subject’s legally authorized 
representative. 
A subject who is rescreened is not required to sign another ICF if the rescreening occurs within 
14 days from the previous ICF signature date and there have been no changes to the ICF 
previously signed by the subject. 
Data Protection 
 Subjects will be assigned a unique identifier by the Sponsor. Any subject records or datasets 
that are transferred to the Sponsor will contain the identifier only; subject names or any 
information which would make the subject identifiable will not be transferred. 


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 The subject must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject. 
 The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
 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. 
 The Sponsor or its representative will not provide individual genotype 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. 
 Extra precautions are taken to preserve confidentiality and prevent genetic data being linked 
to the identity of the subject. In exceptional circumstances, however, certain individuals 
might see both the genetic data and the personal identifiers of a subject. For example, in the 
case of a medical emergency, the Sponsor or representative physician or an Investigator 
might know a subject’s identity and also have access to his or her genetic data. Also, 
regulatory authorities may require access to the relevant files. 
Administrative Structure 
No safety review committee will be initiated for this study. 
Table 13 
Study Administrative Structure 
Function 
Responsible Organization 
Study Operations Management 
Site Monitoring 
Medical Monitoring 
CRO/3rd party 
Study Master File 
CRO 
Data Management 
CRO/3rd party 
Clinical Supply Management 
Sponsor/3rd party 
Quality Assurance Auditing 
Sponsor/CRO/3rd party 
Biostatistics 
Medical Writing 
CRO 
Laboratory Assessments 
3rd party 
Electrocardiogram Collection, Review, and Analysis 
3rd party 
Bioanalytical Sample Analysis 
3rd party 
Pharmacokinetic Analysis 
CRO 
CRO = Contract Research Organization 
 


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Medical Monitor 
The Medical Monitor will be identified and employed before the start of the Study. 
Dissemination of Clinical Study Data 
The results of the study should be reported within 1 year from the end of the clinical study. 
Irrespective of the outcome, the Sponsor will submit to the EU database (EudraCT) a summary 
of the results of the clinical study within 1 year from the end of the clinical study. It shall be 
accompanied by a summary written in a manner that is understandable to laypersons. 
Data Quality Assurance 
 All subject data relating to the study will be recorded on eCRFs unless transmitted to the 
Sponsor or designee electronically (eg, laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
eCRF. 
 The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
 The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections, and provide direct access to source data documents. 
 The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
 Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized study center personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
 Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor. 
Source Documents 
The Investigator/institution should maintain adequate and accurate source documents and study 
records that include all pertinent observations on each of the study center’s subjects. Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, should not obscure the original entry, and should be explained if 
necessary (eg, via an audit trail). 
 Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s study center. 


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 Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
Study and Study Center Closure 
The Sponsor designee reserves the right to close the study center or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study centers will be closed upon study 
completion. A study center is considered closed when all required documents and study supplies 
have been collected and a study center closure visit has been performed. 
The Investigator may initiate study center closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study center by the Sponsor or Investigator may include but 
are not limited to: 
 Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor’s procedures, or GCP guidelines. 
 Inadequate recruitment of subjects by the Investigator. 
 Discontinuation of further study treatment development. 
Publication Policy 
 The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before 
submission. This allows the Sponsor to protect proprietary information and to provide 
comments. 
 The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual study center 
data. In this case, a Coordinating Investigator will be designated by mutual agreement. 
 Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 


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Appendix 3 
Clinical Laboratory Tests 
 The tests detailed in Table 14 will be performed by the central laboratory. 
 Local laboratory results are only required in the event that the central laboratory results are 
not available in time for either study treatment administration and/or response evaluation or 
if local laboratory tests are required by the protocol. If a local sample is required, it is 
important that the sample for central analysis is obtained at the same time. 
 Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 5.0 of the protocol. 
 Additional tests may be performed at any time during the study as determined necessary by 
the Investigator or required by local regulations. 
Table 14 
Protocol-required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
White Blood Cell Count with Differential 
 
Red Blood Cell Count 
Hematocrit 
 
Hemoglobin 
 
Clinical Chemistrya 
Creatinine 
Aspartate aminotransferase (AST) 
 
Glucose (fasting) 
Alanine aminotransferase (ALT) 
 
