A Double-blind, Parallel-group, Phase III Study to Compare the Efficacy, Safety, and Immunogenicity of Proposed Rituximab Biosimilar (DRL_RI) With MabThera® in Subjects With Previously Untreated (CD)20-Positive LTB Follicular Lymphoma
Phase: PHASE3
Conditions: Follicular Lymphoma
Sponsor: Dr. Reddy's Laboratories Limited

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A Randomised, Double-blind, Parallel-group, Phase III Study to Compare the 
Efficacy, Safety, and Immunogenicity of Proposed Rituximab Biosimilar (DRL_RI) with 
MabThera® in Subjects with Previously Untreated, Stage II-IV, Cluster of Differentiation 
(CD)20-Positive, Low Tumour Burden Follicular Lymphoma 
 
ClinicalTrials.gov Identifier: NCT03976102 
 
Date of Protocol: 27 October 2021 

Dr. Reddy’s Laboratories S.A. 
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Protocol RI-01-006 
CONFIDENTIAL 
 
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Title Page 
Protocol Title: A Randomised, Double-blind, Parallel-group, Phase III Study to Compare the 
Efficacy, Safety, and Immunogenicity of Proposed Rituximab Biosimilar (DRL_RI) with 
MabThera® in Subjects with Previously Untreated, Stage II-IV, Cluster of Differentiation 
(CD)20-Positive, Low Tumour Burden Follicular Lymphoma 
Protocol Number: RI-01-006 
Amendment Number: 4 
Compound Number: DRL_RI 
Short Title: A Randomised, Double-blind, Parallel-group, Phase III Study to Compare the Efficacy, 
Safety, and Immunogenicity of Proposed Rituximab Biosimilar (DRL_RI) with MabThera® in 
Subjects with Previously Untreated, Stage II-IV, Cluster of Differentiation (CD)20-Positive, Low 
Tumour Burden Follicular Lymphoma 
Sponsor Name and Legal Registered Address:  Dr. Reddy’s Laboratories S.A. 
Elisabethenanlage 11 
CH-4051 Basel 
Switzerland 
Regulatory Agency Identifying Number(s): Investigational New Drug (IND) number: 112766 
Version number: 5 
Approval Date: 27 Oct 2021 
Date and Version of Previous Protocol: 04 Nov 2020, Version 4. 
The confidential information in this document is provided to you as an Investigator, potential 
Investigator or consultant for review by you, your staff, and applicable Independent Ethics 
Committee and/or Institutional Review Board. It is understood that the information will not be 
disclosed to others without written authorisation from Dr. Reddy’s Laboratories S.A. except to the 
extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. 
 
 
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Sponsor Signature Page 
Declaration of Sponsor or Responsible Medical Expert 
Protocol Title: A Randomised, Double-blind, Parallel-group, Phase III Study to Compare the 
Efficacy, Safety, and Immunogenicity of Proposed Rituximab Biosimilar (DRL_RI) with 
MabThera® in Subjects with Previously Untreated, Stage II-IV, Cluster of Differentiation 
(CD)20-Positive, Low Tumour Burden Follicular Lymphoma 
This clinical study protocol was subjected to critical review. The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational medicinal 
product, as well as with the moral, ethical, and scientific principles governing clinical research as 
set out in the guidelines on Good Clinical Practice (GCP) applicable to this clinical study. 
Sponsor Signatory: 
 
 
Date 
 
 
DocuSign Envelope ID: C3E65751-68F3-45DC-832C-6E9A0F96E744
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Key Study Personnel
Sponsor
Dr. Reddy’s Laboratories S.A.
Elisabethenanlage 11
CH-4051 Basel
Switzerland
Contract Research 
Organisation
 
 
 
 
 
Adverse Event Reporting 
 
 
Medical Monitors
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central Histopathology 
Laboratory
 
 
 
 
 
Bioanalytical Laboratories
 
 
 
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Clinical Study Protocol
Protocol RI-01-006
CONFIDENTIAL
Version 5.0, Final
4 of 153
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Clinical Study Protocol 
Protocol RI-01-006 
CONFIDENTIAL 
 
Version 5.0, Final 
 
 
 
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Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Version 
Date 
Amendment 4 
Protocol Version 5 
27 Oct 2021 
Amendment 3 
Protocol Version 4 
04 Nov 2020 
Amendment 2 
Protocol Version 3 
04 Dec 2019 
Amendment 1 
Protocol Version 2 
04 Jan 2019 
Original Protocol 
Protocol Version 1 
25 Oct 2018 
 
