A Randomized, Double-blind, Parallel Group, Multicenter Study to Assess the Immunogenicity and Safety of Transitioning Subjects With Rheumatoid Arthritis to Biosimilar Rituximab (DRL_RI) or Continued Treatment With Rituxan® or MabThera®
Phase: PHASE3
Conditions: Rheumatoid Arthritis
Sponsor: Dr. Reddy's Laboratories Limited

 
 
 
 
 
 
 
A Randomized, Double-Blind, Parallel Group, Multicenter Study to Assess the Immunogenicity and 
Safety of Transitioning Subjects with Rheumatoid Arthritis to Biosimilar Rituximab (DRL_RI) or 
Continued Treatment with Rituxan® or MabThera® 
                                                                  NCT number: NCT04268771 
                                                        Date of protocol : 10 July 2020 

CONFIDENTIAL 
All financial and nonfinancial support for this study will be provided by Dr. Reddy’s 
Laboratories S.A. The concepts and information contained in this document or generated 
during the study are considered proprietary and may not be disclosed in whole or in part 
without 
the 
expressed, 
written 
consent 
of 
Dr. 
Reddy’s 
Laboratories 
S.A. 
The study will be conducted according to the International Council for Harmonisation 
Harmonised Tripartite Guideline E6(R2): Good Clinical Practice. 
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Dr. Reddy’s Laboratories S.A. 
DRL_RI 
Protocol: RI-01-007 Version 3.0 Amendment 2 
10 Jul 2020 
Protocol Approval – Sponsor Signatory 
Study Title 
A Randomized, Double-Blind, Parallel Group, Multicenter Study to 
Assess the Immunogenicity and Safety of Transitioning Subjects With 
Rheumatoid Arthritis to Biosimilar Rituximab (DRL_RI) or Continued 
Treatment With Rituxan® or MabThera®
Protocol Number RI-01-007
Protocol Date 
10 Jul 2020 
Protocol accepted and approved by: 
 
 
 
 
 
 
 
 
 
 
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CI
CI

Dr. Reddy’s Laboratories S.A. 
DRL_RI 
Protocol: RI-01-007 Version 3.0 Amendment 2 
10 Jul 2020 
Declaration of Investigator 
I have read and understood all sections of the protocol entitled “A randomized, double-blind, 
parallel group, multicenter study to assess the immunogenicity and safety of transitioning 
subjects with rheumatoid arthritis to biosimilar rituximab (DRL_RI) or continued treatment 
with Rituxan® or MabThera®” and the accompanying Investigator’s Brochure. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Final Protocol Version 3.0, Amendment 2, dated 10 Jul 2020, the 
International Council for Harmonisation Harmonised Tripartite Guideline E6(R2): Good 
Clinical Practice and all applicable government regulations. I will not make changes to the 
protocol before consulting with Dr. Reddy’s Laboratories S.A. or implement protocol changes 
without Independent Ethics Committee/Institutional Review Board approval except to 
eliminate an immediate risk to subjects. I agree to administer study treatment only to subjects 
under my personal supervision or the supervision of a sub-investigator. 
I will not supply the investigational drug to any person not authorized to receive it. 
Confidentiality will be protected. Subject identity will not be disclosed to third parties or 
appear in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from Dr. Reddy’s Laboratories S.A. 
Signature of Principal Investigator 
Date 
Name of Principal Investigator 
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Table of Contents 
Table of Contents .......................................................................................................................6 
List of Tables ............................................................................................................................10 
List of Figures ..........................................................................................................................10 
Protocol Synopsis ..................................................................................................................... 11 
List of Abbreviations ................................................................................................................18 
1 
Introduction ......................................................................................................................21 
1.1 
Background and Rationale ......................................................................................21 
1.1.1 
Rituximab .................................................................................................21 
1.1.1.1 
Mechanism of Action ...............................................................................22 
1.1.1.2 
Pharmacodynamics ..................................................................................23 
1.1.1.3 
Efficacy in Rheumatoid Arthritis .............................................................24 
1.1.1.4 
Safety Profile ...........................................................................................26 
1.1.1.5 
Immunogenicity .......................................................................................27 
1.1.2 
Dr. Reddy’s Rituximab (DRL_RI) ...........................................................28 
1.1.2.1 
Nonclinical Studies ..................................................................................29 
1.1.2.2 
Clinical Studies ........................................................................................29 
1.1.3 
Study Rationale ........................................................................................30 
1.1.4 
Risk/Benefit and Ethical Assessment ......................................................30 
2 
Study Objectives and Endpoints .......................................................................................31 
3 
Investigational Plan ..........................................................................................................32 
3.1 
Study Design ...........................................................................................................32 
3.1.1 
Description ...............................................................................................32 
3.1.2 
Rationale of Study Design .......................................................................34 
3.1.3 
Early Termination of the Study ................................................................35 
3.1.4 
End of Study ............................................................................................36 
3.2 
Study Conduct During the COVID-19 Pandemic ...................................................36 
3.2.1 
Benefit-Risk Assessment of Rituximab Treatment During the COVID-19 
Pandemic ..................................................................................................36 
3.2.2 
Contingency Measures Taken During the COVID-19 Pandemic ............37 
4 
Subject Selection and Withdrawal Criteria ......................................................................39 
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4.1 
Selection of Study Population .................................................................................39 
4.1.1 
Inclusion Criteria .....................................................................................39 
4.1.2 
Exclusion Criteria ....................................................................................39 
4.2 
Withdrawal of Subjects From Study Treatment and/or the Study ..........................42 
4.2.1 
Reasons for Withdrawal/Discontinuation ................................................42 
4.2.2 
Handling of Withdrawals .........................................................................43 
4.2.3 
Replacements ...........................................................................................44 
5 
Study Treatments ..............................................................................................................45 
5.1 
Method of Assigning Subjects to Treatment Arms .................................................45 
5.2 
Treatments Administered ........................................................................................45 
5.2.1 
Study Treatment Infusion Preparation .....................................................46 
5.2.2 
Pre-medication for Study Treatment Infusions ........................................46 
5.2.3 
Study Treatment Administration ..............................................................46 
5.3 
Identity of Investigational Product ..........................................................................48 
5.4 
Management of Clinical Supplies ...........................................................................48 
5.4.1 
Packaging .................................................................................................48 
5.4.2 
Labelling ..................................................................................................48 
5.4.3 
Storage .....................................................................................................48 
5.4.4 
Study Treatment Accountability ..............................................................49 
5.5 
Overdose Management ...........................................................................................49 
5.5.1 
Medication Errors ....................................................................................50 
5.6 
Transmission of Infectious Agents ..........................................................................50 
5.7 
Blinding ...................................................................................................................50 
5.7.1 
Breaking the Blind ...................................................................................51 
5.8 
Treatment Compliance ............................................................................................51 
5.9 
Prior and Concomitant Therapy ..............................................................................52 
5.9.1 
Background Medication ...........................................................................52 
5.9.2 
Other Concomitant Medication ...............................................................52 
6 
Study Assessments and Procedures ..................................................................................54 
6.1 
Schedule of Assessments ........................................................................................54 
6.1.1 
Screening Period (Days -14 to 0) .............................................................54 
6.1.2 
Treatment Period (2 Weeks) ....................................................................56 
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6.1.3 
Follow-Up Period (10 Weeks) .................................................................58 
6.1.4 
End of Study/Early Termination Visit (Week 12 ± 7 Days) .....................59 
6.1.5 
Additional Follow-Up Visit (Week 26) ....................................................59 
6.2 
Immunogenicity Endpoint ......................................................................................60 
6.2.1 
Immunogenicity Sampling .......................................................................60 
6.2.2 
Immunogenicity Assay ............................................................................61 
6.3 
Safety Assessments .................................................................................................62 
6.3.1 
Adverse Events ........................................................................................65 
6.3.1.1 
Definitions ...............................................................................................65 
6.3.1.1.1 
Adverse Event/Reaction ...............................................................65 
6.3.1.1.2 
Treatment-Emergent Adverse Event ............................................67 
6.3.1.2 
Recording of Adverse Events ..................................................................67 
6.3.1.3 
Assessment of Severity ............................................................................68 
6.3.1.4 
Assessment of Causality ..........................................................................69 
6.3.1.5 
Reporting of Serious Adverse Events ......................................................71 
6.3.1.6 
Suspected Unexpected Serious Adverse Reactions .................................72 
6.3.2 
Abnormal Laboratory Values/Vital Signs 
Measurements/Electrocardiograms ..........................................................73 
6.3.3 
Deaths ......................................................................................................73 
6.3.4 
Clinical Laboratory Assessments .............................................................74 
6.3.5 
Physical Examination ..............................................................................75 
6.3.6 
Vital Sign Measurements .........................................................................75 
6.3.7 
12-Lead Electrocardiogram .....................................................................75
6.3.8 
Viral Disease Screening ...........................................................................76 
6.4 
Pregnancy ................................................................................................................76 
6.5 
Blood Loss During the Study ..................................................................................77 
7 
Statistical and Analytical Plan ..........................................................................................78 
7.1 
 ........................................................................................78 
7.2 
Analysis Sets ...........................................................................................................78 
7.3 
Description of Subgroups to be Analyzed ..............................................................78 
7.4 
Statistical Analysis Methodology ...........................................................................78 
7.4.1 
General Principles ....................................................................................78 
7.4.2 
Missing Data ............................................................................................79 
7.4.3 
Demographic and Baseline Characteristics .............................................79 
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7.4.4 
Subject Disposition ..................................................................................79 
7.4.5 
Immunogenicity Analysis ........................................................................79 
7.4.6 
Safety Analysis ........................................................................................80 
7.4.7 
Interim Analyses ......................................................................................81 
8 
Quality Control and Quality Assurance ............................................................................82 
8.1 
Case Report Forms/Source Data Handling .............................................................82 
8.2 
Data Management ...................................................................................................82 
9 
Ethics ................................................................................................................................84 
9.1 
Independent Ethics Committee or Institutional Review Board ..............................84 
9.2 
Ethical Conduct of the Study ..................................................................................84 
9.3 
Subject Information and Consent ............................................................................84 
10 Investigator’s Obligations ................................................................................................86 
10.1 Confidentiality ........................................................................................................86 
10.2 Financial Disclosure and Obligations .....................................................................86 
10.3 Investigator Documentation ....................................................................................87 
10.4 Study Conduct .........................................................................................................87 
10.5 Adherence to Protocol .............................................................................................87 
10.6 Adverse Events and Study Report Requirements ...................................................87 
10.7 Records Retention ...................................................................................................88 
10.8 Publications .............................................................................................................88 
11 Study Management ...........................................................................................................89 
11.1 Monitoring ..............................................................................................................89 
11.1.1 
Monitoring of the Study ...........................................................................89 
11.1.2 
Inspection of Records ..............................................................................89 
11.2 Management of Protocol Amendments and Deviations ..........................................90 
11.2.1 
Protocol Amendments ..............................................................................90 
11.2.2 
Protocol Deviations/Violations ................................................................90 
11.3 Study Termination ...................................................................................................91 
11.4 Final Report ............................................................................................................91 
12 Financing and Insurance ...................................................................................................93 
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13 Reference List ...................................................................................................................94 
14 Appendices .......................................................................................................................96 
14.1 Appendix 1: Schedule of Events .............................................................................96 
14.2 Appendix 2: Classification of Functional Status in Rheumatoid Arthritis .............98 
14.3 Appendix 3: Protocol Amendment ..........................................................................99 
14.3.1 
Protocol Amendment 1 – Protocol Version 2.0, Dated 12 Aug 2019 ......99 
14.3.1.1 Overview of Changes ...............................................................................99 
14.3.1.2 Changes to the Protocol Text .................................................................100 
14.3.2 
Protocol Amendment 2 – Protocol Version 3.0, Dated to be added .......105 
14.3.2.1 Overview of Changes .............................................................................105 
 
List of Tables 
Table 2-1 
Objectives and Endpoints ............................................................................... 31 
Table 6-1: 
Blood Loss During the Study .......................................................................... 77 
Table 14-1 
Schedule of Events .......................................................................................... 96 
Table 14-2: 
Classification of Functional Status in Rheumatoid Arthritis .......................... 98 
 
List of Figures 
Figure 3-1 
Study Scheme .................................................................................................. 34 
Figure 6-1: 
Flow Diagram for the Evaluation and Characterization of Anti-Drug 
Antibodies ....................................................................................................... 62 
 
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Protocol Synopsis 
Protocol Number: 
RI-01-007 
Title: 
A randomized, double-blind, parallel group, multicenter study to 
assess the immunogenicity and safety of transitioning subjects 
with rheumatoid arthritis to biosimilar rituximab (DRL_RI) or 
continued treatment with Rituxan® or MabThera® 
Sponsor: 
Dr. Reddy’s Laboratories S.A. 
Elisabethenanlage 11 
CH-4051 Basel 
Switzerland  
Study Phase: 
Phase 3 transition study 
Study Sites: 
It is planned that approximately 50 sites will be initiated for this 
study in up to 7 countries (including, but not restricted to, the 
United States [US]). 
Indication: 
Rheumatoid arthritis (RA) 
Rationale: 
The evaluation of pharmacokinetics (PK), efficacy, safety, and 
immunogenicity between a biosimilar and the innovator product 
is an essential component of an efficient clinical trial program 
collectively providing the evidence of biosimilarity.  
In the DRL_RI development program, Study RI-01-003 was a 
Phase 1/2, randomized, double-blind study comparing the PK and 
pharmacodynamics (PD) of DRL_RI (biosimilar rituximab) with 
United 
States licensed 
rituximab 
(Rituxan®, 
henceforth 
mentioned as US-rituximab) and European Union (EU)-approved 
rituximab (MabThera®, henceforth mentioned as EU-rituximab) 
in subjects with RA. Safety, efficacy, and immunogenicity of the 
treatments were also compared to those of the innovator reference 
products in this study. The study met all pre specified primary and 
secondary endpoints for PK, PD, and efficacy outcomes. 
The evaluation of safety and immunogenicity upon transition 
from a registered medicinal product to a biosimilar product is a 
requirement of US Food and Drug Administration. The objective 
of the current study is to assess the immunogenicity and safety of 
transitioning 
subjects 
with 
RA 
to 
DRL_RI 
from 
US-rituximab/EU-rituximab 
to 
continued 
treatment 
with 
US-rituximab/EU-rituximab. Subjects with RA who have 
received at least 1 full course comprising two 1000 mg infusions 
with either US-rituximab or EU-rituximab and are candidates for 
re-treatment with rituximab will be enrolled.  
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During the initial phase of the clinical use of a newly introduced 
biosimilar product, it is expected that many subjects will 
experience a transition from the currently marketed reference 
product to the biosimilar. Hence, ruling out changes in the safety 
and immunogenicity of the product upon a single transition from 
the reference product to the potential biosimilar is a relevant 
element in the clinical evaluation of the latter. 
Objectives: 
• To assess the immunogenicity of transitioning subjects with 
RA 
to 
DRL_RI 
(biosimilar 
rituximab) 
from 
US-rituximab/EU-rituximab to continued treatment with 
US-rituximab/EU-rituximab. 
• To assess the safety of transitioning subjects with RA to 
DRL_RI from US-rituximab/EU-rituximab to continued 
treatment with US-rituximab/EU-rituximab. 
Study Population: 
Inclusion Criteria 
A subject will be eligible for enrolment in the study if he/she 
meets all of the following criteria: 
1. Male or female subjects aged 18 years or older who have 
provided valid written informed consent. 
2. Subjects with a diagnosis of active RA who are eligible for the 
subsequent 
treatment 
course 
with 
US-rituximab 
or 
EU-rituximab according to the clinical judgment of the 
investigator.  
3. Documented evidence that subject has received at least 1 full 
course comprising two 1000 mg infusions of either 
US-rituximab at least 16 weeks prior to the randomization 
visit or EU-rituximab at least 24 weeks prior to the day of 
randomization visit. 
Note: Subjects are only eligible if they have received the prior 
US or EU-rituximab course within the 15 months prior to the 
date of randomization. 
4. Subjects receiving a stable dose of weekly methotrexate 
(MTX) for at least 4 weeks prior to randomization (between 
7.5 mg and 25 mg) and folic acid (at least 5 mg per week). 
Exclusion Criteria 
Subjects meeting any of the following criteria must not be 
enrolled in the study: 
1. Subjects with RA in functional Class IV (Table 14-2). 
2. Subjects with human immunodeficiency virus (positive 
HIV1Ab or HIV2Ab), hepatitis B virus and/or hepatitis C 
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virus infection, including those with positive results in the 
viral disease screening. 
3. Subjects with active tuberculosis (TB). Subjects with 
evidence of latent TB or a history of TB must have completed 
treatment or have initiated treatment for at least 1 month 
before the first dose of study treatment (Day 1). TB testing is 
required only if it is required by local regulations or practice. 
4. Active systemic infection. 
5. Severely immunocompromised. 
6. History of hypersensitivity to either US-rituximab or 
EU-rituximab or any of its excipients. 
7. Any serious illness or uncontrolled medical condition, 
including, but not limited to, severe infections, significant 
hepatic or renal disease, uncontrolled hypertension despite 
treatment (defined as blood pressure ≥160/95 mmHg), 
congestive heart failure (New York Heart Association 
[NYHA] Class III or IV), or other severe uncontrolled cardiac 
disease or uncontrolled diabetes with immediate risk of acute 
complications. 
8. Any condition that in the opinion of the investigator 
represents an obstacle for study conduct and/or represents a 
potential unacceptable risk for subjects. 
9. Requires treatment with any biological medicinal product 
during the study other than the study treatment. 
10. Previous treatment with B-cell modulating or cell-depleting 
biologic therapy, except US-rituximab or EU-rituximab. 
11. Prior participation in this clinical trial or prior participation in 
any clinical trial with any monoclonal antibody within 
12 months of screening or prior participation in any clinical 
trial within 3 months of screening or within 5 half-lives of the 
investigational drug or until the expected PD effect has 
returned to baseline, whichever is longer. 
12. Treatment 
with 
other 
biologic 
disease-modifying 
anti-rheumatic drugs, or Janus kinase (JAK) inhibitors 
administered within 12 weeks before the first dose of 
rituximab of the prior treatment course onwards till the date 
of randomization. 
13. Subjects with the following laboratory abnormalities: 
• Subjects with screening total white blood cell count 
<3000/μL, platelets <100,000/μL, neutrophils <1500/μL, 
or hemoglobin <8.5 g/dL. 
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• Abnormal liver function tests such as aspartate 
aminotransferase, alanine aminotransferase, or alkaline 
phosphatase >2 × upper limit of normal (ULN). A single 
parameter >2 × ULN can be re-checked as soon as 
possible, at least prior to randomization, if required per the 
investigator’s discretion. 
• Creatinine clearance (Cockcroft & Gault formula) of less 
than 50 mL/min. 
14. History of vaccination with live vaccines within 4 weeks of 
the first dose of study treatment (Day 1) or known to require 
live vaccines during the study. 
15. Lactating or pregnant female. 
16. Women of childbearing potential (WOCBP) who do not 
consent to use highly effective methods of birth control during 
treatment and for at least 12 months after the last 
administration of study treatment. 
Note: Per the Clinical Trial Facilitation Group (CTFG) 
guidelines 2014, a woman is considered of childbearing 
potential if fertile, following menarche until becoming 
postmenopausal (i.e., no menses for 12 months without an 
alternative medical cause) unless permanently sterile through 
hysterectomy, 
bilateral 
salpingectomy, 
and 
bilateral 
oophorectomy). Highly effective birth control measures per 
CTFG guidelines 2014 include the following: 
• combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of 
ovulation - oral, intravaginal, and transdermal 
• progestogen-only hormonal contraception associated 
with inhibition of ovulation - oral, injectable, 
implantable 
• intrauterine device 
• intrauterine hormone-releasing system 
• bilateral tubal occlusion 
• vasectomised partner 
• sexual abstinence 
Site should advise subjects to use any of the methods listed 
above, or per the country/site-specific requirements. 
17. Sexually active male subjects unless permanently sterile by 
bilateral orchidectomy, who do not agree to use 1 of the highly 
effective methods of birth control listed in Exclusion Criterion 
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#16 during treatment and for at least 12 months after the last 
administration of study treatment. 
18. Subject with serum IgG < lower limit of normal  
Study Design: 
This is a randomized, double-blind, parallel group, multicenter, 
Phase 3 transition study. 
A course of treatment with US-rituximab or EU-rituximab in RA 
consists of two 1000 mg intravenous (IV) infusions separated by 
2 weeks. Subjects with RA who have received at least 1 full 
course comprising two 1000 mg infusions with either 
US-rituximab or EU-rituximab will be eligible for the study. For 
this prior course of treatment, subjects will have received either 
US-rituximab or EU-rituximab. 
Subjects will then be randomized by an interactive web response 
system (IWRS) to receive either two 1000 mg infusions of 
DRL_RI (Arm A) or US-rituximab/EU-rituximab (Arm B) on 
Day 1 and Day 15. This will constitute the next course of 
rituximab treatment. Subjects randomized to Arm A will receive 
DRL_RI and subjects randomized to Arm B will continue to 
receive either US-rituximab or EU-rituximab. The rituximab 
reference 
product 
(US-licensed 
rituximab 
[Rituxan] 
or 
EU-approved rituximab [Mabthera]) used should be the same in 
the prior and the randomized treatment course, respectively. 
Subjects having received the prior treatment course with reference 
products other than US-licensed rituximab (Rituxan) or 
EU-approved rituximab (Mabthera) will not be eligible for the 
study. Subjects should not be switched from the prior to the 
randomized treatment course from US-licensed to EU-approved 
reference product or vice versa. 
The study will consist of a screening period (Days -14 to 0) and a 
double-blind period (Day 1 to Week 12). Subjects will attend a 
screening visit followed by visits at Weeks 0 (Day 1), 2, 4, 8, and 
12 (end of study [EOS]) after randomization. An additional 
follow-up visit will be conducted at Week 26 to evaluate safety 
and to perform a serum pregnancy test in WOCBP.  
Subjects having signed the informed consent form versions prior 
to the one introduced by this amendment need to re-consent to 
continue participating in the study after Week 12 through 
Week 26. If a subject does not re-consent for further study 
participation after Week 12, then his/her study data up to Week 12 
will be collected and the subject will be discontinued from the 
study. 
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List of Abbreviations 
Abbreviation 
Definition 
ACR 
American College of Rheumatology 
ADA 
Anti-drug Antibody 
ADL 
Activities of Daily Living 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
Anti-CCP 
Anti-citrullinated Peptide 
AUC 
Area Under The Concentration-time Curve 
AUC0-t 
AUC from Time Zero to the Last Quantifiable Time Point 
β-hCG 
Beta Human Chorionic Gonadotropin 
BP 
Blood Pressure 
C1q 
C1 q Subcomponent 
CD 
Cluster of Differentiation 
CDC 
Complement-dependent Cytotoxicity 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
COVID-19 
Coronavirus Disease - 2019 
CRO 
Clinical Research Organization 
CRP 
C-reactive Protein 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTFG 
Clinical Trial Facilitation Group 
DAS28 
Disease Activity Score  
DMARD 
Disease-modifying Anti-rheumatic Drug 
DRL_RI 
Biosimilar Rituximab 
DVD 
Digital Versatile Disc 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme-linked Immunosorbent Assay 
EOS 
End of Study 
ET 
Early Termination 
EU 
European Union 
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Abbreviation 
Definition 
EULAR 
European League Against Rheumatism 
Fc 
Fragment Crystallizable 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating Hormone 
GCP 
Good Clinical Practice 
HACA 
Human Anti-chimeric antibody 
HAQ-DI 
Health Assessment Questionnaire Disability Index 
HBcAb 
Hepatitis B Core Antibody 
HBsAg 
Hepatitis B Surface Antigen 
HCV 
Hepatitis C Virus 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IRB 
Institutional Review Board 
IRR 
Infusion-related Reaction 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
JAK 
Janus Kinase 
LLN 
Lower Limit Of Normal 
mAb 
Monoclonal Antibody 
MCID 
Minimal Clinically Important Difference 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTX 
Methotrexate 
NAb 
Neutralizing Antibody 
NCI 
National Cancer Institute 
NHL 
Non-Hodgkin’s Lymphoma 
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Abbreviation 
Definition 
PD 
Pharmacodynamic(s) 
PEI 
Paul Ehrlich Institute 
PI 
Prescribing Information 
PK 
Pharmacokinetic(s) 
QTc 
Corrected QT Interval 
RA 
Rheumatoid Arthritis 
RF 
Rheumatoid Factor 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
Tuberculosis 
TEAE 
Treatment-emergent Adverse Event 
TNF 
Tumor Necrosis Factor 
ULN 
Upper Limit Of Normal 
US 
United States 
WOCBP 
Women of Childbearing Potential 
 