Sodium 
Alkaline phosphatase (ALP) 
 
Gamma glutamyl transferase (GGT) 
Creatine kinase 
 
Total bilirubin 
Potassium 
 
Total protein 
Direct and indirect bilirubin 
 
Total cholesterol  
Albumin 
Biomarkers 
C-reactive protein 
Interleukin-6 
Coagulation 
International normalized ratio (INR)b  
Activated partial thromboplastin time 
(aPTT)  
 
 
Fibrinogen 
Urinalysis 
Leucocytes 
Red blood cells 
 
Protein 
pH 
 
Bilirubin 
Nitrite 
 
Urobilinogen 
Specific gravity 
 
Ketones 
Glucose 
 
Microscopy (if clinically indicated) 
 
Viral serology 
HIV I and II 
Hepatitis C Virus 
 
HBsAg 
anti-HBs 
 
anti-HBc 
HBV DNAb 


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Laboratory 
Assessments 
Parameters 
Drugs of abuse 
and alcoholc 
Amphetamine/Metamphetamine  
Opiates/Opioids 
Ethanol 
Benzodiazepines 
 
Marijuana 
Methadone/Methadone metabolite 
 
Cocaine 
Barbiturates 
 
Ketamine 
Ecstasy 
(3,4-Methylenedioxymethamphetamine) 
 
Cotinine 
Phencyclidine 
 
Tricyclin anti-depressants (TCA)  
 
Glycosylated 
hemoglobin 
HbA1c 
SARS-CoV-2 
screening 
Anti-SARS-CoV-2 IgM 
Anti-SARS-CoV-2 IgG 
 
SARS-CoV-2 (RT-PCR) 
Other screening tests 
QuantiFERON-TB Gold Plus interferon-gamma release assay (IGRA). 
Follicle-stimulating hormone (FSH) and estradiol (as needed in women of 
non-childbearing potential only). 
Human Chorionic Gonadotropin (HCG) blood (serum_ test (as needed for women of 
childbearing potential at Screening). 
Human Chorionic Gonadotropin (HCG) urine test (as needed for women of childbearing 
potential at further visits). 
CYP2C9, CYP2C19 and high sensitivity to warfarin genotyping. 
All study-required laboratory assessments will be performed by the central laboratory. 
Abbreviations: anti-HBc = hepatitis B core antibody; anti-HBs = hepatitis B surface antibody; DNA = 
deoxyribonucleic acid; eCRF = electronic case report form; HbA1c = glycosylated hemoglobin A1c; 
HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HIV = human immunodeficiency virus; IgG = 
Immunoglobulin G; IgM = Immunoglobulin M; RT-PCR = reverse transcription polymerase chain reaction; 
SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; TB = tuberculosis. 
NOTES: 
a  The following laboratory abnormalities require prompt retesting after the initial abnormal result is reported to 
the study center (within 72 hours of receiving abnormal liver function test [LFT] results and within 5 days of 
receiving all other abnormal results): 
 
Any single ALT and/or AST elevation >3 × upper limit of normal (ULN), regardless of total bilirubin 
(repeat laboratory testing must include total bilirubin, direct and indirect bilirubin, GGT, INR, ALP, 
creatine kinase, and hematology assessment) 
 
Neutrophil count <1,000 × 106/L (<1,000/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 baseline 
b  HBV DNA test to be performed in anti-HBc positive subjects only. 
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. 


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Laboratory 
Assessments 
Parameters 
b The results from INR samples taken as safety assessments for warfarin (Days 2, 3, 4, 5, and 6, as well as 
Day 21, and Days 23, 24, 25, and 27) should be available within 24 hours (and for the sample taken on 
Day 21, before cocktail administration on Day 22). 
c Urine and breath express tests can be performed at the study center using kits provided by the central 
laboratory. 
 
Investigators must document their review of each laboratory safety report. 