Amendment 4,  
Overall Rationale for the Amendment 
This amendment allows the incorporation of various measures taken to adapt for conduct of the 
clinical study in the Coronavirus disease pandemic situation including adaptations of the study 
results analysis based on the discussions with the United States Food and Drug Administration 
during Biological Product Development type 2 meeting held on 02 Jul 2021.  
The changes from the previous version of the protocol are summarised in a tabulated manner 
below.
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S.
No.
Section Number and Name
Previous Protocol V4.0 dated
04 November 2020
Current Protocol V5.0 dated 27 October 2021
Brief
Rationale
1.
Key Study Personnel;
Medical Monitors
To align with
updated list of
medical
monitors.
2.
Section 1.1, Synopsis
-
The Synopsis reflects changes made in various
sections of the protocol
To align with
changes made
in various
sections of the
protocol
3.
Section 1.2, Schema
N=up to 284*
N=Approximately 312
Number of
subjects to be
randomised is
updated to 312
based on the
revision in the
sample size
calculation
assumptions
and blinded
sample size re-
estimation.
4.
Section 3, Objectives and
Endpoints
Primary objective
Objective: To demonstrate the equivalent
efficacy of DRL_RI and MabThera® in
subjects with B-lymphocyte antigen
CD20-positive, LTB-FL, as measured by
ORR at Week 28, evaluated in accordance
with published response criteria for
malignant lymphoma.
Objective: To demonstrate the equivalent efficacy of
DRL_RI and MabThera® in subjects with B-
lymphocyte antigen CD20-positive, LTB-FL, as
measured by overall response (ORR) up to Week 28,
evaluated in accordance with published response
criteria for malignant lymphoma.
Editorial
change in the
objective
based on the
revision in the
primary
endpoint.
5.
Section 3, Objectives and
Endpoints
Primary endpoints
Section 4.1.1, Description
Section 8.2, Efficacy
assessments
Section 9.4.1.1, Analysis of
Primary efficacy endpoint
End point: The primary endpoint is ORR,
defined as the proportion of subjects in
each treatment group that achieve CR,
CRu or PR at Month 7 (Week 28) based
on central radiology review in accordance
with the response criteria for malignant
lymphoma.
Endpoint: The primary endpoint is BORR, defined as
the proportion of subjects in each treatment group that
achieve a best overall response of either CR, CRu or
PR up to Month 7 (Week 28) based on central
radiology review in accordance with the response
criteria for malignant lymphoma.
Change in the
endpoint based
on the
discussions
with United
States Food
and Drug
Administration
during
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Dr. Reddy’s Laboratories S.A. 
Clinical Study Protocol 
Protocol RI-01-006 
CONFIDENTIAL 
 
Version 5.0, Final 
 
 
 
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27 Oct 2021 
S. 
No. 
Section Number and Name 
Previous Protocol V4.0 dated 
04 November 2020 
Current Protocol V5.0 dated 27 October 2021 
Brief 
Rationale 
Biological 
Product 
Development 
type 2 meeting 
held on 02 Jul 
2021. 
6. 
 Section 3, Objectives and 
Endpoints 
Secondary objectives and 
endpoints 
Objective:  
To compare the ORR at Week 12, CR at 
Week 28 duration of response (DOR), 
PFS and OS of DRL_RI with MabThera® 
in subjects with CD20 positive, LTB FL 
End point: Overall response rate at Week 
12 based on central radiology review in 
accordance with published response 
criteria for malignant lymphoma. 
Objective: To compare the ORR at Week 12 and 
Week 28, CR at Week 28, CR as a best response up 
to week 28, duration of response (DOR), PFS and OS 
of DRL_RI with MabThera® in subjects with CD20 
positive, LTB FL  
Endpoint: Overall response rate at Week 12 and Week 
28 based on central radiology review in accordance 
with published response criteria for malignant 
lymphoma. 
x 
Complete Response (CR) rate as a best 
response up to Month 7 (Week 28). 
 
Addition of 
ORR at Week 
28 and CR rate 
as a best 
response up to 
Month 7. 
7. 
Section 4, Study design 
It is planned to randomise 284 subjects (to 
be reconfirmed under blinded conditions 
on the basis of the observed ORR and 
drop-out rate) at approximately 
≥130 study sites worldwide. 
It is planned to randomise approximately 
312 subjects at approximately ≥130 study sites 
worldwide. 
Number of 
subjects to be 
randomised is 
updated to 312 
based on the 
revision in the 
sample size 
calculation 
assumptions 
and blinded 
sample size re-
estimation.  
8. 
Section 4.5, End of Study 
Definition  
 
Clinical laboratory tests: Blood and urine 
samples will be taken for haematology, 
biochemistry, and urinalysis. 
 