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1 
Introduction 
Rituximab is licensed in the United States (US) as Rituxan® and approved in the European 
Union (EU) as MabThera®, for use in B-cell non-Hodgkin’s lymphoma (NHL), chronic 
lymphocytic leukemia, rheumatoid arthritis (RA) in combination with methotrexate (MTX) in 
adult patients with moderately to severely active RA who had an inadequate response to 1 or 
more tumor necrosis factor (TNF) antagonist therapies, granulomatosis with polyangiitis and 
microscopic polyangiitis in combination with glucocorticoids, and moderate to severe 
pemphigus vulgaris (Rituxan prescribing information [PI] 2020, MabThera Summary of 
Product Characteristics [SmPC] 2020). Rituxan is the commercially available product in the 
US and will be referred to as US-rituximab; MabThera is the commercially available product 
in the EU and will be referred to as EU-rituximab in the protocol. Rituximab biosimilar 
(hereafter, referred to as DRL_RI) is being developed as a potential biosimilar to US-rituximab 
and EU-rituximab. 
The term “biosimilar” refers to a biologic drug that is developed to be similar to an existing 
licensed or approved reference product or reference medicinal product. Biosimilars are 
intended to treat the same diseases as the reference product/reference medicinal product using 
the same dose and treatment regimen. Biosimilars are structurally highly similar to their 
reference products, and minor differences caused by the manufacturing process have no 
clinically meaningful effect on the pharmacokinetics (PK), safety, immunogenicity, or efficacy 
of the biosimilar compared with the reference product/reference medicinal product. 
In the DRL_RI development program, the primary objective in Study RI-01-003 
(Section 1.1.2.2) was to compare the plasma PK profiles of DRL_RI with US-rituximab and 
EU-rituximab; secondary objectives were to compare the pharmacodynamics (PD), efficacy, 
safety, and immunogenicity of DRL_RI with US-rituximab and EU-rituximab. The objective 
of the current study is to assess the immunogenicity and safety of transitioning subjects with 
RA to DRL_RI from US-rituximab/EU-rituximab to continued treatment with 
US-rituximab/EU-rituximab. 
1.1 
Background and Rationale 
1.1.1 
Rituximab 
Rituximab is a genetically engineered chimeric murine/human monoclonal immunoglobulin 
(Ig) G1 kappa antibody directed against the B-lymphocyte antigen cluster of differentiation 
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(CD) 20. Rituximab has a binding affinity for the CD20 antigen of approximately 8.0 nM 
(Rituxan PI 2020, MabThera SmPC 2020). 
Rituximab is approved for use in NHL, chronic lymphocytic leukemia, RA, granulomatosis 
with polyangiitis, microscopic polyangiitis, and moderate to severe pemphigus vulgaris (this 
indication is currently approved in the United States, but not in the European Union). Further 
information is contained within both the PI of US-rituximab and public information including 
the SmPC for EU-rituximab (Rituxan PI 2020, MabThera SmPC 2020). 
Multiple clinical trials have been conducted to support the approval of rituximab for the 
treatment of RA. Rituximab in combination with MTX is indicated for the treatment of adult 
patients with moderately to severely active RA who had an inadequate response to 1 or more 
TNF antagonist therapies (Rituxan PI 2020, MabThera SmPC 2020). 
1.1.1.1 
Mechanism of Action 
Rituximab binds specifically to the transmembrane antigen, CD20, a non-glycosylated 
phosphoprotein, located on pre-B and mature B lymphocytes. The antigen is expressed on 
>95% of all B-cell NHLs. CD20 is found on both normal and malignant B-cells, but not on 
hematopoietic stem cells, pro-B-cells, normal plasma cells, or other normal tissue(s). This 
antigen does not internalize upon antibody binding and is not shed from the cell surface. CD20 
does not circulate in the plasma as a free antigen and thus, does not compete for antibody 
binding (MabThera SmPC 2020). 
The fragment antigen-binding domain of rituximab binds to the CD20 antigen on 
B lymphocytes and the fragment crystallizable (Fc) domain can recruit immune effector 
functions to mediate B-cell lysis. Mechanisms of effector-mediated cell lysis include 
complement-dependent cytotoxicity (CDC) resulting from complement component 
C1 q subcomponent (C1q) binding, and antibody-dependent cellular cytotoxicity mediated by 
1 or more of the Fcγ receptors on the surface of granulocytes, macrophages, and natural killer 
cells. Rituximab binding to CD20 antigen on B lymphocytes has also been demonstrated to 
induce cell death via apoptosis (MabThera SmPC 2020). 
Rheumatoid arthritis is an immune-mediated disease of the joints that is characterized by 
chronic inflammation and synovial hyperplasia that eventually leads to cartilage and bone 
destruction (Komatsu and Takayanagi 2012). Current treatments include disease-modifying 
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anti-rheumatic drugs (DMARDs), tofacitinib, glucocorticoids, etc. (Singh et al 2016). B-cells 
are believed to play a role in the pathogenesis of RA and associated chronic synovitis. In this 
setting, B-cells may be acting at multiple sites in the autoimmune/inflammatory process, 
including thorough production of rheumatoid factor (RF) and other autoantibodies, antigen 
presentation, T-cell activation, and/or pro-inflammatory cytokine production (Rituxan PI 
2020). 
Administration of rituximab in RA patients results in almost complete depletion of peripheral 
B-cells and variable depletion of B-cells in synovium and other sites such as lymphoid tissue 
and bone marrow. The degree of B-cell depletion in the peripheral blood and synovium has 
been correlated positively with the clinical response of rituximab (Mok CC 2014, Cohen MD 
and Keystone E 2015). 
1.1.1.2 
Pharmacodynamics 
In RA patients, immediate depletion of B-cells in the peripheral blood was observed following 
2 infusions of 1000 mg rituximab separated by a 14-day interval. The majority of patients 
demonstrated near complete depletion (CD19 counts below the lower limit of quantification, 
20 cells/µL) within 2 weeks after receiving the first dose of rituximab. The majority of patients 
showed peripheral B-cell depletion for at least 6 months. A small proportion of patients (~4%) 
had prolonged peripheral B-cell depletion lasting more than 3 years after a single course of 
treatment. Peripheral blood B-cell counts began to increase from Week 24 (during the 
follow-up period) and evidence for repopulation was observed in the majority of patients by 
Week 40 (Dr. Reddy’s Laboratories Investigator’s Brochure [IB]). 
Total serum Ig levels, immunoglobulin M (IgM), immunoglobulin G (IgG), and 
immunoglobulin A (IgA) were decreased at 6 months with the largest change observed in IgM. 
At Week 24 of the first course of rituximab treatment, small proportions of patients experienced 
decrease in IgM (10%), IgG (2.8%), and IgA (0.8%) levels below the lower limit of normal 
(LLN). In the experience with rituximab in RA patients during repeated rituximab treatment, 
23.3%, 5.5%, and 0.5% of patients experienced decreases in IgM, IgG, and IgA, respectively 
concentrations below the LLN at any time after receiving rituximab. The clinical consequences 
of decrease in Ig levels in RA patients treated with rituximab are unclear (Dr. Reddy’s 
Laboratories IB). 
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Treatment with rituximab in patients with RA was associated with reduction of certain 
biological markers of inflammation such as interleukin-6, C-reactive protein (CRP), serum 
amyloid protein, S100 A8/S100 A9 heterodimer complex, anti-citrullinated peptide (anti-CCP), 
and RF (Dr. Reddy’s Laboratories IB). 
1.1.1.3 
Efficacy in Rheumatoid Arthritis 
The efficacy and safety of rituximab in alleviating the symptoms and signs of RA in subjects 
with an inadequate response to TNF inhibitors was demonstrated in a pivotal randomized, 
controlled, double-blind, multicenter study. The study evaluated 517 RA subjects who had 
experienced an inadequate response or intolerance to 1 or more TNF inhibitor therapies. 
Rituximab was administered as 2 intravenous (IV) infusions separated by an interval of 15 days. 
Subjects received two 1000 mg IV infusions of rituximab or placebo in combination with MTX. 
All subjects received concomitant 60 mg oral prednisone on Days 2 to 7 and 30 mg on Days 8 
to 14 following the first infusion. The primary endpoint was the proportion of subjects who 
achieved at least 20% improvement in American College of Rheumatology (ACR) score 
(ACR20) at Week 24. Subjects were followed beyond Week 24 for long-term endpoints, 
including radiographic assessment at 56 weeks and at 104 weeks. During this time, 81% of 
subjects from the original placebo group received rituximab between Week 24 and Week 56, 
under an open-label extension study protocol (MabThera SmPC 2020). 
Disease Activity Outcomes 
Rituximab in combination with MTX significantly increased the proportion of subjects 
achieving ACR20 compared with subjects treated with MTX alone. Clinically and statistically, 
significant improvement was also noted in all individual components of the ACR response 
(tender and swollen joint counts, subject and physician global assessment, Health Assessment 
Questionnaire Disability Index [HAQ-DI], pain assessment, and CRP). Subjects treated with 
rituximab in combination with MTX had a significantly greater reduction in Disease Activity 
Score 28 (DAS28) than subjects treated with MTX alone. Similarly, a good to moderate 
European League Against Rheumatism (EULAR) response was achieved by significantly more 
subjects treated with rituximab and MTX compared to subjects treated with MTX alone 
(MabThera SmPC 2020). 
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Radiographic Response 
Structural joint damage was assessed radiographically and expressed as change in modified 
total sharp score and its components, the erosion score, and joint space narrowing score. 
Subjects with inadequate response or intolerance to 1 or more TNF inhibitor therapies, 
receiving rituximab in combination with MTX demonstrated significantly less radiographic 
progression than subjects originally receiving MTX alone at 56 weeks. Of the subjects 
originally receiving MTX alone, 81% received rituximab either as a rescue between Week 16 
to Week 24 or in the extension trial before Week 56. A higher proportion of subjects receiving 
the original rituximab/MTX treatment also had no erosive progression over 56 weeks 
(MabThera SmPC 2020). 
Inhibition of the rate of progressive joint damage was also observed long term. Radiographic 
analysis at 2 years demonstrated significantly reduced progression of structural joint damage 
in subjects receiving rituximab in combination with MTX compared to MTX alone as well as 
a significantly higher proportion of subjects with no progression of joint damage over the 
2-year period (MabThera SmPC 2020). 
Physical Function and Quality of Life Outcomes 
Significant reductions in HAQ-DI and fatigue (Functional Assessment of Chronic Illness 
Therapy-Fatigue [FACIT-F]) scores were observed in subjects treated with rituximab 
compared to subjects treated with MTX alone. The proportions of rituximab-treated subjects 
showing a minimal clinically important difference (MCID) in HAQ-DI (defined as an 
individual total score decrease of >0.22) was also higher than among subjects receiving MTX 
alone (MabThera SmPC 2020). 
Significant improvement in health-related quality of life was also demonstrated with 
significant improvement in both the physical health score and mental health score of the Short 
Form 36 (SF-36) Health Survey. Further, a significantly higher proportion of subjects achieved 
MCIDs for these scores (MabThera SmPC 2020). 
Efficacy in Autoantibody (RF and/or anti-CCP) Seropositive Subjects 
Subjects seropositive to RF and/or anti-CCP who were treated with rituximab in combination 
with MTX showed an enhanced response compared with subjects negative to both. Efficacy 
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outcomes in rituximab-treated subjects were analyzed based on autoantibody status prior to 
commencing treatment. At Week 24, subjects who were seropositive to RF and/or anti-CCP at 
baseline had a significantly increased probability of achieving ACR20 and ACR50 responses 
compared to seronegative subjects (P=0.0312 and P=0.0096). These findings were replicated 
at Week 48, where autoantibody seropositivity also significantly increased the probability of 
achieving ACR70. At Week 48, seropositive subjects were 2 to 3 times more likely to achieve 
ACR responses compared to seronegative subjects. Seropositive subjects also had a 
significantly greater decrease in DAS28-erythrocyte sedimentation rate compared to 
seronegative subjects (MabThera SmPC 2020). 
Long-Term Efficacy With Multiple Course Therapy 
Treatment with rituximab in combination with MTX over multiple courses resulted in 
sustained improvements in the clinical signs and symptoms of RA, as indicated by ACR, 
DAS28-erythrocyte sedimentation rate, and EULAR responses, which were evident in all 
subject populations studied. Sustained improvements in physical function as indicated by the 
HAQ-DI score and the proportion of subjects achieving MCID for HAQ-DI were observed 
(MabThera SmPC 2020). 
Other clinical studies conducted to demonstrate the efficacy of rituximab in RA subjects had 
similar results (Mok CC 2014, Cohen MD and Keystone E 2015, and Rituxan PI 2020). 
1.1.1.4 
Safety Profile 
The overall safety profile of rituximab in RA is based on data from patients from clinical trials 
and from post-marketing surveillance (MabThera SmPC 2020). 
In clinical trials more than 3100 subjects received at least 1 treatment course and were followed 
for periods ranging from 6 months to over 5 years; approximately 2400 subjects received 2 or 
more courses of treatment with over 1000 having received 5 or more courses. The safety 
information collected during post-marketing experience reflects the expected adverse reaction 
profile as seen in clinical trials for rituximab (MabThera SmPC 2020). 
The most frequent adverse drug reactions (ADRs) following receipt of rituximab in clinical 
studies were infusion-related reactions (IRRs). Among the 3189 subjects treated with 
rituximab, 1135 (36%) experienced at least 1 IRR with 733/3189 subjects (23%) experiencing 
an IRR following first infusion of the first exposure to rituximab. The incidence of IRRs 
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declined with subsequent infusions. In clinical trials, fewer than 1% (17/3189) of subjects 
experienced a serious IRR. There were no common terminology criteria for adverse events 
(CTCAE) Grade 4 IRRs and no deaths due to IRRs in the clinical trials. The proportion of 
CTCAE Grade 3 events and of IRRs leading to withdrawal decreased by course, and such 
events were rare from Course 3 onwards. Pre-medication with IV glucocorticoid significantly 
reduced the incidence and severity of IRRs. Severe IRRs with fatal outcome have been reported 
in the post marketing setting (MabThera SmPC 2020). 
Other ADRs reported in greater than 10% of subjects in clinical studies or during post-marking 
surveillance in patients with RA receiving rituximab included upper respiratory tract infection, 
urinary tract infection, headache, and decreased IgM levels (MabThera SmPC 2020). 
The overall rate of infection was approximately 94 per 100 patient-years in rituximab-treated 
patients. The infections were predominately mild to moderate and consisted mostly of upper 
respiratory tract infections and urinary tract infections. The incidence of infections that were 
serious or required IV antibiotics was approximately 4 per 100 patient-years. Cases of 
progressive multifocal leukoencephalopathy with fatal outcome have been reported following 
use of rituximab for the treatment of autoimmune diseases, including RA. Reactivation of 
hepatitis B infection has also been very rarely reported in RA patients receiving rituximab 
(MabThera SmPC 2020). 
Multiple courses of treatment are associated with a similar ADR profile to that observed 
following first exposure. The rate of all ADRs following first rituximab exposure was highest 
during the first 6 months and declined thereafter. This is mostly accounted for by IRRs (most 
frequent during the first treatment course), RA exacerbation, and infections, all of which were 
more frequent in the first 6 months of treatment (MabThera SmPC 2020). 
1.1.1.5 
Immunogenicity 
As rituximab is a chimeric monoclonal antibody (mAb), the development of human 
anti-chimeric antibodies (HACAs) lower the level of the drug and hence, its clinical efficacy 
is a concern (Mok CC 2014). 
A pooled analysis on the long-term safety of rituximab in clinical trials (2578 subjects) 
revealed that HACAs were present in 11% of subjects on at least 1 visit. There was no obvious 
relationship between the dose of rituximab used (500 mg versus 1000 mg) and the incidence 
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of the HACA response. The presence of HACAs to rituximab does not appear to affect the 
efficacy of rituximab in depleting B-cells, clinical efficacy at the study endpoints, and 
re-treatment efficacy. There is also no obvious relationship between the HACA response and 
the occurrence of infusion reactions to rituximab (Mok CC 2014). 
1.1.2 
Dr. Reddy’s Rituximab (DRL_RI) 
Dr. Reddy’s Laboratories S.A. (DRL) is developing a proposed biosimilar version of the 
chimeric anti-CD20 mAb, rituximab (DRL_RI). 
DRL_RI is a chimeric human/murine IgG1 kappa mAb consisting of murine light and heavy 
chain variable regions and human constant region sequences. The molecule is composed of 
2 heavy chains of 451 amino acids each and 2 light chains of 213 amino acids each with a 
molecular weight of 145 kilodaltons. Each of the heavy chains contains 1 N-linked glycan 
(resulting in 2 N-linked glycans per molecule). 
The primary amino acid sequence is identical and the secondary and tertiary structures of 
DRL_RI are indistinguishable from the reference products (US-rituximab and EU-rituximab) 
when compared by a battery of orthogonal analytical methods. The glycosylation variants 
(glycoforms) of DRL_RI are the same as those found in the reference products, and the 
proportions of each of the glycoforms are similar between the 3 proteins. 
Further information can be found in the IB for DRL_RI (Dr. Reddy’s Laboratories IB). 
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1.1.2.1 
Nonclinical Studies 
In Vitro Pharmacology 
The comparison of in vitro functional activities of DRL_RI, US-rituximab, and EU-rituximab 
were performed using multiple cell-based and binding assays. Batches of DRL_RI, 
US-rituximab, and EU-rituximab were compared using 2 one-sided t-test analyses. A 
difference of 20% in the mean relative binding or potency was deemed acceptable. The 
complement dependent cytotoxicity (CDC) and the antibody-dependent cell-mediated 
cytotoxicity (ADCC) activities and the binding of DRL_RI, US-rituximab, and EU-rituximab 
to CD20, C1q, FcγRI, FcγRIIa, FcγRIIb, FcγRIII, and FcRn were found to be similar. 
Therefore, DRL_RI, US-rituximab, and EU-rituximab are considered similar in terms of their 
in vitro functional characteristics (Dr. Reddy’s Laboratories IB). 
1.1.2.2 
Clinical Studies 
Study RI-01-003 was a Phase 1/2, randomized, double-blind study, conducted in subjects with 
RA to compare PK, PD, efficacy, safety, and immunogenicity of DRL_RI with US-rituximab 
and EU-rituximab.  
The PK endpoint results showed that the 91% confidence interval (CI) for the geometric mean 
of the test to reference ratios of all endpoints were within the pre specified similarity 
acceptance range of 80.00% to 125.00% for the comparisons of DRL_RI with EU-rituximab 
and US-rituximab, and for the comparison of EU-rituximab with US-rituximab, demonstrating 
the PK similarity of the 3 products. The primary PK endpoints were area under the 
concentration-time curve (AUC) from time zero extrapolated to infinity for both study 
treatment infusions, AUC from start to the first infusion to the second infusion on Day 14 after 
the first infusion, and AUC from time zero to the last quantifiable time point (AUC0-t) after the 
second infusion of study treatment. The secondary PK endpoints were AUC0-t over the entire 
treatment course and maximum plasma concentration (Cmax after the first and after the second 
infusion. Results from the secondary endpoints of Study RI-01-003 also showed that the safety 
and immunogenicity profiles; CD20-positive peripheral blood B-cell count reductions; the 
proportion of subjects meeting the ACR20, ACR50, and ACR70 improvement criteria from 
baseline to Week 24; and the mean change from baseline to Week 24 in DAS28-CRP, were all 
comparable across DRL_RI, US-rituximab, and EU-rituximab. 
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1.1.3 
Study Rationale 
The evaluation of PK, efficacy, safety, and immunogenicity between a biosimilar and the 
innovator product is an essential component of an efficient clinical trial program collectively 
providing the evidence of biosimilarity. In the DRL_RI development program, 
Study RI-01-003 was a Phase 1/2, randomized, double-blind study comparing the PK and PD 
of DRL_RI with US-rituximab and EU-rituximab in subjects with RA. Safety, efficacy, and 
immunogenicity of the treatments were also compared to those of the innovator reference 
products in this study. The study met all pre specified primary and secondary endpoints for PK, 
PD, and efficacy outcomes (Section 1.1.2.2). 
The evaluation of safety and immunogenicity upon transition from a registered medicinal 
product to a biosimilar product is a requirement of US Food and Drug Administration (FDA). 
The objective of the current study is to assess the immunogenicity and safety of transitioning 
subjects with RA to DRL_RI from US-rituximab/EU-rituximab to continued treatment with 
US-rituximab/EU-rituximab. Subjects with RA, who have received at least 1 full course 
comprising two 1000 mg infusions with either US-rituximab or EU-rituximab and are 
candidates for re-treatment with rituximab, will be enrolled. 
During the initial phase of the clinical use of a newly introduced biosimilar product, it is 
expected that many patients will experience a transition from the currently marketed reference 
product to the biosimilar. Hence, ruling out changes in the safety and immunogenicity of the 
product upon a single transition from the reference product to the potential biosimilar is a 
relevant element in the clinical evaluation of the latter. 
1.1.4 
Risk/Benefit and Ethical Assessment 
There is a substantial body of data related to the safety and efficacy of 
US-rituximab/EU-rituximab in subjects with RA (FDA, Rituxan PI/European Medicines 
Agency MabThera SmPC) (Rituxan PI 2020, MabThera SmPC 2020). Preliminary results of a 
comprehensive head-to-head comparison of DRL_RI to the US-rituximab and the 
EU-rituximab has demonstrated that DRL_RI is similar to the reference products 
(Section 1.1.2). Thus, the risk/benefit of DRL_RI is expected to be comparable to that of 
US-rituximab/EU-rituximab. 
More detailed information about the known and expected benefits/risks and expected adverse 
events (AEs) of DRL_RI may be found in the IB for DRL_RI (Dr. Reddy’s Laboratories IB). 
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2 
Study Objectives and Endpoints 
Table 2-1 
Objectives and Endpoints 
Objectives 
Endpoints 
To assess the immunogenicity of transitioning subjects 
with RA to DRL_RI (biosimilar rituximab) from 
US-rituximab/EU-rituximab to continued treatment 
with US-rituximab/EU-rituximab. 
The immunogenicity endpoint is: 
The incidence of anti-drug antibodies (ADA), 
including titer and neutralizing antibodies (NAb). 
To assess the safety of transitioning subjects with RA 
to DRL_RI from US-rituximab/EU-rituximab to 
continued treatment with US-rituximab/EU-rituximab. 
The primary safety endpoints are: 
• 
Incidence of treatment-emergent adverse events 
(TEAEs) and serious adverse events (SAEs). 
• 
Incidence 
of 
anaphylactic 
reactions, 
hypersensitivity reactions, and IRRs. 
Other safety endpoints are: 
• 
Clinical laboratory parameters 
• 
Vital signs 
• 
Twelve-lead electrocardiograms (ECG) 
• 
Physical examination 
Abbreviations: EU, European Union; IRR, infusion-related reactions; RA, rheumatoid arthritis; US, United 
States. 
 