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Appendix 4 
Concomitant and Excluded Medications/Therapy 
Concomitant Medication 
Must have received MTX, sulfasalazine, or hydroxychloroquine for at least 12 weeks prior to 
Day 1 and in stable dose for at least 6 weeks prior to Day 1 without significant AEs. Stable doses 
of MTX should be 10 mg to 25 mg weekly with folic acid (at least 5 mg weekly or equivalent). 
No significant side effects based on the Investigator’s judgment should be observed during 
treatment by these agents. The maximum allowed doses of sulfasalazine and hydroxychloroquine 
are: 
 Sulfasalazine: 3 g per day 
 Hydroxychloroquine: 400 mg per day 
Note: The doses should remain stable and not be changed from the time of signing the ICF until 
the end of the treatment period (EOT, Day 29). 
Restricted and Excluded Medication 
Excluded medications/therapy is listed below. The use of an excluded medication/therapy is a 
protocol violation and must be recorded in the eCRF. 
As per the exclusion criteria (Section 5.2), the following medications/therapy are not allowed 
within the mentioned time frame: 
Medications 
Restrictions 
DMARDs 
 
Azathioprine, cyclosporine, chloroquine, gold, 
penicillamine, minocycline, or doxycycline 
Restricted within 4 weeks of Day 1 and during the 
study 
Leflunomide alone 
Restricted within 12 weeks of Day 1 and during the 
study 
Leflunomide with elimination procedure with 
cholestyramine at a dosage of 8 grams 3 times daily for 
at least 24 hours 
Restricted within 4 weeks of Day 1 and during the 
study 
Leflunomide with elimination procedure with activated 
charcoal at a dosage of 50 grams 4 times a day for at 
least 24 hours 
Restricted within 4 weeks of Day 1 and during the 
study 
Cyclophosphamide 
Restricted within 24 weeks of Day 1 and during the 
study 
Treatment with any cell depleting therapies 
 
Anticluster of differentiation (CD)20 or investigational 
agents (eg, CAMPATH®, anti-CD4, anti-CD5, anti-
CD3, and anti-CD19) 
Not allowed during the study 
Rituximab 
Not allowed within 6 months of Day 1 and during 
the study 


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Treatment with tumor necrosis factor inhibitors or any 
other biologic therapy for the treatment of RA 
Not allowed within 12 weeks of Day 1 and during 
the study 
Parenteral and/or intra-articular or topical glucocorticoids 
Restricted within 4 weeks prior to Day 1 and during 
the study 
Oral glucocorticoids greater than 10 mg/day prednisone 
(or equivalent) 
May not be used, or the dose changed within 
4 weeks prior to Day 1 and during the study 
NSAIDs 
 
Indomethacin and ketorolac 
Not allowed during the study 
Other NSAIDs 
Must be taken at a stable dose and route of 
administration for at least 2 weeks prior to Day 1 
and during the study 
Hormone replacement therapy 
Restricted within 4 weeks prior to Day 1 and during 
the study 
Vaccination with live vaccines 
Restricted within 6 weeks prior to Day 1 and during 
the study 
Use of aspirin or other antiplatelet agents and 
anticoagulants including warfarin 
Restricted within 4 weeks prior to Day 1 and during 
the study 
Use of any prescription or nonprescription drugs or other 
products (eg, herbal preparations, food products) known to 
be inhibitors/inducers of CYP3A4, CYP2C9, CYP2C19, 
or CYP1A2 otherwise not mentioned above 
Restricted within 4 weeks prior to Day 1 and during 
the study. See Table 15 for a detailed list of these 
compounds 
Use of any other herbal preparations (including foods or 
beverages containing herbal preparations), dietary 
supplements, or natural medications 
Restricted within 14 days prior to Day 1 and during 
the study 
Midazolam and/or omeprazole (or esomeprazole) 
Restricted within 14 days prior to Day 1 and during 
the study 
Consumption of any caffeine-containing drinks or food, 
eg, coffee, tea, chocolate, caffeine-containing energy 
drinks (eg, Red Bull), or cola 
Restricted within 48 hours prior to each 
administration of the cocktail (Day1 and Day 22) 
Medication which could adversely affect gastrointestinal 
motility or transit (eg, diphenoxylate, [loperamide], 
metoclopramide, cisapride, tegaserod, erythromycin) 
Restricted from 7 days prior to each administration 
of the cocktail drugs (Day 1 and Day 22) through 
the 48 hours following each cocktail administration 
 
 


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Table 15 
List of Cytochrome P450 Inhibitors and Inducers 
 