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3 
Investigational Plan 
3.1 Study Design 
3.1.1 
Description 
This is a randomized, double-blind, parallel group, multicenter, Phase 3 transition study in 
subjects with active RA who are eligible for the subsequent treatment course with 
US-rituximab or EU-rituximab according to the clinical judgment of the investigator. 
It is planned to randomize 140 subjects (70 per treatment arm) at approximately 50 sites in up 
to 7 countries (including, but not restricted to the United States). 
A course of treatment with US-rituximab or EU-rituximab in RA consists of two 1000 mg IV 
infusions separated by 2 weeks. Subjects with RA who have received at least 1 full course 
comprising two 1000 mg infusions with either US-rituximab or EU-rituximab will be eligible 
for the study. The rituximab reference product (US-licensed rituximab [Rituxan] or 
EU-approved rituximab [Mabthera]) used should be the same in the prior and the randomized 
treatment course, respectively. Subjects having received the prior treatment course with 
reference products other than US-licensed rituximab (Rituxan) or EU-approved rituximab 
(Mabthera) will not be eligible for the study. Subjects should not be switched from the prior to 
the randomized treatment course from US-licensed to EU-approved reference product or vice 
versa. 
Subjects will then be randomized by interactive web response system (IWRS) to receive either 
two 1000 mg infusions of DRL_RI (Arm A) or US-rituximab/EU-rituximab (Arm B) on Day 1 
and Day 15. This will constitute the next course of rituximab treatment. Subjects randomized 
to Arm A will receive DRL_RI and subjects randomized to Arm B will continue to receive 
either US-rituximab or EU-rituximab. 
The study will consist of a screening period (Days -14 to 0) and a double-blind period (Day 1 
to Week 12). Subjects will attend a screening visit followed by visits at Weeks 0 (Day 1), 2, 4, 
8, and 12 (end of study [EOS]) after randomization. An additional follow-up visit will be 
conducted at Week 26 to evaluate safety and to perform a serum pregnancy test in women of 
childbearing potential (WOCBP). 
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Subjects having signed the informed consent form (ICF) versions prior to the one introduced 
by this amendment need to re-consent to continue participating in the study after Week 12 
through Week 26. If a subject does not re-consent for further study participation after Week 12, 
then his/her study data up to Week 12 will be collected and the subject will be discontinued 
from the study. 
If a subject requires rescue therapy after Week 12, then the same can be administered to the 
subject per investigator’s discretion until the additional safety follow-up visit at Week 26. If 
rituximab re-dosing becomes necessary at a time allowed by the local rituximab label, the same 
can be administered. Specifics of safety analysis of such subjects will be addressed in the 
statistical analysis plan (SAP). Study procedures include physical examination, vital signs 
measurement, clinical laboratory assessments, AEs, and concomitant medication. All subjects 
completing the study at Week 12 or those discontinuing the study at any time will attend an 
EOS/early termination (ET) visit.  
The study endpoints are the incidence of anti-drug antibodies (ADA), including titer and 
neutralizing antibodies (NAbs), treatment-emergent adverse events (TEAEs), serious adverse 
events (SAEs), anaphylactic reactions, hypersensitivity reactions, and IRRs. The subject’s 
response to treatment will be assessed in accordance with usual clinical practice. 
Samples for the evaluation of ADA will be obtained before the administration of study 
treatment on Day 1 and Day 15. Additional samples for detection of ADA will be collected at 
Weeks 4, 8, and 12 (EOS/ET visit). Samples that are confirmed positive for ADA will be further 
tested for titer and NAb. Details are described in Section 6.2. 
A study scheme is provided in Figure 3-1. 
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Figure 3-1 
Study Scheme 
 