CYP1A2 
CYP2C9 
CYP2C19 
CYP3A4 
Inhibitors  
Amiodarone, efavirenz, 
fluoroquinolones, fluvoxamine, 
furafylline, interferon, 
methoxsalen, mibefradil, 
ticlopidine 
 
Strong inhibitors: 
Fluvoxamine, ciprofloxacin 
 
Weak inhibitors: 
Cimetidine 
 
 
Efavirenz, fenofibrate, 
fluconazole, Fluvastatin, 
fluvoxamine, isoniazid, 
lovastatin, metronidazole, 
paroxetine, phenylbutazone, 
probenecid, sertraline, 
sulfamethoxazole, 
sulfaphenazole, teniposide, 
voriconazole, zafirlukast 
 
Strong inhibitors: 
Fluconazole 
 
Moderate inhibitors: 
Amiodarone 
 
PPIs: 
Esomeprazole, lansoprazole, 
omeprazole, pantoprazole 
 
Other: 
Chloramphenicol, cimetidine, 
felbamate, fluoxetine, 
fluvoxamine, indomethacin, 
isoniazid, ketoconazole, 
modafinil, oral contraceptives, 
oxcarbazepine, probenecid, 
ticlopidine, topiramate, 
voriconazole 
Amiodarone, chloramphenicol, 
boceprevir, ciprofloxacin, 
delaviridine, diethyl-
dithiocarbamate, fluvoxamine, 
gestodene, imatinib, mibefradil, 
mifepristone, norfloxacin 
 
Strong inhibitors: 
HIV Antivirals: 
Indinavir, nelfinavir, ritonavir 
 
Clarithromycin, itraconazole, 
ketoconazole, nefazodone, 
saquinavir 
 
Telithromycin 
 
Moderate inhibitors: 
Aprepitant, erythromycin, 
fluconazole, grapefruit juice, 
verapamil, diltiazem 
 
Weak inhibitors: 
Cimetidine 
 
norfluoxetine 
starfruit 
telaprevir 
voriconazole 


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CYP1A2 
CYP2C9 
CYP2C19 
CYP3A4 
Inducers  
Broccoli, brussel sprouts, 
carbamazepine, char-grilled 
meat, insulin, 
methylcholanthrene, modafinil, 
nafcillin, beta-naphthoflavone, 
omeprazole, rifampin, tobacco 
Carbamazepine, enzalutamide, 
nevirapine, phenobarbital, 
rifampin, secobarbital, St. John's 
Wort 
Carbamazepine, efavirenz, 
enzalutamide, norethindrone, 
prednisone, rifampicin, ritonavir, 
St. John's Wort 
HIV Antivirals: 
Efaviren, nevirapine 
 
Barbiturates, carbamazepine, 
enzalutamide, glucocorticoids, 
modafinil, oxcarbazepine, 
phenobarbital, phenytoin, 
pioglitazone, rifabutin, rifampin, 
St. John's Wort, troglitazone 
Abbreviations: CYP = Cytochrome P450 isozyme; HIV = Human immunodeficiency virus; PPI = proton-pump inhibitor 
Source: https://drug-interactions.medicine.iu.edu/Main-Table.aspx 
 
 


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Appendix 5 
Stages of Heart Failure – New York Heart Association 
Classification 
The Stages of heart failure – New York Heart Association classification: 
 
Class I (Mild) 
No Limitation of physical activity. Ordinary physical activity does 
not cause undue fatigue, palpitation, or dyspnea (shortness of 
breath) 
Class II (Mild) 
Slight limitation of physical activity. Comfortable at rest, but 
ordinary physical activity results in fatigue, palpitation, or dyspnea 
Class III (Moderate) 
Marked limitation of physical activity. Comfortable at rest, but less 
than ordinary physical activity results in fatigue, palpitation, or 
dyspnea 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort. 
Symptoms of cardiac insufficiency at rest. If any physical activity is 
undertaken, physical discomfort is increased 
 
Reference 
The Criteria Committee of the New York Heart Association. Nomenclature and criteria for 
diagnosis of diseases of the heart and great vessels. 9th ed. Boston (MA): Little, Brown & Co; 
1994:253-256. 
 


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Appendix 6 
Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile (i.e. of childbearing potential) following menarche and until 
becoming postmenopausal unless permanently sterile (see below). 
Women in the Following Categories Are Not Considered WOCBP 
1. Female who is surgically sterile (ie, bilateral tubal ligation or removal of both ovaries and/or 
uterus at least 6 months prior to first dosing). 
2. Female who is naturally postmenopausal (spontaneous cessation of menses) for at least 
24 consecutive months prior to first dosing, with a follicle-stimulating hormone level at 
Screening of ≥40 mIU/mL. 
 
Contraception Guidance 
Female Subjects 
 Female subjects defined at Screening as WOCBP are eligible to participate if they continue 
to have negative pregnancy test AND agree to use ONE of the highly effective contraception 
methods (see below) for duration of study (starting from signed ICF) and for 6 months after 
the OKZ dosing. 
Highly Effective Contraceptive Methods for Female Subjects of Childbearing Potential are: 
 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 Screening (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 copper intrauterine device (IUD). 
 Pregnant and breastfeeding women are not eligible to participate in this study. 
Male Subjects 
 Male subjects with female partners of childbearing potential are eligible to participate if they 
agree to ONE of the following: 


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 Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent for 
duration of study (starting from signed ICF) and for 6 months after the OKZ dosing. 
 Agree to use a male condom and have their partner use of a contraceptive method 
with a failure rate of <1% per year (see below) when having penile-vaginal 
intercourse with a WOCBP who is not currently pregnant. 
 In addition, male subjects must refrain from donating sperm for the duration of the study 
(starting from signed ICF) and for 6 months after the OKZ dosing. 
 Male subjects with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration 
for duration of study (starting from signed ICF) and for 6 months after the OKZ dosing. 
Highly Effective Contraceptive Methods for Female Partners of Childbearing Potential 
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulationb 
 
Oral. 
 
Intravaginal. 
 
Transdermal. 
Progestogen only hormonal contraception associated with inhibition of ovulation 
 
Oral. 
 
Injectable.  
Highly Effective Methods That Are User Independent a  
Implantable progestogen only hormonal contraception associated with inhibition of ovulationb 
 
Intrauterine device (IUD). 
 
Intrauterine hormone-releasing system (IUS). 
Bilateral tubal occlusion. 
Sexual Abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatment. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the subject.  
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for subjects participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the efficacy 
of the contraceptive method. In this case, 2 highly effective methods of contraception should be utilized during 
the treatment period and for at least 6 months after the last dose of study treatment.  
 


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Protocol CL04041026 – Amendment 3 
 
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Collection of Pregnancy Information 
 The Investigator will attempt to collect pregnancy information (course and outcome) on any 
female subject of childbearing potential or male subject’s female partner who becomes 
pregnant while the subject is in this study. This applies only to subjects who receive OKZ 
dosing. 
 If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy by submitting a Pregnancy Report via eCRF. 
 The female study subjects are considered agreeable to allow follow-up on pregnancy by 
signing study ICF. 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. 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.  
 The pregnant female subject or female partner of male subject will be followed to determine 
the outcome of the pregnancy. Generally, the follow-up will be no longer than 6 to 8 weeks 
following the estimated delivery date.  
 Once any additional information on pregnancy course and outcomes is obtained, the 
Investigator will update the Pregnancy Report in eCRF.  
 Any termination of the pregnancy will be reported regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
 Outcome of each pregnancy (spontaneous abortion, elective abortion or for medical reasons, 
normal delivery or delivery of a child with congenital abnormalities or birth defects) should 
be recorded even if the subject withdrew from the study.  


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Protocol CL04041026 – Amendment 3 
 