Abbreviations: ADA, anti-drug antibody; DRL_RI, biosimilar rituximab; N, total number of subjects; n, number 
of subjects in each treatment arm; RA, rheumatoid arthritis. 
Data until Week 12 will be analyzed and reported in the final Clinical Study Report (CSR) after 
all subjects complete Week 12 visit (EOS/ET). The subsequent follow-up data from Week 12 
to Week 26 will be reported as an addendum to the final CSR and for the data up to and 
including the Week 12 or ET visit. 
3.1.2 Rationale of Study Design 
This is a randomized, double-blind, parallel group, multicenter study designed to assess the 
immunogenicity 
of 
transitioning 
subjects 
with 
RA 
to 
DRL_RI 
from 
US-rituximab/EU-rituximab to continued treatment with US-rituximab/EU-rituximab. The 
study is part of the DRL_RI development program to support DRL_RI as a biosimilar. The 
comparators used in this study are US-licensed rituximab (Rituxan) or EU-approved rituximab 
(MabThera). 
The parallel and double-blinded design study also allows for independent assessment of safety 
and immunogenicity of the DRL_RI arm of the study relative to the control arms in these 
population to support registration. It also allows for the 2 control arms to be evaluated relative 
to each other. Randomization prevents the selection bias and insures against the accidental bias. 
Subjects who have received at least 1 full course comprising two 1000 mg infusions of either 
US-rituximab or EU-rituximab and are candidates for re-treatment with rituximab will be 
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enrolled. DRL_RI will be administrated in combination with MTX as two 1000 mg infusions 
on Day 1 and Day 15, which is consistent with the recommended dose for RA as described in 
the PI of Rituxan and the SmPC for MabThera (Rituxan PI 2020, MabThera SmPC 2020). 
Study endpoints are the incidence of ADA, including titer and NAb; TEAEs; and SAEs, 
anaphylactic reactions, hypersensitivity reactions, and IRRs. Samples for the evaluation of 
ADA will be obtained before the administration of study treatment on Day 1 and Day 15, and 
at Weeks 4, 8, and 12 (EOS/ET) visits. Samples that are confirmed positive for ADA will be 
further tested for titer and NAb. An additional follow-up visit will be conducted at Week 26 to 
evaluate safety and to perform a serum pregnancy test in WOCBP. 
A validated enzyme-linked immunosorbent assay (ELISA) will be used to test ADA, titer and 
NAb by specialist laboratories (sponsor designated laboratories) in this study.  
Along with immunogenicity sample, a time-matched blood sample (approximately 5 mL) will 
be collected for the estimation of rituximab concentration. The evaluation of the samples will 
be performed to interpret safety and/or immunogenicity data appropriately, if needed. 
3.1.3 
Early Termination of the Study 
This study may be terminated prematurely at any time by Dr. Reddy’s Laboratories S.A. for 
medical, operational, or ethical reasons at individual or all study sites. 
If the study is prematurely terminated or discontinued, Dr. Reddy’s Laboratories S.A./clinical 
research organization (CRO) will promptly notify the investigators, institutions, and all 
competent regulatory authorities in writing outlining the reasons for the termination. The 
investigator or Dr. Reddy’s Laboratories S.A./CRO will promptly inform the Independent 
Ethics Committee (IEC)/Institutional Review Board (IRB). After notification, the investigator 
must contact all participating subjects and the hospital pharmacies (if applicable) within a 
reasonable time period and inform them of the premature termination/discontinuation of the 
study. 
The clinical research associate will contact the investigators to schedule a close-out visit for 
all participating sites. 
As directed by Dr. Reddy’s Laboratories S.A./CRO, all unused study documents/materials (for 
e.g., study drugs, packing slips, stickers, etc.) shall be collected. All electronic case report 
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forms (eCRFs) will be completed. All documents required for archiving at the site will be 
retained at the site itself. The study monitor will ensure that any outstanding data clarification 
issues and queries are resolved, and that all study records at the study site are complete. 
3.1.4 
End of Study 
End of study is defined as the time at which all subjects enrolled in the study have been 
followed for 10 weeks after treatment unless lost to follow-up or the subject has died. The EOS 
is achieved at the last subject’s Week 12 visit. After EOS, an additional follow-up visit will be 
conducted at Week 26 to evaluate safety and to perform a serum pregnancy test in WOCBP. 
3.2 Study Conduct During the COVID-19 Pandemic 
Coronavirus disease of 2019 (COVID-19) is a viral illness caused by the novel coronavirus 
(also called the SARS-CoV-2) and has impacted most of the countries across the globe. It was 
declared as a global public health emergency by the World Health Organization on 
30 Jan 2020. This pandemic has impacted the conduct of clinical trials in various ways. 
3.2.1 
Benefit-Risk Assessment of Rituximab Treatment During the 
COVID-19 Pandemic 
Rituximab is a known immunosuppressant drug and immunosuppression/immunomodulation 
is the known mechanism of action for its various approved indications and clinical use, 
including its use in RA.  
The current knowledge about human immune response to COVID-19 is limited. It is also not 
precisely known whether patients on rituximab are associated with a higher risk or with a 
higher severity of COVID-19. However, given the general immunosuppressive nature, it 
cannot be ruled out entirely. Methotrexate used concomitantly with rituximab in the treatment 
of RA is also a known immunosuppressant. It is known to increase the risk of opportunistic 
infections and has to be avoided during active infection. 
Rheumatoid arthritis is a chronic, symmetrical, inflammatory autoimmune disease that initially 
affects small joints, progressing to larger joints, and eventually affecting the skin, eyes, heart, 
kidneys, and lungs. At the advanced stage it leads to deformities and bone erosion, usually very 
painful for a patient (Komatsu and Takayanagi 2012; Bullock et al 2018). Moreover, there 
could be worsening of the disease, if the patient is deprived of the treatment. Hence, it is 
important to analyse the benefit-risk ratio for a particular patient on a case to case basis. 
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Moreover, per recommendation by the ACR, in patients with moderate to high disease activity 
despite optimal conventional synthetic DMARDs, biologics may be started (Mikuls TR et al 
2020). In patients already on biologics who need a switch to rituximab, the same considerations 
would be expected to apply. 
Hence, based on the above considerations, the benefit of rituximab treatment outweigh the 
risks associated with the current COVID-19 situation provided all steps are taken towards 
ensuring the subject interest and various contingency and safety measures are implemented 
towards the same. Various such measures have been taken to ensure safety and to minimize the 
risks for the subjects in compliance with the various recommendations and regulatory 
guidelines as well as disease management guidelines. 
3.2.2 
Contingency Measures Taken During the COVID-19 Pandemic 
Based upon the above mentioned considerations, the following measures have been 
implemented in the study: 
1. COVID-19 protective measures: Advice to the sites to implement general hygienic 
measures for both ongoing subjects and any new subject to educate on such protective 
and preventive measures. 
2. Assurance of subject safety by investigator before enrolment (by COVID-19 related 
screening questionnaire). 
3. Measures to be taken if investigator suspect COVID-19-related symptoms or if a 
subject is found positive to COVID-19. 
4. In order to protect subject’s safety and welfare, it is also recommended that site contacts 
subjects periodically (preferably on Day 7, 14; Weeks 6, 10, 14, 18, and 22) via 
telephone to inquire about his/her overall well-being, to seek information on alarm 
symptoms (fever, cough, breathlessness, COVID-19-related skin lesion, etc) of 
COVID-19 infection, information on subject’s contact with any COVID-19-positive 
patient, and to guide the subject to take appropriate medical care. 
If a study subject has an event suspected to be COVID-19 related, the investigator will 
have to decide on performing COVID-19 testing per local health authority or study site 
guidance. 
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Any new AE or change in the intensity of ongoing AE(s) with special focus on 
symptoms related to COVID-19, new medication(s) taken by the subject since his/her 
last visit, or any change in dose/frequency of medication(s), which is received, will be 
also documented in the source documents and eCRF.  
5. Any event of COVID-19 is to be considered as an “Event of Special Interest” and all 
relevant detailed information will be collected, such as diagnosis, management and 
outcome. All events related to or linked to COVID-19 and meeting SAE criteria must 
be reported to 
Pharmacovigilance within 24 hours of the investigator’s knowledge 
of the event by facsimile or other appropriate method. 
Moreover, due to current COVID-19 pandemic situation, remote source data 
verification may be performed per local regulations. All details of remote monitoring 
will be captured in the monitoring plan, if required. 
A detailed information about the type of data to be collected, handing of missing data 
or assessment/procedure will be captured in the eCRF filling guidelines/data 
management plan if required. Listings/summaries of all subjects affected due to 
COVID-19, including protocol deviations, additional safety contingency measures will 
be generated based on the available data if required. Corresponding details will be 
mentioned in the SAP. 
If COVID-19 wanes off, the sponsor may not collect COVID-19-specific data (as 
mentioned above) and may not follow-up with the subject for COVID-19-related 
information. In such a case, the CRO and site will be notified for further action.  
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4 
Subject Selection and Withdrawal Criteria 
4.1 Selection of Study Population 
Approximately 140 subjects will be enrolled at approximately 50 sites in up to 7 countries. 
Subjects will be assigned to study treatment only if they meet all of the inclusion criteria and 
none of the exclusion criteria. 
Deviations from the inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability, or subject 
safety. Therefore, adherence to the criteria as specified in the protocol is essential. 
4.1.1 Inclusion Criteria 
A subject will be eligible for enrolment in the study if he/she meets all of the following criteria: 
1. Male or female subjects aged 18 years or older who have provided valid written 
informed consent. 
2. Subjects with a diagnosis of active RA who are eligible for the subsequent treatment 
course with US-rituximab or EU-rituximab according to the clinical judgment of the 
investigator. 
3. Documented evidence that subject has received at least 1 full course comprising two 
1000 mg infusions of either US-rituximab at least 16 weeks prior to the randomization 
visit or EU-rituximab at least 24 weeks prior to the day of randomization visit. 
Note: Subjects are only eligible if they have received the prior US or EU-rituximab 
course within the 15 months prior to the date of randomization. 
4. Subjects receiving a stable dose of weekly MTX for at least 4 weeks prior to 
randomization (between 7.5 mg and 25 mg) and folic acid (at least 5 mg per week). 
4.1.2 Exclusion Criteria 
Subjects meeting any of the following criteria must not be enrolled in the study: 
1. Subjects with RA in functional Class IV (Table 14-2). 
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2. Subjects with human immunodeficiency virus (positive HIV1Ab or HIV2Ab), 
hepatitis B virus and/or hepatitis C virus infection, including those with positive results 
in the viral disease screening (Section 6.1.1). 
3. Subjects with active tuberculosis (TB). Subjects with evidence of latent TB or a history 
of TB must have completed treatment or have initiated treatment for at least 1 month 
before the first dose of study treatment (Day 1). TB testing is required only if it is 
required by local regulations or practice. 
4. Active systemic infection. 
5. Severely immunocompromised. 
6. History of hypersensitivity to either US-rituximab or EU-rituximab or any of its 
excipients. 
7. Any serious illness or uncontrolled medical condition, including, but not limited to, 
severe infections, significant hepatic or renal disease, uncontrolled hypertension 
despite treatment (defined as blood pressure [BP] ≥160/95 mmHg), congestive heart 
failure (New York Heart Association [NYHA] Class III or IV), or other severe 
uncontrolled cardiac disease or uncontrolled diabetes with immediate risk of acute 
complications. 
8. Any condition that in the opinion of the investigator represents an obstacle for study 
conduct and/or represents a potential unacceptable risk for subjects. 
9. Requires treatment with any biological medicinal product during the study other than 
the study treatment. 
10. Previous treatment with B-cell modulating or cell-depleting biologic therapy, except 
US-rituximab or EU-rituximab. 
11. Prior participation in this clinical trial or prior participation in any clinical trial with 
any monoclonal antibody within 12 months of screening or prior participation in any 
clinical trial within 3 months of screening or within 5 half-lives of the investigational 
drug or until the expected PD effect has returned to baseline, whichever is longer. 
12. Treatment with other biologic DMARDs, or Janus kinase (JAK) inhibitors 
administered within 12 weeks before the first dose of rituximab of the prior treatment 
course onwards till the date of randomization. 
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13. Subjects with the following laboratory abnormalities: 
• Subjects 
with 
screening 
total 
white 
blood 
cell 
count 
<3000/μL, 
platelets <100,000/μL, neutrophils <1500/μL, or hemoglobin <8.5 g/dL. 
• Abnormal liver function tests such as aspartate aminotransferase, alanine 
aminotransferase, or alkaline phosphatase >2 × upper limit of normal (ULN). A 
single parameter >2 × ULN can be re-checked as soon as possible, at least prior to 
randomization, if required as per the investigator’s discretion. 
• Creatinine clearance (Cockcroft & Gault formula) of less than 50 mL/min. 
14. History of vaccination with live vaccines within 4 weeks of the first dose of study 
treatment (Day 1) or known to require live vaccines during the study. 
15. Lactating or pregnant female. 
16. Women of childbearing potential who do not consent to use highly effective methods 
of birth control during treatment and for at least 12 months after the last administration 
of study treatment. 
Note: Per the Clinical Trial Facilitation Group (CTFG) guidelines 2014, a woman is 
considered of childbearing potential if fertile, following menarche until becoming 
postmenopausal (i.e., no menses for 12 months without an alternative medical cause) 
unless permanently sterile through hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy). Highly effective birth control measures per CTFG guidelines 2014 
include the following: 
• combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation - oral, intravaginal, and transdermal 
• progestogen-only hormonal contraception associated with inhibition of 
ovulation - oral, injectable, and implantable 
• intrauterine device 
• intrauterine hormone-releasing system 
• bilateral tubal occlusion 
• vasectomised partner 
• sexual abstinence 
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Site should advise subjects to use any of the methods listed above, or per the 
country/site-specific requirements. 
17. Sexually active male subjects unless permanently sterile by bilateral orchidectomy, 
who do not agree to use 1 of the highly effective methods of birth control listed in 
Exclusion Criterion #16 during treatment and for at least 12 months after the last 
administration of study treatment. 
18. Subjects with serum IgG <LLN. 
4.2 Withdrawal of Subjects From Study Treatment and/or the Study 
The duration of the study is defined for each subject as the date when signed written ICF is 
provided through the EOS visit on Week 12. An additional follow-up visit will be conducted 
at Week 26 to evaluate safety and to perform a serum pregnancy test in WOCBP. Subjects 
having signed the ICF versions prior to the one introduced by this amendment need to 
re-consent to continue participating in the study after Week 12 through Week 26. If a subject 
does not re-consent for further study participation after Week 12, then his/her study data up to 
Week 12 will be collected and the subject will be discontinued from the study. 
4.2.1 Reasons for Withdrawal/Discontinuation 
Subjects may withdraw from the study at any time and for any reason without prejudice to their 
future medical care by the investigator or at the study site. Every effort should be made to keep 
subjects in the study. The reasons for subjects not completing the study will be recorded. A 
subject may be withdrawn from the study for any of the following reasons: 
1. The subject does not meet the protocol inclusion or exclusion criteria before the last 
scheduled dose of study treatment is administered. If the first dose of study drug was 
already administered, the subject should not receive the second dose of study drug, but 
study follow-up should be completed. 
2. The subject is noncompliant with the protocol that in the investigator’s opinion requires 
withdrawal from the study. 
3. The subject has a serious or intolerable AE(s) that in the investigator’s opinion requires 
withdrawal from the study. 
4. The subject has symptoms or an intercurrent illness not consistent with the protocol 
requirements or that justify withdrawal. 
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5. The subject is lost to follow-up. 
6. Other reasons (e.g., pregnancy, development of contraindications of use of study 
treatment). 
7. The subject withdraws consent from study participation or from further treatment, or 
the investigator or sponsor decides to discontinue the subject’s participation for a 
specific safety reason in the study, or the subject does not re-consent to continue 
participation in the study after Week 12. 
Note: If a subject withdraws consent for further study treatment, but not for study participation, 
the subject can continue further visits and data can continue to be collected until Week 26. 
However, if a subject withdraws consent for further participation in the study there will be no 
further data collection and the subject will be discontinued from the study. If a subject having 
signed the ICF versions prior to the one introduced by this amendment does not re-consent for 
further study participation after Week 12, then his/her study data up to Week 12 will be 
collected and the subject will be discontinued from the study. If Dr. Reddy’s Laboratories S.A. 
terminates the study all subjects will be withdrawn.  
Upon occurrence of a serious or intolerable AE, the investigator will confer with the sponsor 
before withdrawing the subject. If a subject is discontinued because of an AE, the event will 
be followed until it is resolved, or it is deemed in the opinion of the investigator that the AE is 
stabilized and further follow-up is not required. Any subject may withdraw his or her consent 
at any time. 
4.2.2 Handling of Withdrawals 
During the study, the subjects can independently withdraw from study treatment and/or study 
participation at any time. Also, the subjects may be withdrawn from the study at any time at 
the discretion of the investigator or sponsor for safety, behavioral, or administrative reasons, 
or the inability of the subject to comply with the protocol required schedule of study visits or 
procedures at a given study site. 
The decision to withdraw consent and discontinue participation in the study will not prejudice 
the subject’s future medical treatment in any way. If a subject does not return for a scheduled 
visit, every effort will be made to contact the subject. All attempts to contact the subject and 
information received during contact attempts (3 attempts with minimum 2 different modes to 
follow-up/contact) must be documented in the subject’s medical record. In any circumstance, 
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every effort will be made to document subject outcome, if possible. The investigator should 
inquire about the reason for withdrawal and request the subject to return for the EOS/ET 
(Week 12) visit, if applicable, and follow-up with the subject regarding any unresolved AEs. 
An additional follow-up visit will be conducted at Week 26 to evaluate safety and to perform 
a serum pregnancy test in WOCBP. The investigator or sub-investigator or designee will be 
responsible for reporting subject withdrawal to Dr. Reddy’s Laboratories S.A./CRO. Subjects 
withdrawn from the study cannot be re-enrolled at a later time, regardless of the reason for 
withdrawal. The reason of withdrawal should be provided in the eCRF. 
If the subject withdraws consent for further treatment, but consents to study participation, data 
will continue to be collected until Week 26.  
Subjects having signed the ICF versions prior to the one introduced by this amendment need 
to re-consent to continue participating in the study after Week 12 through Week 26. If a subject 
does not re-consent for further study participation after Week 12, then his/her study data up to 
Week 12 will be collected and the subject will be discontinued from the study.  
If a subject withdraws consent from study participation after Week 12 but before the additional 
follow-up visit at Week 26, he/she will be required to undergo the Week 26 assessments on the 
day of study discontinuation. If a subject consents to undertake additional and optional study 
procedures/assessments but withdraws consent for doing so at a later visit, he/she will be 
retained in the study for the routine study procedures/assessments. 
If a subject withdraws from the study and also withdraws consent for disclosure of future 
information, the subject will undergo ET visit assessments. Dr. Reddy’s Laboratories 
S.A./CRO may retain and continue to use any data collected before such withdrawal of consent. 
4.2.3 Replacements 
Subjects who withdraw or discontinue after randomization are not to be replaced. 
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5 
Study Treatments 
5.1 Method of Assigning Subjects to Treatment Arms 
After written informed consent is obtained from an eligible subject, a unique subject 
identification number will be assigned to this subject at screening visit. Subjects will be 
identified during the whole study only by their assigned subject identification number.  
Subjects will be randomly assigned at the baseline/randomization visit (Day 1) to receive 
DRL_RI or US-rituximab or EU-rituximab using a 1:1 allocation ratio. An IWRS will be used 
to administer the randomization schedule. Biostatistics will generate the randomization 
schedule using statistical analysis system (SAS) software Version 9.4 or later (SAS Institute 
Inc, Cary, North Carolina, US) for IWRS, which will link sequential subject randomization 
numbers to treatment codes. The randomization schedule will be stratified by region (US/EU). 
It will also use an appropriate block size, which will not be revealed.  
Dispensing of study treatment will be coordinated by IWRS on Day 1 and Day 15. The system 
will assign a kit number corresponding to the randomization arm by region (US/EU). 
Randomization plan document will be prepared before the generation of randomization 
schedule. The randomization code will be computer-generated and kept by a statistician 
independent from the project team. 
This randomization number identifies which treatment will be allocated to each subject. The 
subject identification number of subjects who withdraw or discontinue before or after the 
randomization will not be re-used. 
5.2 Treatments Administered 
This is a randomized, double-blind, and parallel group clinical study. 
Following signing of ICF, subjects will be registered into the study to receive a unique subject 
identification number. Randomization will be performed using an IWRS. Subjects will be 
randomized in a 1:1 ratio to 1 of the 2 study treatment arms as follows: 
• Arm A: 
DRL_RI (proposed rituximab biosimilar) 
• Arm B: 
US-rituximab or EU-rituximab 
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The study treatments DRL_RI or US-rituximab/EU-rituximab will be administered as two 
1000 mg IV infusions separated by 2 weeks (Section 5.2.3). Subjects will be pre-medicated 
before each infusion (Section 5.2.2). 
5.2.1 
Study Treatment Infusion Preparation 
Study treatment (DRL_RI or US-rituximab/EU-rituximab) solutions for infusion will be 
prepared by unblinded pharmacist designated as site team member in this study. Study 
treatment will be administered by IV infusion. It should not be administered as an IV push or 
bolus. 
Pharmacists should use aseptic techniques appropriate to parenteral administration projects. 
Study treatment vials and prepared solutions should be inspected visually for particulate matter 
and discoloration prior to administration. The necessary amount of study treatment will be 
withdrawn and diluted to a final concentration of 1 to 4 mg/mL in an infusion bag containing 
either 0.9% sodium chloride, United States Pharmacopeia, or 5% dextrose Injection, United 
States Pharmacopeia. The infusion bag should be gently inverted to mix the solution. Do not 
use vials if particulates or discoloration are present. Further information can be obtained in the 
pharmacy manual. 
5.2.2 Pre-medication for Study Treatment Infusions 
Pre-medication consisting of an antipyretic and an antihistamine (e.g., paracetamol 
[acetaminophen] and diphenhydramine) should always be administered before each infusion 
of rituximab. 
All subjects should also receive pre-medication with 100 mg IV methylprednisolone or its 
equivalent to be completed at least 30 minutes prior to rituximab infusions to decrease the 
incidence and severity of acute IRRs. 
Acute IRRs are most often observed during the first infusion of rituximab. Any reduction in 
use of pre-medications during subsequent infusion must be in compliance with local labelling 
and regulation(s). 
5.2.3 Study Treatment Administration 
Study treatments (DRL_RI or US-rituximab/EU-rituximab) will be administered by IV 
infusion using the escalating infusion rate described in the Health Authority-approved product 
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labels for US-rituximab/EU-rituximab. The infusion rate must be well controlled to reduce the 
incidence of serious IRRs. 
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
biological agents. 
Study treatment infusions should be administered under close medical supervision and in an 
environment where full resuscitation facilities are immediately available. Vital signs will be 
monitored every 30 minutes (± 5 minutes) during the course of the treatment administration or 