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Appendix 7 
Genetics 
Use/Analysis of DNA 
 Genetic variation may impact a subject’s response to study treatment, susceptibility to, and 
severity, and progression of disease. Variable response to study treatment may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and excretion; 
mechanism of action of the drug; disease etiology; and/or molecular subtype of the disease 
being treated. Therefore, where local regulations and IRB/IEC allow, a blood sample will be 
collected for DNA analysis from consenting subjects. 
 DNA samples will be used for research related to study treatment and related diseases. They 
may also be used to develop tests/assays including diagnostic tests related to study treatment 
and/or treatments of this drug class and RA. Genetic research may consist of the analysis of 
1 or more candidate genes or the analysis of genetic markers throughout the genome. 
 DNA samples will be analyzed for intermediate metabolizers of CYP2C9 (genotype 
*1/*2,*1/*3), poor metabolizers of CYP2C9 (genotype *2/*2, 2/*3; *3/*3) or CYP2C19 
(genotype *2/*2, *3/*3), ultra-rapid metabolizers of CYP2C19 (*17/*17) or high sensitivity 
to warfarin (VKORCI genotype AG and AA). Additional blood sampling for genotype for 
the long-term storage will be performed. Additional analyses may be conducted if it is 
hypothesized that this may help further understand the clinical data. 
 The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to study treatment or study treatments of this class to understand study 
disease or related conditions. 
 The results of genetic analyses may be reported in the Clinical Study Report (CSR) or in a 
separate study summary. 
 The Sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality. 
 The samples will be retained while research on study treatment or study treatments of this 
class or indication continues but no longer than 5 years or other period as per local 
requirements. 


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Protocol CL04041026 – Amendment 3 
 
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Appendix 8 
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 (ie, sharing the same household, or 
other enclosed environment, such as a social gathering place, workplace, 
or facility, for extended periods during the day) with an individual with 
active TB 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 (eg, 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 16) (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: 


CONFIDENTIAL 
Protocol CL04041026 – Amendment 3 
 
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Table 16 
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 
Congo 
325 (295–356) 
Mauritania 
111 (79–148) 
Thailand 
171 (90–276) 


CONFIDENTIAL 
Protocol CL04041026 – Amendment 3 
 
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Country 
Incidencea 
Country 
Incidencea 
Country 
Incidencea 
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. 
 


CONFIDENTIAL 
Protocol CL04041026 – Amendment 3 
 
 Page 113 of 115 
Appendix 9 
DAS28 Joint Table 
Left 
Right 
Joint 
Tender 
Joint? 
Swollen 
Joint? 
Joint 
Tender 
Joint? 
Swollen 
Joint? 
Shoulder 
 
 
Shoulder 
 
 
Elbow 
 
 
Elbow 
 
 
Wrist 
 
 
Wrist 
 
 
Knee 
 
 
Knee 
 
 
Hand 
Digit 1 
IP 
 
 
Hand 
Digit 1 
IP 
 
 
MCP 
 
 
MCP 
 
 
Digit 2 
PIP 
 
 
Digit 2 
PIP 
 
 
MCP 
 
 
MCP 
 
 
Digit 3 
PIP 
 
 
Digit 3 
PIP 
 
 
MCP 
 
 
MCP 
 
 
Digit 4 
PIP 
 
 
Digit 4 
PIP 
 
 
MCP 
 
 
MCP 
 
 
Digit 5 
PIP 
 
 
Digit 5 
PIP 
 
 
MCP 
 
 
MCP 
 
 
IP = Interphalangeal joint (IP) on digit 1; MCP = metacarpophalangeal joints on digits 1 to 5; PIP = proximal 
interphalangeal joints on digits 2 to 5. 
 
Figure 2 
Visual Analog Scale – Bullet Style 
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, where 0 is “very well” and 10 is “very 
poorly”. 
 
 
 
 


CONFIDENTIAL 
Protocol CL04041026 – Amendment 3 
 
 Page 114 of 115 
Appendix 10 
Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 


CONFIDENTIAL 
Protocol CL04041026 – Amendment 3 
 
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Appendix 11 
Signature of Investigator 
PROTOCOL TITLE: A Phase 1, Open-label, Study in Subjects with Rheumatoid Arthritis to 
Evaluate the Effect of a Single Dose of Olokizumab on the Pharmacokinetics of Substrates for 
CYP1A2, CYP2C9, CYP2C19, and CYP3A4 
PROTOCOL NO: 
CL04041026 
VERSION:  
 
Protocol Amendment 3 
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 the Sponsor. 
Instructions to the Investigator: Please SIGN and DATE this signature page. PRINT your name, title, and the name of the study 
center in which the study will be conducted. Return the signed copy to CRO. 
 
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 Center:  
___________________________ 
 
 
 
 
 
___________________________ 
 
 
 
 
 
___________________________