more frequently as necessary. 
The study treatments will be administered as two 1000 mg IV infusions on Day 1 and Day 15. 
Below instructions should be followed in consolidation with the local product labelling if it 
differs from these instructions. 
• First infusion (Day 1): Initiate infusion at a rate of 50 mg/hour. In the absence of 
infusion toxicity, increase infusion rate by 50 mg/hour increments at 30-minute 
intervals, to a maximum of 400 mg/hour. 
• Second infusion (Day 15): Initiate infusion at a rate of 100 mg/hour. In the absence of 
infusion toxicity, increase rate by 100 mg/hour increments at 30-minute intervals, to a 
maximum of 400 mg/hour. 
• Subjects should be closely monitored post-dose for at least 1 hour for the onset of IRRs. 
Subjects who develop evidence of severe reactions, especially severe dyspnea, 
bronchospasm, or hypoxia should have the infusion interrupted immediately. In all 
subjects, the infusion should not be restarted until complete resolution of all symptoms 
and normalization of laboratory values is achieved. At this time, the infusion can be 
initially resumed at not more than one-half the previous rate. If the same severe 
reactions occur for a second time, the decision to stop the treatment should be seriously 
considered on a case-by-case basis. 
• Mild to moderate IRRs usually respond to a reduction in the rate of infusion. The 
infusion rate may be increased upon improvement of symptoms. 
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5.3 Identity of Investigational Product 
Proposed rituximab biosimilar (DRL_RI) or US-rituximab/EU-rituximab will be provided as 
study treatment to the participating sites. 
DRL_RI and US-rituximab/EU-rituximab will be supplied as sterile, preservative-free, 
non-pyrogenic, single-use vials. Each 100 mg vial will contain 100 mg unit dose of DRL_RI 
or US-rituximab/EU-rituximab in 10 mL single-use vial or each 500 mg vial will either contain 
500 mg unit dose of DRL_RI or US-rituximab/EU-rituximab in 50 mL single-use vial. 
5.4 Management of Clinical Supplies 
5.4.1 Packaging 
Rituximab concentrate for solution for infusion will be packaged in a carton or kit. Each carton 
or kit will have 2 vials of 500 mg vials to achieve 1000 mg of single dose (on Day 1 and 
respectively on Day 15) OR 10 vials of 100 mg to achieve 1000 mg of single dose (on Day 1 
and respectively on Day 15). Each carton will be packaged with a tamper-resistant seal. The 
sponsor must be notified of any study medication in which the tamper-resistant seal has been 
broken and this medication should not be used. Further details will be provided in the pharmacy 
manual. 
5.4.2 Labelling 
Medication labels will comply with the legal requirements of each country and be printed in 
local language, if required. They will supply no information about the subjects. 
5.4.3 Storage 
DRL_RI and US-rituximab/EU-rituximab 100 mg/10 mL single-use vials and 500 mg/50 mL 
single-use vials should be stored at 2°C to 8°C (36°F to 46°F). Do not use beyond expiration 
date stamped on carton. DRL_RI and US-rituximab/EU-rituximab vials should be protected 
from direct sunlight. Do not freeze or shake. 
From a microbiological point of view, the prepared DRL_RI and US-rituximab/EU-rituximab 
solutions for infusion should be used immediately. Further details regarding preparation and 
storage of study treatments will be provided in pharmacy manual. 
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The investigator, or an approved representative (e.g., pharmacist), will ensure that all study 
treatment is stored in a secured (locked) area with restricted access, and in accordance with 
applicable regulatory requirements. 
Study treatment should be stored in accordance with the drug label. Investigators and site staff 
should ensure that thermometers are working correctly, and the drug is being stored as required 
for proper storage of study treatments. More details will be captured in pharmacy manual. Any 
temperature excursions should be reported to the sponsor or sponsor designate. 
Deviations from the storage requirements, including any actions taken, must be documented 
and reported to the sponsor or sponsor designate. Once a deviation is identified, the study 
treatment must be quarantined and not used until the sponsor provides documentation of 
permission to use the study treatment. 
5.4.4 Study Treatment Accountability 
Records will be maintained of the delivery of study treatment to the study sites, the inventory 
at the study sites, the use of each subject, and the return to the sponsor. 
These records shall include dates, quantities, batch numbers, expiry dates, and the unique code 
numbers assigned to the study medication and to the study subjects. 
The investigator shall be responsible for ensuring that the records adequately document that 
the subjects were provided the study treatment specified by the IWRS and that all study 
medication received from the sponsor is reconciled. 
5.5 Overdose Management 
An overdose is any dose of study treatment given to a subject or taken by a subject that exceeds 
the dose described in the protocol. Every overdose must be reported to the sponsor or sponsor’s 
designated safety services within 24 hours of awareness, irrespective of whether the overdose 
was associated with an AE/SAE. Overdoses without signs or symptoms do not need to be 
recorded as AEs; in case of any AEs associated with an overdose, these should be reported in 
the relevant AE/SAE sections of the eCRF. 
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5.5.1 Medication Errors 
Medication errors may result in this study from the administration or consumption of the wrong 
drug, by the wrong subject, at the wrong time, or at the wrong dosage strength. In the event of 
medication dosing error, the sponsor should be notified immediately. 
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including: 
• Medication errors involving subject exposure to the study treatment. 
• Potential medication errors or uses outside of what is foreseen in the protocol that do or do 
not involve the participating subject. 
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error should be captured on the medication error version of the AE 
page and, if applicable, any associated AEs are captured on an AE eCRF page. 
5.6 Transmission of Infectious Agents 
All subjects will be provided with patient alert card with each infusion. The alert card contains 
important safety information for subjects regarding potential increased risk of infections, 
including progressive multifocal leukoencephalopathy. 
5.7 Blinding 
A double-blind design is employed so that both the investigators and the subjects will be 
unaware of the treatment assignment during the whole study. Moreover, study center staff 
involved in study treatment administration and study endpoints assessments, CRO personnel, 
and the sponsor team including study statistician will be blinded to the treatment received. The 
clinical laboratories analyzing the blood/plasma samples and the concentration/incidence of 
anti-rituximab antibodies will also be blinded to the treatment assignment. A team from the 
CRO, independent to the clinical monitoring group, shall be responsible for maintaining drug 
accountability logs. An unblinded study coordinator or pharmacist at each site will be 
responsible for maintaining drug accountability as well as for dispensing. The final CSR will 
include all end points, after all subjects complete the Week 12 (EOS/ET) visit and the database 
up to the Week 12 (EOS/ET visit) has been locked. The study will be unblinded after the 
database up to the EOS/ET visit has been locked. The subsequent follow-up data from Week 12 
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to 26 will be reported as an addendum to the final CSR and for the data up to and including the 
Week 12 or ET visit. 
5.7.1 Breaking the Blind 
A subject’s treatment assignment will not be broken until the EOS unless medical treatment of 
the subject depends on knowing the study treatment the subject received. In the event that the 
blind needs to be broken because of a medical emergency, the investigator may unblind an 
individual subject’s treatment allocation. 
The study site investigator and appropriate project team members will be authorized to access 
the emergency unblinding functionality within the IWRS. The system will require the user to 
enter an authorization key number to complete the emergency unblinding transaction. The 
exact description of the treatment assigned to the individual subject then will be accessible. 
Emergency unblinding can thus be made for any subject without affecting the double-blind 
nature of the study. Subject treatment information may only be accessed in the event of an 
emergency and out of necessity to know the identity of the allocated study treatment in order 
to institute appropriate therapeutic management. Should a situation arise where unblinding is 
urgently required (i.e., knowledge of treatment code is required to adequately manage a 
life-threatening situation), the investigator at that study site may perform immediate unblinding 
through the IWRS. If time allows, the investigator should contact the medical monitor prior to 
unblinding the individual subject to discuss the rationale for emergency unblinding. 
In the event that emergency unblinding is performed, the investigator can view and must print 
the blinded confirmation document from IWRS. The investigator must record on the 
confirmation document printout the reason for the emergency unblinding and sign the 
document. The confirmation document must then be kept in a safe place until Week 26. Once 
a randomization code has been broken for a subject, he/she must be withdrawn from the study. 
The investigator must inform the medical monitor/designee in writing within 24 hours. 
5.8 Treatment Compliance 
Study treatment will be administered under the supervision of the investigator and site 
personnel. Compliance will be monitored by study personnel at the site by using the source 
documents and the eCRF. The site study unblinded pharmacist/authorized designee is 
responsible for drug preparation, the maintenance of accurate and complete dispensing and 
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accountability forms showing the receipt and dispensation of the study treatment. The 
pharmacist will also be responsible for performing accountability and reconciliation of the 
study treatments. 
5.9 Prior and Concomitant Therapy 
Medications that are considered necessary for the subject’s safety and well-being may be given 
during the course of the study at the discretion of the investigator and must be recorded in the 
appropriate sections of the eCRF. 
All medications taken by a subject within 1 month prior to the screening visit are regarded as 
prior medication and must be documented as such in the eCRF. 
All medications still being taken by a subject at randomization and which continue to be taken 
during the study and medications started during the study are regarded as concomitant 
medication and must be documented as such in the eCRF.  
5.9.1 Background Medication 
A stable dose of weekly MTX (7.5 mg to 25 mg) and folic acid (at least 5 mg per week) that 
the subject is receiving are considered as background medications. Subjects have to be on a 
stable dose of weekly MTX (between 7.5 mg and 25 mg) for at least 4 weeks prior to 
randomization and during the study and folic acid (at least 5 mg per week). 
Note: MTX and folic acid should be used in accordance with the guidelines specified in the 
local label (e.g., SmPC in the EU, US PI for the US). Folinic acid at the same dose of folic 
acid, can be given in place of folic acid if it is allowed by the local label. Subject should take 
the same folate supplementation throughout the duration of the study. 
5.9.2 Other Concomitant Medication 
Low-dose 
corticosteroids 
(≤10 mg/day 
prednisone 
equivalent) 
and 
non-steroidal 
anti-inflammatory drugs as needed are permitted concomitant medications for RA during this 
study. 
Concomitant administration of any other experimental drug, biological medicinal products, 
B-cell modulating or cell-depleting biologic therapy, JAK inhibitors, anti-rheumatic drugs 
including DMARDs other than MTX (along with folic acid), tofacitinib, glucocorticoids used 
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as pre-medication other than methylprednisolone or its equivalent, or immunotherapy is 
prohibited during study participation. 
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6 
Study Assessments and Procedures 
Before performing any study procedures, all potential subjects will sign an ICF. Subjects will 
have the opportunity to have any questions answered before signing the ICF. The investigator 
must address all questions raised by the subject. The investigator or designee will also sign the 
ICF. 
6.1 Schedule of Assessments 
An overview of the protocol visits and procedures is provided in Table 14-1. 
The investigator may plan unscheduled visits in addition to those listed on the schedule of 
activities, in order to conduct evaluations or assessments required to protect the well-being of 
the subject. If any unscheduled visits happen at any time during the study, visit 
details/appropriate data including the reason will be collected in the eCRF. 
6.1.1 Screening Period (Days -14 to 0) 
Subjects will undergo a screening visit, within 14 days prior to the planned first day of study 
treatment. During the screening visit, subjects will be screened at the study site to confirm their 
eligibility for participation in the study. The investigator or sub-investigator will discuss with 
each subject the nature of the study, its requirements, and its restrictions. Written and signed 
ICF must be obtained from each subject prior to the conduct of any protocol-specific 
procedures. 
Screening procedures and assessments will be as follows: 
The proposed chronological order of the assessments below should be followed. 
1. Obtain written informed consent from the subject in accordance with local regulations. 
2. Register screening of the subject. 
3. Review subject eligibility (inclusion and exclusion criteria). Any questions regarding 
subject eligibility can be addressed to the medical monitor. 
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4. Document medical and surgical history (includes full history of RA and other rheumatic 
diseases, including their related procedures, all ongoing conditions at the time of 
screening, all major surgical procedures [i.e., those involving opening of cavities or 
epidural or general anesthesia] with their reason, and any past event or procedure 
considered relevant by the investigator as well as any minor event occurring in the 
month prior to screening). 
5. Document subject demographics. 
6. Clinical assessments will include the following: physical examination (including height 
and weight), vital signs measurement (seated BP, heart rate, respiration rate, and oral 
body temperature). 
7. Serum pregnancy test (beta-human chorionic gonadotropin [β-hCG]) to be performed 
for WOCBP. Female subjects with documented history of hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy, medically confirmed ovarian failure, or 
screening follicle-stimulating hormone (FSH) test demonstrating postmenopausal status 
are exempted from pregnancy testing. 
8. Clinical laboratory assessments: a blood sample will be taken for hematology and 
biochemistry; urinalysis will also be performed. 
9. Tuberculosis screening (if required by local regulation or practice). 
10. Viral disease screening: hepatitis B surface antigen (HBsAg), hepatitis B core antibody 
(HBcAb), hepatitis C virus (HCV), and human immunodeficiency virus (HIV). 
Note: For HBcAb, site is requested to perform HBcAb IgG and HBcAb IgM. If any of 
these 2 results is positive, then the subject will be considered as screen failure. 
11. Twelve-lead electrocardiogram (ECG). 
12. Assess AE(s). 
13. Prior and ongoing medications. 
14. Serum Immunoglobulin (IgG and IgM) 
Subjects who do not meet the criteria for participation in this study (screen failure) may be 
rescreened at the investigator’s discretion, following discussion with the sponsor designee 
medical monitor. Subjects not included in the study due to latent TB (in the locations where 
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TB screening is required) will also require rescreening after appropriate treatment has been 
administered per local guidance. 
6.1.2 Treatment Period (2 Weeks) 
Subjects will attend study visits at Week 0 (Day 1) + 1 day and Week 2 (Day 15) + 1 day. 
Samples for the evaluation of ADA, including titer and NAb (immunogenicity assessments), 
will be obtained before the administration of study treatment on Day 1 and Day 15.  
In the description of evaluations below: 
Study Day 1 (Week 0, Baseline Visit) 
Eligible subjects will return to the study site for the baseline (Week 0, Day 1) visit. Subjects 
must satisfy all inclusion/exclusion criteria in order to be eligible for randomization. 
Baseline procedures and assessments should be conducted in chronological order as follows: 
1. Re-review subject eligibility (inclusion and exclusion) criteria to ensure that the subject 
continues to be eligible for inclusion into the study. Any questions regarding subject 
eligibility can be addressed to the medical monitor. 
2. Clinical assessments will include the following: physical examination, vital signs 
measurement (seated BP, heart rate, respiration rate, and oral body temperature). 
3. Urine pregnancy test for WOCBP. 
4. Clinical laboratory assessments: a blood sample will be taken for hematology and 
biochemistry; urinalysis will also be performed (see Section 6.3.4 for the list of clinical 
laboratory assessments).  
Note: Viral disease screening (HBsAg, HBcAb, HCV, HIV), and serum IgG and IgM 
and TB screening will not be repeated on Day 1 of the study. Clinical laboratory 
assessments scheduled on Day 1 can be performed 1 day prior to dosing. 
Note: For HBcAb, site is requested to perform HBcAb IgG and HBcAb IgM. If any of 
these 2 results is positive, then the subject will be considered as screen failure. 
5. Randomize the subject in accordance with the IWRS. 
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6. Collect plasma samples for immunogenicity assessments prior to administration of 
study treatment. 
7. Collect a time-matched blood sample (approximately 5 mL) for the estimation of 
rituximab concentration.  
8. Study treatment administration and observation for at least an hour post infusion. 
9. Assess AE(s). 
10. Record concomitant medication(s). 
Study Day 15 (Week 2 + 1 Day) 
The procedures and assessments are as follows: 
1. Clinical assessments will include the following: physical examination, vital signs 
measurement (seated BP, heart rate, respiration rate, and oral body temperature). 
2. Urine pregnancy test for WOCBP. 
3. Clinical laboratory assessments: a blood sample will be taken for hematology and 
biochemistry; urinalysis will also be performed. 
4. Collect plasma samples for immunogenicity assessments prior to administration of 
study treatment. 
5. Collect a time-matched blood sample (approximately 5 mL) for the estimation of 
rituximab concentration. 
6. Study treatment administration and observation for at least an hour post infusion. 
7. Assess AE(s). 
8. Review concomitant medications. 
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6.1.3 Follow-Up Period (10 Weeks) 
Week 4 ± 7 Days 
The procedures and assessments for Week 4 ± 7 days are as follows: 
1. Clinical assessments will include the following: physical examination (including 
weight), vital signs measurement (seated BP, heart rate, respiration rate, and oral body 
temperature). 
2. Urine pregnancy test for WOCBP. 
3. Clinical laboratory assessments: a blood sample will be taken for hematology and 
biochemistry; urinalysis will also be performed. 
4. Collect plasma samples for immunogenicity assessments. 
5. Collect a time-matched blood sample (approximately 5 mL) for the estimation of 
rituximab concentration. 
6. Assess AE(s). 
7. Review concomitant medications. 
Week 8 ± 7 Days 
The procedures and assessments for Week 8 ± 7 days are as follows: 
1. Clinical assessments will include the following: physical examination (including 
weight), vital signs measurement (seated BP, heart rate, respiration rate, and oral body 
temperature). 
2. Urine pregnancy test for WOCBP. 
3. Clinical laboratory assessments: a blood sample will be taken for hematology and 
biochemistry; urinalysis will also be performed. 
4. Collect plasma samples for immunogenicity assessments. 
5. Collect a time-matched blood sample (approximately 5 mL) for the estimation of 
rituximab concentration. 
6. Assess AE(s). 
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7. Review concomitant medications. 
6.1.4 End of Study/Early Termination Visit (Week 12 ± 7 Days) 
Subjects who complete the study or discontinue from the study at any time will attend an 
EOS/ET visit.  
The EOS/ET assessments are as follows: 
1. Clinical assessments will include the following: physical examination (including 
weight), vital signs measurement (seated BP, heart rate, respiration rate, and oral body 
temperature). 
2. Serum pregnancy test (β-hCG) for WOCBP. Female subjects with documented history 
of hysterectomy, bilateral salpingectomy, bilateral oophorectomy, medically confirmed 
ovarian failure, or screening FSH test demonstrating postmenopausal status are 
exempted from pregnancy testing. 
3. Clinical laboratory assessments: a blood sample will be taken for hematology and 
biochemistry; urinalysis will also be performed. 
4. Twelve-lead ECG. 
5. Collect plasma samples for immunogenicity assessments. 
6. Collect a time-matched blood sample (approximately 5 mL) for the estimation of 
rituximab concentration. 
7. Assess AE(s). 
8. Review concomitant medication(s). 
6.1.5 Additional Follow-Up Visit (Week 26) 
The following assessments will be performed at Week 26: 
1. Clinical assessments will include the following: physical examination (including 
weight), vital signs measurement (seated BP, heart rate, respiration rate, and oral body 
temperature). 
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2. Serum pregnancy test for WOCBP. Female subjects with documented history of 
hysterectomy, bilateral salpingectomy, bilateral oophorectomy, medically confirmed 
ovarian failure, or screening FSH test demonstrating postmenopausal status are 
exempted from pregnancy testing. 
3. Clinical laboratory assessments: a blood sample will be taken for hematology 
(especially absolute neutrophil count) and biochemistry; urinalysis will also be 
performed. 
4. Twelve-lead ECG. 
5. Assess AE(s). 
6. Review concomitant medications. 
6.2 Immunogenicity Endpoint 
The immunogenicity endpoint is the incidence of ADA, including titer and NAb. 
6.2.1 Immunogenicity Sampling  
Blood samples for detection of ADA (including NAb) will be collected prior to initiation 
(preferably within 30 minutes) of infusion of study treatment on Day 1 and Day 15 and then 
on visits at Weeks 4, 8, and 12 (EOS/ET) as specified in Table 14-1 and Section 6.1. 
Whole blood samples (approximately 10 mL) will be collected and processed to obtain 
approximately 4 mL of plasma for ADA (including titer and NAb) detection at each time point. 
Samples should be processed per detailed instructions in the laboratory manual for collection 
by the central laboratory. The samples will be shipped to laboratories for ADA titer and NAb 
analysis by the central laboratory as detailed in the laboratory manual. 
Along with the immunogenicity sample, a time-matched blood sample (approximately 5 mL) 
will be collected for the estimation of rituximab concentration. The evaluation of the samples 
will be performed to interpret safety and/or immunogenicity data appropriately, if needed. 
The central laboratory shipment address and assay laboratories contact information will be 
provided to the investigator prior to or during the initiation of the study. 
Further details on sample collection, processing, and shipment are provided in full in the 
laboratory manual. 
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6.2.2 Immunogenicity Assay 
Immunogenicity samples will be analyzed by designated analytical laboratory(ies) using 
validated methods. Analysis of ADA samples will follow a tiered approach of screening, 
confirmation, and titer determination. Samples that are confirmed positive for ADA will be 
further tested for titer and NAb using validated assays. 
Immunological testing in human subjects will involve a multi-tiered approach as outlined 
below: 
Tier I Screening Assay: All the clinical samples for immunogenicity assessment will be 
subjected to a screening assay. The methodology is based on the principle of capture of the 
ADA by the drug and detection by biotin-labelled drug, using ELISA. The test methodology 
may be modified after the method validation is completed. During method validation, an assay 
cut point is statistically determined. The samples that show a response equal to or above the 
pre-determined screening cut point will be called as “screening positive” and the ones that 
show a response below the assay cut point will be called as “negative”.  
Tier II Confirmation Assay: All the clinical samples that are “screening positive” will be 
subjected to a confirmation assay. This will involve the inhibition of the response seen in the 
screening assay with high concentration of drug. The assay format is an adaptation of the 
screening assay, where the samples are spiked with phosphate-buffered saline or drug and 
incubated for 1 hour at 37°C prior to evaluation according to the screening assay procedure. 
The samples that show a response equal to or above the pre-determined confirmatory cut point 
will be called as “confirmed positive” and the ones that show a response below the assay cut 
point will be called as “negative”.  
Tier III Titer Determination: It is the semi-quantitative assay where titers of the confirmed 
ADA-positive samples will be evaluated with respect to a previously established titer cut point. 
During the clinical sample analysis, serial 2-fold dilutions of confirmed positive samples will 
be performed and the reciprocal of the dilution able to yield a response at or above the titration 
cut point will be reported as the titer of the ADAs.  
Tier IV Neutralizing Antibodies Assay: This is based on the principle that any sample 
containing NAbs would reduce or abolish the biological activity associated with a known 
concentration of drug product used in a cell-based NAb assay. This is based on the mechanism 
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of action of the drug (rituximab) and is used to characterize the neutralizing activity of the 
confirmed ADA-positive samples. Rituximab induces CDC. The ability of the ADA to 
neutralize the CDC activity of rituximab will be assessed in a cell-based assay. This assay is 
developed and will be validated prior to clinical sample analysis. This assay is a 
characterization of the confirmed ADAs.  
The diagrammatic representation of the immunogenicity assessment of rituximab in the clinical 
study is shown in Figure 6-1. 
Figure 6-1: Flow Diagram for the Evaluation and Characterization of Anti-Drug 
Antibodies 
 
Abbreviation: ADA, anti-drug antibody. 
 
Comprehensive information regarding validity, specificity, and sensitivity of immunogenicity 
assays used in this study will be provided in a separate report. 
6.3 Safety Assessments 
The safety endpoints of this study are as follows:  
• Incidence of TEAEs and SAEs. 
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• Incidence of anaphylactic reactions, hypersensitivity reactions, and IRRs. 
Other safety endpoints will include the following:  
• Clinical laboratory parameters 
• Vital signs 
• Twelve-lead ECG 
• Physical examination 
Definitions 
Infusion-related Reactions 
Infusion-related reactions are defined as a group of acute reactions to the allergen (or 
therapeutic protein for this study) that occur during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion. 
Signs/symptoms may include the following: allergic reaction (including drug fever), arthralgia 
(joint pain), bronchospasm, cough, dizziness, dyspnea (shortness of breath), fatigue (asthenia, 
lethargy, malaise), headache, hypertension, hypotension, myalgia (muscle pain), nausea, 
pruritis/itching, rash/desquamation, rigors/chills, sweating (diaphoresis), tachycardia, tumor 
pain (onset or exacerbation of tumor pain due to treatment), urticaria (hives, welts, wheals), 
and vomiting (Doessegger L and Banholzer ML 2015). 
Hypersensitivity Reactions 
Any AE, which occurs 24 hours of completion of infusion and with clinical or clinical 
laboratory (if performed) features suggesting an immunoallergic mechanism and without any 
other supported alternative explanation and not fulfilling the provided definition of 
anaphylactic reaction. 
Hypersensitivity reactions to biologic agents are less common than standard IRRs. Although 
some clinical signs and symptoms are more unique to hypersensitivity reactions, many are 
similar. Hypersensitivity and standard IRRs can have gastrointestinal symptoms, dyspnea, 
flushing, pruritus, and back pain. Symptoms that are more suggestive of a hypersensitivity 
reaction would include urticaria, wheezing, frequent coughing, and anaphylactic symptoms 
(Khan DA 2016). 
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Anaphylaxis 
Anaphylaxis is highly likely when any 1 of the following 3 criteria (criteria of the National 
Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network), which 
will be applied for diagnosing anaphylaxis (Sampson HA 2006) are fulfilled based on the 
principal investigator’s discretion or clinical evaluation: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen 
lips-tongue-uvula) AND AT LEAST 1 OF THE FOLLOWING: 
a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow or hypoxemia). 
b. Reduced BP or associated symptoms of end organ dysfunction (e.g., hypotonia 
[collapse], syncope, incontinence). 
2. Two or more of the following that occur rapidly after exposure to a likely allergen 
for that subject (minutes to several hours): 
a. Involvement of the skin mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula). 
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow, hypoxemia). 
c. Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence). 
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting). 
3. Reduced BP after exposure to known allergen for that subject (minutes to several 
hours): 
a. Infants and children: low systolic BP (age specific) or greater than 30% decrease 
in systolic BP (this study is going to be conducted in adult subject population, 
hence this criterion will not be applicable here). 
b. Adults: systolic BP of less than 90 mmHg or greater than 30% decrease from 
that person’s baseline. 
Note: Above differentiating features of IRRs, hypersensitivity and anaphylaxis are 
recommendations based on the literature (Doessegger L and Banholzer ML 2015, Khan DA 
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2016, Sampson HA 2006). The investigator should use his/her clinical judgment to document 
it as IRRs and/or hypersensitivity reactions and/or anaphylaxis. 
The timing and frequency of safety assessments are described in Section 6.1. 
6.3.1 Adverse Events 
6.3.1.1 
Definitions 
The definitions for AEs, SAEs, and TEAEs are given below. It is of the utmost importance that 
all site personnel involved in the study are familiar with the content of this section. The 
principal investigator is responsible for ensuring this. 
6.3.1.1.1 
Adverse Event/Reaction 
An AE is 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 unfavorable and unintended sign, 
symptom, or disease temporally associated with the use of a study treatment, whether or not 
related to the study treatment. 
Any relevant observations made at the screening visit (prior to signing the ICF) are to be 
recorded as a preexisting condition; an AE will only be recorded if there is a worsening of the 
preexisting condition during study conduct with regards to nature, severity, or frequency.  
An ADR is an untoward and unintended response to a study treatment related to any dose 
administered. All AEs judged by either the reporting investigator or the sponsor as having a 
reasonable causal relationship to a medicinal product qualify as ADRs. The expression of 
“reasonable causal relationship” means to convey in general that there are facts or arguments 
meant to suggest a causal relationship. 
A pre-treatment event is defined as any untoward medical occurrence in a clinical investigation 
subject who has signed informed consent to participate in a study but prior to administration 
of any study drug; it does not necessarily have to have a causal relationship with study 
participation. 
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Serious Adverse Event 
An SAE is defined as an AE that results in 1 of the following outcomes: 
• Results in death. 
Death is not an AE/SAE itself, but an outcome. The cause of the death is an AE, which 
resulted in death. 
• Is life-threatening. 
Life-threatening means that the subject was at immediate risk of death at the time of the 
SAE, it does not refer to an SAE that hypothetically might have caused death if it were 
more severe. 
• Requires in-subject hospitalization or prolongs existing hospitalization (This does not 
include prolonged hospitalization for study purposes). 
Hospitalization is defined as at least 1 overnight formal admission into hospital, usually to 
perform additional tests, provide treatment that it is not possible to provide at home and/or 
to allow specific monitoring of the subject due to their unstable medical condition. Current 
hospitalization due to preplanned hospitalizations (known already prior to signing the ICF) 
will not be considered an SAE, unless any of the above criteria are fulfilled over the course 
of the hospitalization due to unplanned complications. Following the initial discharge from 
hospital, subsequent hospitalizations are to be considered an SAE. “Social” hospitalization, 
defined as administrative impossibility to discharge the subject is not necessarily an SAE. 
Complications that occur during hospitalization are AEs unless they would qualify as an 
SAE for any of the above criteria. If the complication delays the subject’s release from 
hospital, then the AE becomes an SAE. Hospitalizations due to diagnostic procedures 
which are not performed due to an AE are not regarded as SAE. 
• Results in persistent or significant disability/incapacity. 
The term significant disability refers to any condition that impairs physical/psychological 
well-being to the extent that the subject is unable to function normally. Physical disability 
may include, but is not limited to, permanent disability of locomotion or motility, but also 
systemic permanent dysfunction as development of heart failure, liver insufficiency, or 
pulmonary fibrosis. 
• Is a congenital anomaly/birth defect. 
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• Is an important medical event. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment 
they may jeopardize the subject or the subject may require medical or surgical intervention 
to prevent 1 of the outcomes listed in this definition. 
6.3.1.1.2 
Treatment-Emergent Adverse Event  
Treatment-emergent AEs are defined as any AE occurring or worsening on or after the first 
dose of study medication. 
6.3.1.2 
Recording of Adverse Events 
Any relevant observations made at the screening visit (prior to signing the ICF) are to be 
recorded as a preexisting condition. For the purposes of this study, any detrimental change in 
the subject’s condition, after signing the ICF and up to completion of the 26-week study period, 
should be considered as a TEAE/SAE.  
The following variables will be recorded for each AE: verbatim/AE description and date for 
AE start and stop, severity, seriousness, causality rating, whether or not the AE caused the 
subject to discontinue, action taken with the study treatment, and the outcome. If the severity 
of the event changes, the event with the highest severity will be recorded. 
Serious AEs and TEAEs will be recorded starting after signing of the ICF. All SAEs and AEs 
have to be recorded, whether or not considered causally related to the study treatment or to the 
study procedure(s). 
All ongoing nonserious AEs should be followed up until resolution or stabilization or the 
EOS/ET visit, whichever occurs first, with the exception of any ongoing treatment-related 
nonserious AEs that should be followed until that AE is stabilized, resolved, or, in the 
investigator's opinion, the AE is unlikely to resolve due to the subject's underlying condition. 
All ongoing SAEs should be followed up until resolution or stabilization/or until a pre-defined 
outcome is reached.  
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Note: Outcome information received on on-going SAE beyond the date of data base lock, will 
be captured in safety database and reported as follow-up report in the form of individual case 
safety report. 
At any time after the additional follow-up visit, if an investigator learns of an SAE that can be 
reasonably related to study treatment, he/she should promptly notify the sponsor/designee. 
6.3.1.3 
Assessment of Severity 
Whenever possible, the intensity of clinical AEs will be graded according to National Cancer 
Institute (NCI) CTCAE (Version 5.0 or any latest version) grading system. Adverse events not 
listed in the NCI CTCAE grading system will be graded on a 5-point scale (mild, moderate, 
severe, life-threatening, and death) as described below, and reported in detail as indicated on 
the eCRF. 
Severity Grading for Adverse Events Listed in NCI CTCAE (Version 5.0 or any Latest 
Version): 
• 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 activities of daily living (ADL) (Instrumental ADL refers to 
preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc). 
• Grade 3: Severe: or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL (Self-care ADL refers to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden). 
• Grade 4: Life-threatening: life-threatening consequence; urgent intervention indicated. 
• Grade 5: death related to AE. 
Note the distinction between the severity and the seriousness of an AE. A severe event is not 
necessarily an SAE. For example, a headache may be severe (interferes significantly with 
subject’s usual function) but would not be classified as serious unless it meets 1 of the criteria 
for SAEs, listed in Section 6.3.1.1.1. 
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6.3.1.4 
Assessment of Causality 
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of AE/SAE. The investigator will use clinical judgment to determine the 
relationship. Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. The investigator will also consult the IB 
and/or product information, for marketed products, in his/her assessment. There may be 
situations in which an SAE has occurred, and the investigator has minimal information to 
include in the initial report in the eCRF. However, it is very important that the investigator 
always make an assessment of causality for every event before the initial transmission of 
the SAE data via eCRF. The investigator may change his/her opinion of causality in light of 
follow-up information and change the assessment in the eCRF, which will trigger an alert to 
the sponsor’s designated safety services. The causality assessment is 1 of the criteria used when 
determining regulatory reporting requirements. 
The following “binary” decision choice will be used by the investigator to describe the 
causality assessment: 
• Reasonable possibility of relatedness (i.e., related) 
• No reasonable possibility of relatedness (i.e., not related) 
The term “reasonable possibility of relatedness” is meant to convey, in general, that there is 
enough evidence or argument to suggest the causal relationship. The investigator should 
consider the following before reaching a decision on causality assessment: 
• Time relationship between study treatment intake and event’s onset; 
• Dechallenge; 
• Rechallenge; 
• Medical history; 
• Study treatment; 
• Mechanism of action of study treatment; 
• Class effect; 
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• Concomitant treatments in use; 
• Withdrawal of study treatment; 
• Lack of efficacy/worsening of existing condition; 
• Erroneous treatment with study medication or concomitant medication; 
• Protocol-related process. 
Action taken with study treatment due to the AE: 
• Dose not changed; 
• Drug interruption; 
• Drug withdrawn; 
• Unknown; 
• Not applicable. 
Outcome: 
Each single AE must be rated by choosing 1 of the following: 
• Recovered/resolved; 
• Recovering/resolving; 
• Not recovered/not resolved; 
• Recovered with sequelae/resolved with sequelae; 
• Fatal; 
• Unknown. 
Note: If an event is stabilized per opinion of the investigator, then outcome option of “Not 
recovered/not resolved” to be selected in drop down list of outcome in eCRF. However, in 
AE/SAE description free filed of eCRF, investigator has to mention the event is assessed as 
“Stabilized” on a given date. 
The investigator and the sponsor (or sponsor’s designee) will review each SAE report and the 
sponsor/CRO will evaluate the seriousness and the causal relationship of the event to study 
intervention. In addition, the sponsor (or sponsor’s designated agent) will evaluate the 
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expectedness according to the reference document (IB or SmPC or PI). Based on the 
investigator and sponsor’s assessment of the event, a decision will be made concerning the 
need for further action. 
6.3.1.5 
Reporting of Serious Adverse Events 
Investigators and other site personnel must inform as appropriate to the sponsor’s designated 
safety services of any SAEs that occur (whether or not attributable to the study treatment) in 
the course of the study within 1 day (24 hours) (i.e., immediately but no later than the end of 
the next calendar day) of when he or she becomes aware of it. 
Follow-up information on SAEs must also be reported by the investigator to the sponsor’s 
designated safety services within the same time frames. 
If a nonserious AE becomes serious, this and other relevant follow-up information must also 
be provided to sponsor’s designated safety services within 24 hours as described above. 
All SAEs must be reported, whether or not considered causally related to the study treatment 
or study procedure(s). All SAEs will be recorded in the eCRF; paper forms will be used as a 
back-up only if the eCRF is unavailable. The investigator is responsible for informing the 
IEC/IRB of the SAE per local requirements. 
Source documents relevant for the SAE must be reported upon request by sponsor’s designated 
safety services. Due to data protection laws, please ensure redaction of the subject’s identifiers 
(name, address, and date of birth [only year of birth is allowed]) from the discharge summary, 
autopsy report, laboratory reports, and any other documents/reports when sending to the 
sponsor’s designated safety services. 
The completed and signed SAE or pregnancy report form must be attached to the email. A 
notification email of the event describing it in the email text is not sufficient. 
There may be situations when an SAE has occurred, and the investigator has minimal 
information to include in the initial SAE report. However, it is very important that the 
investigator always makes an assessment of causality for every event prior to transmission of 
the SAE report form. Minimum criteria are identifiable subject (number), a suspect product 
(i.e., study treatment or concomitant medication), an identifiable reporting source 
(investigator/study site identification), and an event or outcome that can be identified as 
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serious. The investigator may change his/her opinion of causality in the light of follow-up 
information, amending the SAE report form accordingly. The causality assessment is 1 of the 
criteria used when determining regulatory reporting requirements for SAEs. 
When an SAE is discovered by the site or is identified by a clinical research associate during 
site visits, SAEs will be entered by the site members into the eCRF, which contains specific 
questions for events regarded as serious. The designated personnel will receive the alert 
through automated email notification. 
The sponsor/designee representative will work with the investigator to compile all the 
necessary information and ensure that the appropriate sponsor representative receives a report 
within 1 calendar day (24 hours) for all fatal and life-threatening cases and within 5 calendar 
days for all other SAEs per the applicable local regulatory guidelines. All SAEs and follow-up 
information on the SAEs are to be reported to 
Pharmacovigilance in 24 hours regardless 
of seriousness criteria. 
Prompt notification of SAEs to the sponsor/designee, as described above, is essential so that 
regulatory requirements and ethical obligations to the subjects involved in the study can be 
met. The investigator is responsible for informing the IEC/IRB of the SAE per local 
requirements. Unblinding relating to suspected unexpected serious adverse reactions 
(SUSARs) (if required) will be performed by the sponsor/designee in accordance with standard 
operating procedures (SOPs), working practice documents, and documented study-specific 
procedures. 
6.3.1.6 
Suspected Unexpected Serious Adverse Reactions 
Any AE that is serious, associated with the use of the study intervention, and unexpected 
(SUSAR) has additional reporting requirements as described below. 
• If the SUSAR is fatal or life-threatening, associated with study intervention, and 
unexpected, regulatory authorities and IEC/IRB will be notified within 7 calendar days 
after the sponsor learns of the event. Additional follow-up (cause of death, autopsy report, 
and hospital report) information should be reported within an additional 8 days (15 days 
total). 
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• If the SUSAR is not fatal or life-threatening but is otherwise serious, associated with study 
intervention, and unexpected, regulatory authorities and IEC/IRB will be notified within 
15 calendar days after the sponsor learns of the event. 
The sponsor’s designated safety services will also provide periodic and annual safety updates 
to the regulatory authorities, IEC/IRB responsible for the study, and investigators per local 
regulations. These updates will include information on SUSARs and other relevant safety 
findings. 
6.3.2 Abnormal Laboratory Values/Vital Signs 
Measurements/Electrocardiograms 
Laboratory/vital signs/ECG abnormalities should be reported as an AE/SAE if any 1 of the 
following criteria is met: 
• Result is associated with signs/symptoms; 
• Requires additional diagnostic testing and/or interventions; 
• Leads to a change in dose, discontinuation of, or interruption to the study treatment. 
Repeats of an abnormal test result without any of the above criteria do not constitute an AE. 
Any test result determined to be an error is not required to be reported as an AE. 
6.3.3 Deaths 
Should a death occur within the study period, an AE form and an SAE report form should be 
completed, detailing the AE that resulted in the death (Note: death is an outcome, not an event). 
The SAE must be reported to the sponsor or the sponsor’s designated safety services within 
24 hours as described in Section 6.3.1.5. 
Expedited reporting is determined by the CRO depending on the information provided by the 
site, e.g., AEs that are fatal/life-threatening and related to the study drug would be considered 
as expedited and reported to regulatory authorities and IEC/IRB within 7 calendar days. 
Adverse events with any other seriousness criteria and relatedness would be reported to 
regulatory authorities and IEC/IRB within 15 calendar days. 
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6.3.4 Clinical Laboratory Assessments 
Clinical laboratory assessments will be performed as indicated in Table 14-1. Hematology, 
biochemistry, and urinalysis will be conducted at the following visits: screening, on Day 1, 
Day 15, and at Weeks 4, 8, 12 (EOS/ET), and 26 (additional follow-up). Serum pregnancy test 
will be conducted at screening, Week 12 (EOS/ET), and Week 26 (additional follow-up) visits. 
Urine pregnancy test will be conducted on Day 1 prior to randomization, and Day 15 (before 
dosing), at Week 4 and Week 8 visits. 
Hematology, biochemistry, urinalysis, and pregnancy tests will be performed by the local 
laboratory according to local practice. Local laboratory normal ranges will be collected prior 
to first subject first visit at each site and provided to data management via the study team. 
Laboratory results collected from the local laboratory should be entered in the eCRF by the 
investigator. The following parameters will be assessed: 
• Hematology: red blood cell count, white blood cell count with differential count and 
percentages (including absolute neutrophil count), total hemoglobin, hematocrit, platelet 
count, and prothrombin time. 
• Biochemistry: creatinine, blood urea nitrogen, fasting serum glucose, aspartate 
aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase, total 
bilirubin, albumin, chloride, calcium, phosphorous, uric acid, total protein, sodium, and 
potassium. 
• Serum IgG and IgM. 
• Urinalysis (specific gravity, pH, protein, glucose, and blood). 
• Pregnancy test: serum β-hCG test and urine pregnancy test for WOCBP. 
• Serum FSH for postmenopausal women. 
Note: Per CTFG 2014 guidelines, a postmenopausal state is defined as no menses for 
12 months without an alternative medical cause. A high FSH level in postmenopausal women 
is to be used to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a 
single FSH measurement is insufficient. Hence, in such cases or in some other cases in which 
if menopausal status is difficult to confirm, then investigators are advised to investigate further 
to rule out childbearing potential along with serum FSH. 
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Blood and urine collection and blood sample preparation will be performed according to 
procedures from the local laboratories. 
6.3.5 Physical Examination 
Complete physical examinations will be performed as indicated in Table 14-1. The following 
parameters and body systems will be examined and any abnormalities described: weight, 
height (at screening visit only), general appearance, skin (e.g., presence of rash), head, eyes, 
ears, nose, throat, lungs (auscultation), heart (auscultation for presence of murmurs, gallops, 
rubs), extremity exam for the presence of peripheral edema, abdominal (palpation and 
auscultation), and neurologic (mental status and motor and sensory function). The physical 
examination must include a thorough assessment of the lymph nodes, liver, and spleen. The 
genitourinary system may be excluded unless there are signs or symptoms involving that 
system. Any clinically significant changes from the screening visit after initial dosing with 
study treatment should be recorded as AEs. 
6.3.6 Vital Sign Measurements 
Vital signs, including heart rate, seated BP, respiration rate, and oral body temperature, will be 
measured as detailed in Table 14-1 and in the event of an IRR. 
Blood pressure will be measured in the subject’s arm and recorded to the nearest mmHg after 
the subject has been seated quietly for at least 2 minutes. The same arm and position should be 
used throughout the study, using an appropriate cuff size. All BP readings should be measured 
after resting for at least 5 minutes. When the timing of these measurements coincides with 
blood collection, the BP and heart rate should be obtained first. 
Vital signs are to be obtained prior to each study treatment infusion, every 30 minutes 
(± 5 minutes) during infusion, at the end of infusion, and as clinically indicated. In the event 
of hypersensitivity reaction, vital signs should be obtained at additional time points until 
recovery per investigator judgment. 
6.3.7 12-Lead Electrocardiogram 
Twelve-lead ECGs will be performed as indicated in Table 14-1 under medical supervision. 
Before recording, subjects should be resting in a quiet supervised setting with minimal 
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stimulation (e.g., no television, loud music, and computer games) and lie in a resting position 
for 10 minutes before ECG recording. 
All ECGs are to be read locally with local ECG equipment by an appropriately qualified and 
experienced ECG reader at the study site. 
Corrected QT interval (QTc) value will be calculated using the Fridericia formula 
(QTc = QT/(RR-1/3), QTc should be expressed in milliseconds, the provided formula assumes 
QT also in milliseconds and RR in seconds. The QTc interval will be automatically calculated. 
In the case of clinically significant ECG abnormalities, the investigator should report these as 
an AE if not due to a preexisting condition or if a preexisting condition worsens in frequency 
or intensity. 
6.3.8 Viral Disease Screening 
Subjects will be tested for HIV, hepatitis B, and/or hepatitis C to determine eligibility at 
screening visit. 
HBsAg, HBcAb, HCV, and HIV are to be determined by each site’s local laboratory. 
Note: For HBcAb, site is requested to perform HBcAb IgG and HBcAb IgM. If any of these 
2 results is positive, then the subject will be considered as screen failure. 
6.4 
Pregnancy 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study treatment 
may have interfered with the effectiveness of a contraceptive medication. If a pregnancy is 
reported for a subject, no further study treatment will be administered to this subject and the 
outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) must be followed up and documented. Follow-up should be done up 
to delivery and after the examination of the newborn a follow-up report should be sent with 
any new information regarding the pregnancy and the outcome of the newborn. 
All congenital abnormalities/birth defects should be classified as SAEs. Spontaneous 
miscarriages should also be reported and handled as SAEs. Elective abortions without 
complications should not be handled as SAEs but should be reported as an AE. All outcomes 
of pregnancy must be reported to the sponsor on a pregnancy outcomes report form. 
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Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the female partner. 
Pregnancies must be reported to the sponsor or sponsor’s designated safety services using the 
reporting details provided in Section 6.3.1.5 within 24 hours of awareness. 
6.5 Blood Loss During the Study 
For the safety evaluation, approximately 10 mL of blood will be withdrawn from the subjects 
at each time point. A total of approximately 145 mL of blood will be collected per subject 
during the study for immunogenicity, for estimation of rituximab concentration, and safety 
evaluation as mentioned in Table 6-1. 
Table 6-1: 
Blood Loss During the Study 
Abbreviations: ADA, anti-drug antibody; NAb, neutralizing antibody. 
Note: For safety evaluation, more than 10 mL of blood can be withdrawn based on the site/local laboratory 
practice and will not be considered as a deviation. 
 
Time Points 
Safety 
Evaluation 
(Laboratory) 
ADA and NAb 
Evaluation 
For Estimation of 
Rituximab Concentration 
(Approximately) 
Total Volume 
of Blood Loss 
Screening 
10 mL 
- 
 
10 mL 
Week 1/Day 1 
10 mL 
10 mL 
5 mL 
25 mL 
Week 2/Day 15 
10 mL 
10 mL 
5 mL 
25 mL 
Week 4 
10 mL 
10 mL 
5 mL 
25 mL 
Week 8 
10 mL 
10 mL 
5 mL 
25 mL 
Week 12 
10 mL 
10 mL 
5 mL 
25 mL 
Week 26 
10 mL 
- 
- 
10 mL 
Total volume of blood 
loss 
70 mL 
50 mL 
25 mL 
145 mL 
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7 
Statistical and Analytical Plan 
7.1 Sample Size Calculations 
 
 
7.2 Analysis Sets 
The safety population will include all subjects who are randomized and receive at least 1 dose 
of study treatment. 
Immunogenicity population will include all subjects with at least 1 post-dose ADA assessment 
result available. 
Analyses of safety parameters will be based on the safety population, and immunogenicity 
parameters (ADA and NAb) will be based on the immunogenicity population. 
7.3 Description of Subgroups to be Analyzed 
Immunogenicity and key safety parameters will be presented overall and by region, as 
appropriate. 
7.4 Statistical Analysis Methodology 
7.4.1 General Principles 
The statistical analysis will be performed using SAS Version 9.4 or later. 
The immunogenicity and safety data will be analyzed descriptively. All individual data as well 
as results of statistical analyses, whether explicitly discussed in the following sections or not, 
will be presented in individual subject data listings and statistical summary tables. 
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In general, continuous variables will be summarized using the following standard descriptive 
summary statistics: number of observations, arithmetic mean, standard deviation, minimum, 
median, and maximum. Categorical variables will be displayed by means of frequency tables 
including percentages. 
Baseline is defined as the last non-missing pre-dose assessment. Overall summaries and 
analyses will be performed based on data pooled from all sites. 
A SAP will be prepared and finalized before the clinical study database is closed. 
7.4.2 Missing Data 
All efforts will be made to ensure that all values are populated for start and stop date of 
AE/concomitant medication and severity and causality of AE. In case of any missing or partial 
dates for AEs, concomitant medication, and any other dates required for analysis still exists, 
then those will be imputed in an appropriate conservative way. For AEs, missing severity and 
relationship with treatment, if any, will also be imputed in an appropriate conservative way. 
Further details will be described in the SAP. 
Other missing values will not be imputed, unless otherwise specified in each analysis section. 
7.4.3 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be analyzed in a descriptive fashion and results 
will be presented overall and by treatment arm. 
7.4.4 Subject Disposition 
The following will be summarized (overall and by treatment arm where applicable): 
• Subjects screened. 
• Subjects randomized. 
• Subjects in the safety analysis set. 
• Subjects completing the study/withdrawing early (including withdrawal reason). 
7.4.5 Immunogenicity Analysis 
The immunogenicity endpoint of this study is the incidence of ADA, including titer and NAb. 
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Immunogenicity data (ADA and NAb) will be summarized and analyzed descriptively for each 
scheduled protocol assessment time point by treatment arm and overall. 
Further details of the analysis will be described in the SAP. 
7.4.6 Safety Analysis 
The safety analysis will be based on the safety population and will be analyzed according to 
the treatment they actually received. Detail methods will be described in the SAP. 
The safety endpoints are as follows: 
• Incidence of AEs. 
• Incidence of anaphylactic reactions, hypersensitivity reactions, and IRRs. 
Other safety endpoints will include the following:  
• Clinical laboratory parameters 
• Vital signs 
• Twelve-lead ECG 
• Physical examination. 
Treatment-emergent AEs will be described using descriptive statistics and coded according to 
the Medical Dictionary for Regulatory Activities (MedDRA), system organ class and MedDRA 
preferred term, graded according to CTCAE (Version 5.0 or any latest version), by treatment 
arm and overall. TEAEs observed, will be summarized separately by treatment arm. 
Treatment-related TEAEs and SAEs, TEAEs leading to study discontinuation, and deaths will 
be also summarized by treatment arm. 
Incidence of anaphylactic reactions, hypersensitivity reactions, and IRRs will be summarized 
by treatment arm and overall. 
Clinical safety laboratory data will be presented by treatment arm and overall. For each visit, 
the actual result and the change from baseline will be presented. Shift tables for values outside 
the clinical normality status will be presented as appropriate. 
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Otherwise, safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate. For continuous measurements (laboratory and vital signs 
data), change from baseline will be additionally summarized by treatment arm and visit. 
Subject listings will be produced for all safety endpoints. 
7.4.7 Interim Analyses 
There will be no interim analysis in this study. 
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8 
Quality Control and Quality Assurance 
This study will be conducted according to the International Council for Harmonisation (ICH) 
E6(R2) risk and quality processes described in the applicable procedural documents. The 
quality management approach to be implemented in this study will be documented and will 
comply with the current ICH guidance on quality and risk management. 
8.1 
Case Report Forms/Source Data Handling 
An eCRF is required and should be completed for each included subject. The investigator shall 
be provided with standardized eCRF and shall ensure that all data from subject visits are 
promptly entered into the eCRF in accordance with the specific instructions given. 
The investigator must maintain source documents at the study site to support the data entered 
into the eCRF. Source documents are considered to be all information in original records and 
certified copies of original records of clinical findings, observations, data, or other activities in 
a clinical study necessary for the reconstruction and evaluation of the study, such as laboratory 
reports, edges, consultation reports, complete medical history, and physical examination 
reports. 
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the eCRF and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required. The 
eCRF must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the eCRF is true. 
8.2 Data Management 
A data management plan will be prepared before data collection initiates. The data management 
plan will describe all study specifics functions, processes, and specifications for data 
collection, cleaning, and validation. The eCRFs will include programmable edits to obtain 
immediate feedback if data are missing, out of range, illogical, or potentially erroneous. 
Concurrent manual data review will be performed based on parameters dictated by the plan. 
Ad hoc queries will be generated within the electronic data capture system and followed up for 
resolution. Data quality will be enhanced through a series of programmed data quality checks 
that automatically detect out-of-range or anomalous data. Data collection and entry is the 
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responsibility of CRO that will develop a quality control plan to assure that the data entered in 
the eCRFs reflects the source documents maintained on site. Entered data will be verified by 
the clinical monitor/data manager/designee who will query the site for potential discrepancies. 
The site investigator or designee will be responsible for resolution of queries. Coding of 
medical history, AEs, and concurrent conditions will be performed using latest version of 
MedDRA and coding of prior and concomitant medications and therapies will be performed 
using the current version of World Health Organization Drug (WHODRUG) Dictionary. The 
eCRFs and any supporting documentation should be available for retrieval or review at any 
given time. 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the subjects treated as part of the research under this 
protocol. The investigator agrees to maintain accurate eCRFs and source documentation as part 
of the case histories. These source documents may include laboratory reports, ECG strips, etc. 
Investigative site personnel will enter subject data into the electronic data capture system. The 
analysis data sets will be a combination of these data and data from other sources (e.g., 
laboratory data). 
Clinical data management will be performed in accordance with applicable
 standards and 
data cleaning procedures to ensure the integrity of the data, e.g., removing errors and 
inconsistencies in the data. 
After database lock, each investigator will receive a compact disc/digital versatile disc (DVD) 
with portable document format (PDF) files for the subjects enrolled at their site and the sponsor 
will receive a Master DVD of all project data. These files will contain all of their site specific 
eCRF data as entered into Medidata Rave® for the study, including full discrepancy and audit 
history. The Medidata Rave database will be stored by Medidata. In all cases, subject initials 
will not be collected or transmitted to the sponsor. Additionally, a compact disc read-only 
memory copy of all of the study site’s data from the study will be created and sent to the 
sponsor for storage. 
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9 
Ethics 
9.1 Independent Ethics Committee or Institutional Review Board 
Prior to the start of the study, the investigator is responsible for ensuring that the protocol and 
consent form have been reviewed and approved by a relevant IEC/IRB. Federal regulations 
and the ICH guidelines require that approval be obtained from an IRB/IEC before participation 
of human subjects in research studies. Before study onset, the protocol, informed consent, 
advertisements to be used for the recruitment of study subjects, and any other written 
information regarding this study to be provided to the subject must be approved by the 
IRB/IEC. Documentation of all IRB/IEC approvals and of the IRB/IEC compliance with ICH 
Harmonised Tripartite Guideline E6(R2): Good Clinical Practice (GCP) will be maintained by 
the site and will be available for review by the sponsor or its designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must 
identify the IRB/IEC name and address, the clinical protocol by title or protocol number or 
both, and the date approval or a favorable opinion was granted. 
The investigator is responsible for providing written summaries of the progress and status of 
the study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The 
investigator must promptly supply the sponsor or its designee, the IRB/IEC, and, where 
applicable, the institution, with written reports on any changes significantly affecting the 
conduct of the study or increasing the risk to subjects. 
9.2 Ethical Conduct of the Study 
This study shall be conducted in accordance with the provisions of the Declaration of Helsinki 
(October 1996) and all revisions thereof, and in accordance with FDA regulations (Code of 
Federal Regulations [CFR], Sections 312.50 and 312.56) and with ICH GCP (Committee for 
Medicinal Products for Human Use [CHMP] 135/95). 
9.3 Subject Information and Consent 
The ICF will be used to explain the risks and benefits of study participation to the subject in 
simple terms before the subject will be entered into the study. The ICF contains a statement 
that the consent is freely given, that the subject is aware of the risks and benefits of entering 
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the study, and that the subject is free to withdraw from the study at any time. Written consent 
must be given by the subject, after the receipt of detailed information on the study. 
All ICFs must be available in the local languages required at the site and include subject 
information sheets/brochures that outline the study procedures. All ICFs must be signed and 
dated by the subject. 
For subjects who are unable to read and write, the subject information sheet and ICF should be 
read to the subject in his/her native language in the presence of an impartial witness who is 
literate and not affiliated with the study. The subject having understood the information given 
to him/her in the presence of an impartial witness will thumbprint the ICF and the same will 
be countersigned by the impartial witness. If the subject cannot read, then an impartial witness 
will witness and attest the entire consent process and will be required to sign the consent form. 
Confirmation of a subject’s informed consent must also be documented in the subject’s medical 
record prior to any testing under this protocol, including screening tests and assessments. 
The investigator is responsible for ensuring that informed consent is obtained from each 
subject, along with their signatures and dates on the informed consent document, prior to the 
performance of any protocol procedures including the administration of study drug. The 
investigator will provide each subject with a copy of the signed and dated consent form while 
the originals will be retained in the investigator’s records. 
The consent documents to be used for the study shall include all the elements of informed 
consent as outlined in the applicable SOP(s), applicable regulatory requirements, and be 
reviewed and approved by the appropriate IEC/IRB prior to use. 
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to 
the protocol. If the ICF is revised, it must be reviewed and approved by the appropriate 
IEC/IRB and signed by all subjects subsequently enrolled in the study as well as those currently 
participating in the study. 
Note: Sites are advised to follow local or country-specific guidelines while obtaining consent 
from the subject. 
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10 Investigator’s Obligations 
The following administrative items are meant to guide the investigator in the conduct of the 
study but may be subject to change based on industry and government SOPs, working practice 
documents, or guidelines. Changes will be reported to the IRB/IEC but will not result in 
protocol amendments. 
10.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject confidentiality. All records will be kept in a secure storage 
area with limited access. Clinical information will not be released without the written 
permission of the subject, except as necessary for monitoring and auditing by the sponsor, its 
designee, the US FDA, local regulatory(ies), or the IRB/IEC. 
The investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
10.2 Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow the sponsor to 
submit the complete and accurate certification or disclosure statements required under 
21 CFR 54. In addition, the investigator must provide to the sponsor/CRO a commitment to 
promptly update this information if any relevant changes occur during the course of the 
investigation and for 1 year following the completion of the study. 
Neither the sponsor nor CRO is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the absence 
of specific arrangements, neither the sponsor nor CRO is financially responsible for further 
treatment of the subject’s disease. 
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10.3 Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH E6(R2) 8.2 and 
Title 21 of the CFR by providing the following essential documents, including but not limited 
to: 
• IRB/IEC approval 
• Original investigator-signed investigator agreement page of the protocol. 
10.4 Study Conduct 
Dr. Reddy’s Laboratories S.A./CRO shall implement and maintain quality control and quality 
assurance procedures with written SOPs to ensure that the study is conducted, and data are 
generated, documented, and reported in compliance with the protocol, ICH GCP and applicable 
regulatory requirements. 
The investigator may not deviate from the protocol without a formal protocol amendment 
having been established and approved by an appropriate IEC/IRB, except when necessary to 
eliminate immediate hazards to the subject or when the change(s) involve(s) only logistical or 
administrative aspects of the study. Any deviations may result in the subject having to be 
withdrawn from the study and render that subject non evaluable. 
The investigator agrees that the study will be conducted according to the principles of ICH 
E6(R2). The investigator will conduct all aspects of this study in accordance with all national, 
state, and local laws or regulations. Study information from this protocol will be posted on 
publicly available clinical trial registers before enrollment of subjects begins. 
10.5 Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6(R2) and all applicable guidelines and regulations. 
10.6 Adverse Events and Study Report Requirements 
By participating in this study, the investigator agrees to submit reports of SAEs to the sponsor 
and/or IRB/IEC, and to any other regulatory (if required by local regulatory and laws) 
according to the timeline and methods outlined in the protocol. In addition, the investigator 
agrees to submit annual reports to the study site IRB/IEC as appropriate. 
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10.7 Records Retention 
To enable evaluations and/or audits from regulatory authorities or sponsor, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, e.g., eCRFs and hospital records), all original signed ICFs, copies 
of all eCRFs, safety reporting forms, source documents, and detailed records of treatment 
disposition, and adequate documentation of relevant correspondence (e.g., letters, meeting 
minutes, telephone calls reports). The records should be retained by the investigator according 
to ICH, local regulations, or as specified in the clinical study agreement, whichever is longer. 
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (e.g., retirement, relocation), sponsor and/or CRO should be prospectively 
notified. The study records must be transferred to a designee acceptable to the sponsor, such 
as another investigator, another institution, or to an independent third party arranged by the 
sponsor. Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. The 
investigator must obtain sponsor's written permission before disposing of any records, even if 
retention requirements have been met. 
10.8 Publications 
The sponsor shall retain the ownership of all data. When the study is complete the sponsor 
shall arrange the analysis and tabulation of data. A CSR (Section 11.4) shall then be prepared, 
which may be used for publication, presentation at scientific meetings, or submission to 
regulatory authorities. All proposed publications based on this study must be subject to the 
sponsor’s approval requirements. 
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11 Study Management 
11.1 Monitoring 
11.1.1 Monitoring of the Study 
The investigator shall permit the site monitor to review study data as frequently as deemed 
necessary to ensure that data are being recorded in an adequate manner and that protocol 
adherence is satisfactory. 
The investigator shall access medical records for the monitor in order that entries in the eCRF 
may be verified. The investigator, as part of his/her responsibilities, is expected to cooperate 
with the sponsor/CRO in ensuring that the study adheres to GCP requirements. 
The investigator may not recruit subjects into the study until such time that a visit, or with the 
agreement of the sponsor, or attendance at the investigator meeting, has been made by a 
sponsor/CRO monitor to conduct a detailed review of the protocol and eCRF. 
The clinical monitor, as a representative of the sponsor, has the obligation to follow the study 
closely. In doing so, the monitor will visit the investigator and study site at periodic intervals, 
in addition to maintaining necessary telephone and letter contact. The monitor will maintain 
current personal knowledge of the study through observation, review of study records and 
source documentation, and discussion of the conduct of the study with the investigator and 
personnel. 
All aspects of the study will be carefully monitored, by the sponsor or its designee, for 
compliance with applicable government regulation with respect to current GCP and current 
standard operating procedures. 
Note: Due to COVID-19 pandemic, provisions of remote monitoring have been added in the 
protocol (Section 3.2, Study Conduct during the COVID-19 Pandemic). 
11.1.2 Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, audits, 
IRB/IEC review, and regulatory inspections by providing direct access to all study records. In 
the event of an audit, the investigator agrees to allow the sponsor, representatives of the 
sponsor, or a regulatory agency access to all study records. 
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The investigator should promptly notify the sponsor and CRO of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to the sponsor. 
11.2 Management of Protocol Amendments and Deviations 
11.2.1 Protocol Amendments 
Before the start of the study, the study protocol and/or other relevant documents will be 
approved by the IEC/IRB/competent authorities, in accordance with local legal requirements. 
The sponsor/authorized CRO representative must ensure that all ethical and legal requirements 
have been met before the first subject is enrolled in the study. Any changes in this research 
activity, except those necessary to remove an apparent, immediate hazard to the subject, the 
same needs to be promptly reported to the sponsor or its designee and the IEC/IRB and must 
be reviewed and approved by the sponsor or its designee. Amendments to the protocol must be 
submitted in writing to the investigator’s IRB/IEC for approval before subjects can be enrolled 
into an amended protocol.  
This protocol is to be followed exactly. To alter the protocol, amendments must be written, 
receive approval from the CRO and/or from sponsor, and receive IEC/IRB/competent authority 
approval prior to implementation (if appropriate). In the United States: Following approval, 
the protocol amendment(s) will be submitted to the Investigational New Drug application 
under which the study is being conducted. 
Administrative changes (not affecting the subject benefit/risk ratio) may be made without the 
need for a formal amendment. All amendments will be distributed to all protocol recipients, 
with appropriate instructions. 
11.2.2 Protocol Deviations/Violations 
A deviation from the protocol is an unintended or unanticipated departure from the procedures 
or processes approved by the sponsor and the IRB/IEC and agreed to by the investigator. A 
significant deviation occurs when there is non-adherence to the protocol by the subject or 
investigator that results in a significant, additional risk to the subject. Significant deviations 
can include non-adherence to inclusion/exclusion criteria or non-adherence to FDA regulations 
or ICH GCP guidelines, and may lead to the subject being withdrawn from the study 
(Section 4.2). 
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All deviations from the approved protocol must be documented and notified to the 
sponsor/CRO at the earliest. The investigator should not deviate from the protocol, except for 
subject safety reasons, in which case the deviation must be reported to the sponsor/CRO 
immediately. The sponsor will not assume any resulting responsibility or liability from 
unapproved deviations. The investigator, according to applicable regulations and the 
IRB/IEC’s established procedures, will inform the IRB/IEC of protocol deviations. 
All instances where the requirements of the study protocol are not complied with, 
investigator/designee will file the protocol deviation and the same will be captured in a protocol 
deviation/violation log. Corresponding subjects may be withdrawn from the study at the 
discretion of the sponsor/designee. Deviations from the study protocol should not be made 
other than as part of a protocol amendment. An amendment must be agreed upon by the 
sponsor, but not implemented until written IEC/IRB approval is obtained, except where 
necessary to eliminate an immediate hazard to study subjects or when the change(s) involves 
only logistical or administrative aspects. Protocol deviations/violations and the reason why 
they occurred will be documented in the CSR. 
11.3 Study Termination 
Although Dr. Reddy’s Laboratories S.A. has every intention of completing the study, 
Dr. Reddy’s Laboratories S.A. reserves the right to discontinue the study at any time for clinical 
or administrative reasons. 
11.4 Final Report 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
CSR is prepared and provided to the regulatory agency(ies) as required by the applicable 
regulatory requirement(s). The sponsor will also ensure that the CSR in marketing applications 
meet the standards of the ICH Harmonised Tripartite Guideline E3: Structure and Content of 
Clinical Study Reports. 
Data until Week 12 will be analyzed and reported in the final CSR after all subjects complete 
Week 12 visit (EOS/ET). The subsequent follow-up data from Week 12 to Week 26 will be 
reported as an addendum to the final CSR and for the data up to and including the Week 12 or 
ET visit. 
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Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the CSR. The investigator will be provided reasonable access to 
statistical tables, figures, and relevant reports and will have the opportunity to review the 
complete study results. 
Upon completion of the CSR, the sponsor will provide the investigator with the full summary 
of the study results. 
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12 
Financing and Insurance 
The sponsor shall carry an insurance policy to cover compensation of subjects’ health injuries 
arising from the study. If a subject incurs a study-related injury, the subject may be treated (and 
other necessary measures taken) at the study site and/or another medical institution. If it is 
necessary to compensate for the treatment, the sponsor will cover the cost. The sponsor shall 
not impose on the subject the burden of proving the causal relation between the study and the 
injury. 
If any of the following is confirmed, the sponsor may refuse or restrict the payment of the 
compensation: 
1. A serious GCP or protocol deviation by the investigator or sub-investigator (except 
deviation medically necessary to avoid an immediate hazard to the study subjects). 
2. Intentional act or negligence on the part of the investigator or sub-investigator or 
malpractice thereby. 
3. Injury caused by unlawful act or delinquency of a third party. 
4. Injury caused by intentional act or negligence of the subject. 
If compensation becomes necessary for a study-related injury, the site will promptly notify the 
sponsor and will cooperate with the sponsor and its insurer (or their legal representatives) in 
their handling thereof. 
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13 Reference List 
Bullock J, Rizvi SAA, Saleh AM, et al. Rheumatoid arthritis: a brief overview of the treatment. 
Med Princ Pract. 2018;27(6):501–7. 
Clinical Trial Facilitation Group (CTFG). Recommendations related to contraception and 
pregnancy 
testing 
in 
clinical 
trials 
[internet]; 
2014 Sep 15. 
Available 
from: 
https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. Accessed 
02 Jul 2020. 
Cohen MD and Keystone E. Rituximab for rheumatoid arthritis. Rheumatol Ther. 
2015;2(2):99–111. 
Doessegger L and Banholzer ML. Clinical development methodology for infusion-related 
reactions with monoclonal antibodies. Clin Transl Immunology. 2015;4(7):e39. 
Dr. Reddy’s Laboratories S.A. DRL_RI. Investigator’s Brochure Version 7.0 (13 Sep 2019). 
Khan DA. Hypersensitivity and immunologic reactions to biologics: opportunities for the 
allergist. Ann Allergy Asthma Immunol. 2016;117(2):115-20. 
Komatsu N and Takayanagi H. Inflammation and bone destruction in arthritis: synergistic 
activity of immune and mesenchymal cells in joints. Front Immunol. 2012;3:77. 
MabThera® (rituximab): [summary of product characteristics]. Roche Registration GmbH. 
Germany; [cited 25 Mar 2020]. Available from: 
https://www.medicines.org.uk/emc/product/3801/smpc. Accessed 22 June 2020. 
Mikuls TR, Johnson SR, Fraenkel L, et. al. American College of Rheumatology guidance for 
the management of adult patients with rheumatic disease during the COVID‐19 pandemic. 
Arthritis 
Rheumatol. 
2020. 
Available 
from: 
https://www.rheumatology.org/Portals/0/Files/ACR-COVID-19-Clinical-Guidance-
Summary-Patients-with-Rheumatic-Diseases.pdf. Accessed on 01 Jun 2020. 
Mok CC. Rituximab for the treatment of rheumatoid arthritis: an update. Drug Des Devel Ther. 
2014;8:87–100. 
Rituxan® 
(rituximab) 
Prescribing 
Information. 
2020. 
Available 
at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/103705Orig1s5458lbl.pdf. 
Accessed 02 Jul 2020. 
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Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition and 
management of anaphylaxis: summary report — second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network symposium. Ann Emerg Med. 
2006;47(4):373-80. 
Singh JA, Saag KG, Brigdes SL Jr, et al. 2015 American College of Rheumatology guideline 
for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016;68(1):1-26. 
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14 Appendices 
14.1 Appendix 1: Schedule of Events 
Table 14-1 
Schedule of Events 
Study Period 
Screening 
Visit  
Days -14 to 
0 
Treatment Visit 
Follow-Up Visits 
EOS/E
Ta 
Visit 
Additio
nal 
Follow-
up 
Visitm 
Study Week 
 
0 
(Day 1) 
2 
(Day 
15) 
4 
8 
12 
26 
Visit Window 
 
+1 day 
+1 day 
±7 days 
Informed consentb 
X 
- 
- 
- 
- 
- 
- 
Inclusion/exclusion 
criteriac 
X 
Xk 
- 
- 
- 
- 
- 
Medical and surgical 
history 
X 
- 
- 
- 
- 
- 
- 
Prior and ongoing 
medication 
X 
- 
- 
- 
- 
- 
- 
Demographics 
X 
- 
- 
- 
- 
- 
- 
TB screening (if 
required)d 
X 
- 
- 
- 
- 
- 
- 
Viral disease screeninge 
X 
- 
- 
- 
- 
- 
- 
Physical examinationf 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
measurementsg 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
- 
- 
- 
- 
X 
X 
Pregnancy testh 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory 
assessmentsi 
X 
Xl 
X 
X 
X 
X 
X 
Randomization 
- 
X 
- 
- 
- 
- 
- 
Study treatment 
administration 
- 
X 
X 
- 
- 
- 
- 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Immunogenicityj 
- 
X 
X 
X 
X 
X 
- 
Blood sample for 
estimation of rituximab 
concentration 
- 
X 
X 
X 
X 
X 
- 
Concomitant medications 
- 
X 
X 
X 
X 
X 
X 
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Abbreviations: ADA, anti-drug antibody; ECG, electrocardiogram; EOS, end of study; ET, early termination; 
EU-rituximab, European Union approved rituximab (MabThera); HBcAb, hepatitis B core antibody; HBsAg, 
hepatitis B surface antigen; HCV, hepatitis C virus; HIV, human immunodeficiency virus; 
IgG, immunoglobulin G; IgM, immunoglobulin M; NAb, neutralizing antibody; TB, tuberculosis; 
US-rituximab, United States-licensed rituximab (Rituxan). 
Note: For assessments related to COVID-19, see Section 3.2 of the protocol. 
a 
All subjects completing the study at Week 12 or those discontinuing the study at any time will attend an 
EOS/ET visit. The allowable window for the EOS/ET visit is ±7 days. 
b 
Informed consent must be obtained prior to undergoing any protocol-specific procedure. 
c 
All eligibility criteria must be met before a subject is randomized to study treatment. Subjects must have 
received at least 1 full course comprising two 1000 mg infusion of either US-rituximab at least 16 weeks or 
EU-rituximab at least 24 weeks prior but not more than 15 months prior to the day of randomization visit. 
d 
Tuberculosis testing is to be done only if it is required by local regulations or practice. 
e 
The following tests are to be conducted by each site’s local laboratory: HBsAg, HBcAb, HCV, HIV, serum 
IgG and IgM. 
Note: For HBcAb, site is requested to perform HBcAb IgG and HBcAb IgM. If any of these 2 results is 
positive, then the subject will be considered as screen failure. 
f 
Complete physical examination will be performed at all visits. Height will be recorded at screening only. 
g 
Body temperature (oral), blood pressure, heart rate, and respiration rate will be recorded at each visit. Vital 
signs will be monitored every 30 minutes (± 5 minutes) during the course of the treatment administration or 
more frequently as necessary. 
h 
Subjects who are WOCBP will have a serum pregnancy test at the screening visit, Week 12 (EOS/ET), and 
Week 26 (additional follow-up) and a urine pregnancy test on Day 1 prior to randomization and Day 15 
(before dosing), Week 4, and Week 8 visits. All tests will be performed by the local laboratory according to 
local practice. 
i 
Clinical laboratory assessments (hematology/biochemistry/urinalysis) will be performed by the local 
laboratory. See Section 6.3.4 for the list of tests. 
j 
Plasma samples for detection of ADA will be collected before the administration of study treatment on Day 1 
and Day 15 (preferably within 30 minutes prior to infusion). Additional samples for detection of ADA will 
be collected at Weeks 4, 8, and 12 (EOS/ET). Samples that are confirmed positive for ADA will be further 
tested for titer and NAb. Details are provided in Section 6.2. 
k 
Viral disease screening (HBsAg, HBcAb, HCV, and HIV), serum IgG and IgM, and TB screening will not be 
repeated on Day 1 of the study. 
l 
Clinical laboratory assessments scheduled on Day 1 can be performed 1 day prior to dosing. 
m 
Additional follow-up visit will be conducted at Week 26 to evaluate safety and to perform a serum pregnancy 
test in WOCBP. 
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14.2 Appendix 2: Classification of Functional Status in Rheumatoid 
Arthritis 
Table 14-2: 
Classification of Functional Status in Rheumatoid Arthritis 
Class I 
Complete functional capacity with ability to carry on all usual duties without handicaps 
Class II 
Functional capacity adequate to conduct normal activities despite handicap of discomfort 
or limited mobility of one or more joints 
Class III 
Functional capacity adequate to perform only few or none of the duties of usual 
occupation or of self-care 
Class IV 
Largely or wholly incapacitated with patient bedridden or confined to wheelchair, 
permitting little or no self-care 
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14.3 Appendix 3: Protocol Amendment 
14.3.1 
Protocol Amendment 1 – Protocol Version 2.0, Dated 12 Aug 2019 
14.3.1.1 
Overview of Changes 
Summary of significant changes includes the following: 
1. Updated exclusion criterion 2 for clarity. 
2. Added Exclusion Criterion 18. Subjects with hypogammaglobulinemia (low IgG) are 
immunocompromised and more susceptible for both infections and side effects; hence, 
such subjects should be excluded. 
3. ‘Section 5.4.1 Packaging’ has been reworded for better clarity. Further details will be 
captured in Pharmacy Manual/other appropriate plan. Sentence modified from: 
“Rituximab concentrate for solution for infusion will be packaged as blinded supplies 
in which the external packaging (carton) for all products will appear identical and 
identified with a unique container number.” 
To 
Rituximab concentrate for solution for infusion will be packaged in a carton or kit. 
4. Added following text in Section 6.1 of Schedule of Assessment in order to clarify 
unscheduled visit data capturing: “If any unscheduled visits happens at any time during the 
study, visit details/appropriate data including reason will be captured in the electronic case 
report forms (eCRF).”  
5. Added assessment of IgG (Section 6.1.1) in-line with addition of new Exclusion Criterion 
18 to exclude the subjects with low IgG. 
6. Added clarification for estimation of rituximab concentration in Section 3.1.2 and 
Section 6.2.1, time matched blood samples for estimation of rituximab concentration were 
added to aid in subsequent data interpretation as and if needed. Relevant procedures (i.e. 
time matched blood sample collection and blood loss for estimation of rituximab 
concentration) are added in Section 6.1.2, Section 6.1.3, Section 6.1.4, Section 6.5, and 
Appendix 1. 
7. Other administrative and minor formatting changes were made throughout the protocol for 
consistency.  
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14.3.1.2 
 Changes to the Protocol Text 
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol. Additions to the study protocol are shown in bold and 
deletions are shown in strike through text. Corrections of obvious typing errors or omissions 
are not highlighted. 
Protocol Synopsis 
• 
Exclusion criteria 
2. 
Subjects with human immunodeficiency virus (positive HIV1Ab or HIV2Ab), 
hepatitis B virus and/or hepatitis C virus infection, including those with 
positive results in the viral disease screening. 
18. 
Subject with serum IgG < lower limit of normal 
List of Abbreviations 
LLN 
Lower limit of normal 
Pharmacodynamics (Section 1.1.1.2) 
Total serum Ig levels, immunoglobulin M (IgM), immunoglobulin G (IgG), and 
immunoglobulin A (IgA) were decreased at 6 months with the largest change observed in IgM. 
At Week 24 of the first course of rituximab treatment, small proportions of patients experienced 
decrease in IgM (10%), IgG (2.8%), and IgA (0.8%) levels below the lower limit of normal. 
(LLN). In the experience with rituximab in RA patients during repeated rituximab treatment, 
23.3%, 5.5%, and 0.5% of patients experienced decreases in IgM, IgG, and IgA, respectively 
concentrations below the lower limit of normal LLN at any time after receiving rituximab. The 
clinical consequences of decrease in Ig levels in RA patients treated with rituximab are unclear 
(Dr. Reddy’s Laboratories IB). 
Rationale of Study Design (Section 3.1.2) 
A validated enzyme linked immunosorbent assay will be used to test ADA, titer and NAb by 
specialist laboratories (sponsor designated laboratories) in this study.  
Along with immunogenicity sample, a time matched blood sample (approximately 5 mL) 
will be collected for the estimation of rituximab concentration. The evaluation of the 
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samples will be performed to interpret safety and/or immunogenicity data appropriately, 
if needed. 
Exclusion criteria (Section 4.1.2): 
Subjects meeting any of the following criteria must not be enrolled in the study: 
2. 
Subjects with human immunodeficiency virus (positive HIV1Ab or HIV2Ab), 
hepatitis B virus and/or hepatitis C virus infection, including those with 
positive results in the viral disease screening (Section 6.1.1). 
18. 
Subject with serum IgG <LLN 
Schedule of Assessments (Section 6.1) 
The investigator may plan unscheduled visits schedule visits (unplanned visits) in addition to 
those listed on the schedule of activities, in order to conduct evaluations or assessments 
required to protect the well-being of the subject. If any unscheduled visits happen at any 
time during the study, visit details/appropriate data including the reason will be collected 
in the eCRF. 
Packaging (Section 5.4.1) 
Rituximab concentrate for solution for infusion will be packaged in a carton or kit as blinded 
supplies in which the external packaging (carton) for all products will appear identical and 
identified with a unique container number. 
Screening Period (Day 14 to 0) (Section 6.1.1) 
Screening procedures and assessments will be as follows: 
The proposed chronological order of the assessments below should be followed. 
14. 
Serum Immunoglobulin (IgG) 
Treatment Period (2 Weeks) (Section 6.1.2) 
Study Day 1 (Week 0, Baseline Visit) 
4. 
Clinical laboratory assessments: a blood sample will be taken for hematology and 
biochemistry; urinalysis will also be performed (See Section 6.3.4 for the list of 
clinical laboratory assessments). 
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Note: Viral disease screening (HBsAg, HBsAb HBcAb, HCV, HIV), and serum 
IgG and TB screening will not be repeated on Day 1 of the study. On Day 1, 
clinical laboratory assessments can be performed 1 day prior to dosing. 
7. 
Collect a time matched blood sample (approximately 5 mL) for the estimation 
of rituximab concentration. 
Study Day 15 (Week 2 + 1 Day) 
5. 
Collect a time matched blood sample (approximately 5 mL) for the estimation 
of rituximab concentration. 
Follow-Up Period (10 Weeks) (Section 6.1.3) 
Week 4 ± 7 Days 
5. 
Collect a time matched blood sample (approximately 5 mL) for the estimation 
of rituximab concentration. 
Week 8 ± 7 Days 
5. 
Collect a time matched blood sample (approximately 5 mL) for the estimation 
of rituximab concentration. 
End of Study/Early Termination Visit (at Week 12 ± 7 Days) (Section 6.1.4) 
EOS/ET assessments are as follows: 
6. 
Collect a time matched blood sample (approximately 5 mL) for the estimation 
of rituximab concentration. 
Immunogenicity Sampling (Section 6.2.1) 
Whole blood samples (approximately 10 mL) will be collected and processed to obtain 
approximately 4 mL of plasma for ADA (including titer and NAb) detection at each time point. 
Samples should be processed as per detailed instructions in the laboratory manual for collection 
by the central laboratory. The samples will be shipped to laboratories for ADA titer and NAb 
analysis by the central laboratory as detailed in the laboratory manual. 
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Along with the immunogenicity sample, a time matched blood sample (approximately 5 
mL) will be collected for the estimation of rituximab concentration. The evaluation of the 
samples will be performed to interpret safety and/or immunogenicity data appropriately, 
if needed. 
The central laboratory shipment address and assay laboratories contact information will be 
provided to the investigator prior to or during the initiation of the study. 
Clinical Laboratory Assessments (Section 6.3.4) 
Clinical laboratory assessments will be performed as indicated in Table 14-1. Hematology, 
biochemistry, and urinalysis will be conducted at screening, on Day 1, Day 15, and at Weeks 4, 
8, and 12 (EOS/ET) visits. Serum pregnancy test will be conducted at screening and Week 12 
visit. Urine pregnancy test will be conducted on Day 1 prior to randomization and Day 15 
(before dosing), at Weeks 4 and 8 visits. 
The following parameters will be assessed: 
Serum IgG 
Blood Loss During the Study (Section 6.5) 
For the safety evaluation, approximately 10 mL of blood will be withdrawn from the subjects 
at each time point. A total of approximately 110 135 mL of blood will be collected per subject 
during the study for immunogenicity, for estimation of rituximab concentration and safety 
evaluation as mentioned in Table 6-1. 
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Table 6-1 
Blood Loss During the Study 
Abbreviations: ADA=anti-drug antibody; NAb=neutralizing antibodies 
Note: For safety evaluation, more than 10 mL of blood can be withdrawn based on the site/local laboratory 
practice and will not be considered as deviation. 
 
Appendix 1: Schedule of Events (Section 14.1) 
Table 14-1 
Schedule of Events 
Study Period 
Screening 
Visit  
Days -14 to 0 
Treatment Visit 
Follow-Up Visits 
EOS/ETa 
Visit 
Study Week 
 
0 
(Day 1) 
2 
(Day 15) 
4 
8 
12 
Visit Window 
 
+1 day 
+1 day 
±7 days 
Viral disease screeninge 
X 
 
 
 
 
 
Pregnancy testh 
X 
X 
X 
X 
X 
X 
Immunogenicityj 
 
X 
X 
X 
X 
X 
Blood samples for 
estimation of rituximab 
concentration 
 
X 
X 
X 
X 
X 
Concomitant medications 
 
X 
X 
X 
X 
X 
e HBsAg, HBcAb, hepatitis C virus, and HIV, and Serum IgG to be conducted by each site’s local laboratory. 
h Subjects of childbearing potential will have a serum pregnancy test at the screening visit and a urine pregnancy 
test on Day 1 prior to randomization and Day 15 (before dosing), and at Week 2, Week 4 and Week 8 visits. 
A serum pregnancy test will be repeated at EOS/ET visit. All tests will be performed by the local laboratory 
according to local practice. 
k Viral disease screening (HBsAg, HBsAb HBcAb, HCV, and HIV), serum IgG and TB screening will not be 
repeated on Day 1 of the study. 
Time Points 
Safety Evaluation 
(Laboratory) 
ADA and NAb 
Evaluation 
For estimation 
of rituximab 
concentration 
(Approx.)  
Total Volume of 
Blood Loss 
Screening 
10 mL 
- 
 
10 mL 
Week 1/Day 1 
10 mL 
10 mL 
5 mL 
20 25 mL 
Week 2/Day 15 
10 mL 
10 mL 
5 mL 
20 25 mL 
Week 4 
10 mL 
10 mL 
5 mL 
20 25 mL 
Week 8 
10 mL 
10 mL 
5 mL 
20 25 mL 
Week 12 
10 mL 
10 mL 
5 mL 
20 25 mL 
Total volume of blood loss 
60 mL 
50 mL 
25 mL 
110 135 mL 
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14.3.2 
Protocol Amendment 2 – Protocol Version 3.0, Dated to be added 
The overall reason for this amendment is to address feedback from Paul Ehrlich Institute (PEI), 
Medical Regulatory Authority, Germany. Further to these changes, minor revisions for clarity, 
formatting, abbreviations, and spelling changes have been made throughout the document. 
14.3.2.1 
Overview of Changes 
Summary of significant changes includes the following: 
• The duration of study is extended by 6 months post treatment. The study now includes an 
additional follow-up visit at Week 26 (24 weeks [6 months] after the last study treatment 
administration on Day 15). At the additional follow-up visit (Week 26), safety will be 
evaluated and a serum pregnancy test will be performed in WOCBP. Further it is also 
clarified in the protocol that subjects need to re-consent if they want to continue 
participating in the study after Week 12 through Week 26. Additional text/clarity has been 
included when a subject requires rescue therapy/re-dosing of rituximab after Week 12. 
o New text has been added and existing text has been revised as applicable throughout the 
protocol, with the following affected sections: Protocol Synopsis (Study Design and 
Estimated Study Duration sections), Section 3.1.1 (Description), Section 3.1.2 (Rationale 
of Study Design), Section 3.1.4 (End of Study), Section 4.2 (Withdrawal of Subjects From 
Study Treatment and/or Study), Section 4.2.2 (Handling of Withdrawals), Section 5.7 
(Blinding), Section 6.1.5 (Additional Follow-up Visit [Week 26]), Section 6.3.1.2 
(Recording of Adverse Events), Section 6.3.4 (Clinical Laboratory Assessments), 
Section 6.5 (Blood Loss During the Study), Section 11.4 (Final Report), and Appendix 1 
(Schedule of Events). 
Reason: Above changes have been done to address recommendations from PEI, Medical 
Regulatory Authority, Germany to follow subjects for safety in line with SmPC and for further 
monitoring of contraception in WOCBP until 6 months post-dose considering the longer half-
life of Rituximab (approximately 20 days). 
• Clarified that the final CSR will be prepared after the EOS (Week 12) is achieved by all 
subjects. Data for the time period from Week 12 through Week 26 (additional follow-up) 
will be presented as an addendum to the final CSR.  
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o Text regarding this clarification revised in the following sections: Section 3.1.1 
(Description), Section 5.7 (Blinding), and Section 11.4 (Final Report). 
Reason: Changes have been made in accordance with the changes of extending the study up to 
26 weeks (as mentioned above) as all the data required for the primary objective would have 
been collected by Week 12. 
• Detailed information regarding study conduct and contingency measures to be taken for 
smooth functioning of the study during the COVID-19 pandemic are added. In addition, 
benefit-risk assessment of rituximab treatment during the COVID-19 pandemic have also 
been discussed in the protocol. 
o New section (Section 3.2 [Study Conduct During the COVID-19 Pandemic]), including 
subsections (Section 3.2.1 [Benefit-Risk Assessment of Rituximab Treatment During the 
COVID-19 Pandemic] and Section 3.2.2 [Contingency Measures Taken During the 
COVID-19 Pandemic]) are added. 
Reason: Above changes have been made to describe the risk-benefit assessment of the study 
conduct along with risk mitigation measures and to describe contingency measures for the 
ongoing COVID 19 pandemic, as also recommended by PEI, Medical Regulatory Authority, 
Germany. 
• Exclusion Criterion #6 has been revised in Protocol Synopsis and Section 4.1.2 (Exclusion 
Criteria) to update the requirement of historical “severe” hypersensitivity to US-rituximab 
or EU-rituximab or any of its excipients requiring drug discontinuation to any severity of 
hypersensitivity to these treatments or excipients. 
Reason: Above change has been made to avoid the risk of hypersensitivity reaction in the 
subject as an additional safety measure. 
• Exclusion Criterion #16 updated to include definition of WOCBP and highly effective birth 
control measures per the CTFG 2014 guidelines in Protocol Synopsis and Section 4.1.2 
(Exclusion Criteria). 
Reason: Above change has been made to define WOCBP and to describe highly effective 
measures of birth control as per the CTFG 2014 guidelines. This change is also considered for 
better clarity and in line with the recommendation from PEI, Medical Regulatory Authority, 
Germany. 
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• Exclusion Criterion #17 related to subjects who are men involved in any sexual intercourse 
that could lead to pregnancy is updated in Protocol Synopsis and Section 4.1.2 (Exclusion 
Criteria) to clarify that sexually active male subjects (unless permanently sterile by bilateral 
orchidectomy), who do not agree to use 1 of the highly effective methods of birth control 
during treatment and for at least 12 months after the last administration of study treatment, 
will be excluded from the study. 
Reason: Above change has been made to describe highly effective measures of birth control as 
per the CTFG, 2014 guidelines and for better clarity and in line with the recommendation from 
PEI, Medical Regulatory Authority, Germany. 
• Clarified that if a subject withdraws consent for further study treatment, but not for study 
participation, the subject can continue further visits and data can continue to be collected 
until Week 26. However, if a subject withdraws consent for further participation in the 
study there will be no further data collection and the subject will be discontinued from the 
study. Subjects need to re-consent to continue participating in the study after Week 12 
through Week 26, If a subject does not re-consent, then his/her study data up to Week 12 
will be collected and the subject will be discontinued from the study. 
o Text added for this clarification in Protocol Synopsis (Study Design), Section 3.1.1 
(Description), Section 4.2 (Withdrawal of Subjects From Study Treatment and/or the 
Study), Section 4.2.1 (Reasons for Withdrawal/Discontinuation), and Section 4.2.2 
(Handling of Withdrawals) 
Reason: Above change has been made to categorize withdrawal criteria (i.e. consent 
withdrawal for further study treatment or for further study participation) and to make it uniform 
with the section 4.2.2 (Handling of Withdrawals). 
• Text in Section 4.2.2 (Handling of Withdrawals) revised to emphasize that subjects can 
take their own independent decision to withdraw from study treatment and/or study 
participation at any time. 
Reason: Above change has been made to emphasize that subjects can take their own 
independent decision to withdraw from study treatment and/or study participation. Moreover, 
text has been revised to add the clause for the consent withdrawal at Week 12 based on the 
earlier change of extending study duration up to Week 26, post-dose. 
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• Clarified that MTX and folic acid, which are background medications in the study, should 
be used in accordance with the guidelines specified in the local labels. Also, clarification 
has been provided that folinic acid at the same dose of folic acid, can be given in place of 
folic acid if it is allowed by the local label. A note has been added in protocol synopsis 
(Study Treatment, Dosage, and Route of Administration) and Section 5.9.1 (Background 
Medications). 
Reason: Above change has been made in line with the recommendation from PEI, Medical 
Regulatory Authority, Germany and for better clarity to the investigators  
• Complete physical examination will be performed now at all study visits and not as 
indicated only at screening and EOS/ET visits in the Schedule of Assessments of the earlier 
protocol (Version 2.0, Amendment 1).  
o Text updated in the following sections: Section 6.1 (Schedule of Assessments [including 
relevant subsections]) and Appendix 1 (Schedule of Events; footnote “f”). 
Reason: Above change has been made for better clarity and for uniformity across the document. 
• Information regarding immunological testing in humans has been included in Section 6.2.2 
(Immunogenicity Assay). 
Reason: Above change has been made to add more information about the testing/methods of 
primary endpoints. 
• Detailed definitions of IRRs and hypersensitivity reactions is added in Section 6.3 (Safety 
Assessments).  
Reason: Above change has been made to guide the investigator while differentiating IRRs, 
hypersensitivity reactions and/or anaphylaxis. 
• Clarified that all ongoing SAEs should be followed up until resolution or stabilization or 
until a pre-defined outcome is reached, whereas all ongoing nonserious AEs should be 
followed up until resolution or stabilization or the EOS/ET visit, whichever occurs first, 
except any ongoing treatment-related nonserious AEs that should be followed until that AE 
is stabilized, resolved, or, in the investigator's opinion, the AE is unlikely to resolve due to 
the subject's underlying condition. 
o Text updated and note has been added in Section 6.3.1.2 (Reporting of Adverse Events). 
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Reason: Above changes have been made for better clarity and in line with the recommendation 
from PEI, Medical Regulatory Authority, Germany. 
• Clarification note has been provided for assessment of adverse events outcome in 
Section 6.3.1.4 (Assessment of Causality).  
Reason: Above change has been made for better clarity to the investigator.  
• Absolute neutrophil count is added to the list of hematology parameters to be assessed in 
the study. List of hematology parameters to be assessed in the study are provided in 
Section 6.3.4 (Clinical Laboratory Assessments) updated. 
Reason: Above change has been made to clarify and to emphasize safety evaluation i.e. late 
neutropenia and also in line with earlier changes. 
• Serum FSH testing will be performed in postmenopausal women. 
o Text added in Section 6.3.4 (Clinical Laboratory Assessments). 
Reason: Above change has been made in line with earlier changes and per the CTFG 
guidelines 2014. 
• Clarification note is added for HBcAb evaluation 
o A clarification note is added in the Section 6.1.1 (Screening Period [Days -14 to 0]), 
Section 6.1.2 (Treatment Period [(2 Weeks]), Section 6.3.8 (Viral Disease Screening) and 
in Appendix 1 (Schedule of Events; footnote “e”). 
Reasons: Above changes have been done for better clarity to the investigators. 
• Additional Serum Immunoglobulin evaluation (IgM) is added in the Section 6.1.1 
(Screening Period [Days -14 to 0]), Section 6.1.2 (Treatment Period [2 weeks]; Study 
Day 1 [Week 0, Baseline visit]), Section 6.3.4 (Clinical Laboratory Assessments), and in 
Appendix 1 (Schedule of Events; footnote “e” and footnote “k”) 
Reasons: Above change has been made in line with the recommendation from PEI, Medical 
Regulatory Authority, Germany 
• All references to legally authorised or legally acceptable representatives or subject’s legal 
guardian and any equivalents have been removed. Moreover, it is further clarified that the 
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10 Jul 2020 
Page 110 
study sites are advised to follow local or country-specific guidelines while obtaining 
consent from the subject. 
o Text added in Section 9.1 (Independent Ethics Committee or Institutional Review Board), 
Section 9.3 (Subject Information and Consent). Section 10.1 (Confidentiality). 
Reason: Above change has been made to remove all references of legally authorised or legally 
acceptable representatives or subject’s legal guardian and any equivalents from the protocol 
with consideration that only those subjects who are capable of providing informed consent will 
be included in this clinical study. This change has also been done in line with the 
recommendation from PEI, Medical Regulatory Authority, Germany. 
• The sponsor contact details on the title page of this protocol are updated. 
Reasons: Administrative change 
Minor revisions for clarity, formatting, abbreviations, and spelling changes have been made 
throughout the document. 
Page 289

 
 
DRL_RI 
Protocol: RI-01-007 Version 3.0 Amendment 2 
 
10 Jul 2020 
Page 1 
 
Protocol Clarification Letter #1 
22 Jul 2020 
To Whom So Ever It May Concern 
 
This letter is to inform you about an typographical error in clinical study protocol of RI-01-007 
A Randomized, Double-Blind, Parallel Group, Multicenter Study to Assess the 
Immunogenicity and Safety of Transitioning Subjects With Rheumatoid Arthritis to 
Biosimilar Rituximab (DRL_RI) or Continued Treatment With Rituxan® or MabThera®  
Version 3.0 Amendment 2, dated 10 Jul 2020. The following sections require further 
clarification:  
Protocol Amendment 2  Protocol Version 3.0, Dated to be added  is mentioned in Table of 
contents (Section 14.3.2) and in the title of Section 14.3.2 which should be read as Protocol 
Amendment 2  Protocol Version 3.0, Dated 10 Jul 2020 . 
This letter will serve as documentation of this typographical change to protocol RI-01-007. If 
at a later date the protocol is amended, this change will be incorporated into the document at 
that time. 
 
Sincerely, 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
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