Clinical laboratory tests: Blood and urine samples will 
be taken for haematology, coagulation, biochemistry, 
and urinalysis 
Viral disease screening at the EOS Visit  
COVID-19 questionnaire. 
Editorial 
changes to 
keep the 
section 
consistent with 
the Schedule 
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Rationale
of assessments
(SoA)
9.
Section 9, Statistical
Considerations
9.1.3 Inter-current events due to COVID-19:
Handling
(i.e.,
analysis
and
presentation)
of
intercurrent events and data/visit impacted due to
COVID-19 pandemic will be described in the SAP. 
The following events are considered as inter-current
events due to COVID-19 pandemic and any study
data missing as an outcome of these events will be
handled as missing data impacted due to COVID-19.
-
COVID-19 infection or death due to
COVID-19 (as an Event of Special Interest)
-
Protocol deviation including missing
assessment due to COVID-19 pandemic
Any other documented event which may interfere
the study conduct and is reasonable related to
COVID- 19 pandemic
Full details of the COVID 19 related inter-current
events definitions will be provided in SAP.
Addition of
inter-current
events based
on the
discussions
with United
States Food
and Drug
Administration
during
Biological
Product
Development
type 2 meeting
held on 02 Jul
2021.
10.
Section 9.2, Sample size
determination
Published data for rituximab versus watch
and wait9 revealed
Published data for rituximab versus a “watch and 
wait” strategy in the first line treatment of LTBFL
(Ardeshna et al 2014) revealed
ed
Based on the
revised sample
size
justification
and blinded
sample size re-
estimation,
there is
revision in the
sample size.
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Section Number and Name
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Rationale
 
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Clinical Study Protocol
Protocol RI-01-006
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Version 5.0, Final
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S.
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Section Number and Name
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Current Protocol V5.0 dated 27 October 2021
Brief
Rationale
.
Based on the observed pooled best overall response
(BOR) rate, up to week 28, the revised total sample
size obtained in the BSSR is 312 subjects (156 per
group) to be recruited.
11.
Section 9.3.2, Per Protocol
Population
The PP Population will include all
subjects who are randomised into the
study, receive at least one dose of study
drug (sufficient compliance to be
evaluated under blind conditions), have
measurable disease at Baseline as
The PP Population will include all subjects who are
randomised into the study, receive at least one dose of
study drug (sufficient compliance to be evaluated
under blind conditions), have measurable disease at
Baseline as confirmed by central review, have an at
least one available valid response evaluation up to
Revision in the
text for better
clarity and as
per the other
changes made
in endpoints.
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Version 5.0, Final
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confirmed by central review, have an
available valid response evaluation at
7 months (+, and no major protocol
deviations (such as administration of a
forbidden treatment) that would
significantly impact the primary efficacy
endpoint. If the forbidden treatment was
administered due to PD, the subject will
be included in the PP Population as a non-
responder. In the EMA analysis, both ITT
and PP population will be considered as
primary.
7 months (± 4 weeks), and no major protocol
deviations (such as administration of a forbidden
treatment) that would significantly impact the primary
efficacy endpoint. If the forbidden treatment was
administered due to PD, the subject will be included in
the PP Population as a non-responder. In the EMA
analysis, both ITT and PP population will be
considered as primary.
12.
Section 9.4.1.1, Analysis of
Primary Efficacy Endpoint
Equivalence will be concluded for FDA if
the 90% CI and for EMA if the 95% CI of
the ORR difference is completely
contained within the pre-defined interval
(-16%, 16%).
. Full
details of the primary endpoint analysis
including multiplicity considerations will
be provided in the SAP.
Equivalence will be concluded for FDA if the 90% CI
and for EMA if the 95% CI of the ORR difference is
completely contained within the pre-defined interval
(- 17%, 17%).
Full details of the primary endpoint
analysis including multiplicity considerations will be
provided in the SAP.
Updated in the
equivalence
margin based
on the changes
made in the
9.2, Sample
size
determination
13.
Section 9.4.2, Safety
Analyses
TEAEs will be described using
descriptive statistics and coded according
to the MedDRA (version 21.1 or latest)
system organ class and MedDRA
preferred term, graded according to
TEAEs including Event of Special Interest (COVID-
19 infection or death due to COVID-19 infection)
will be described using descriptive statistics and coded
according to the MedDRA (version 21.1 or latest)
system organ class and MedDRA preferred term,
Inclusion of
text regarding
COVID-19
events based
on the earlier
changes
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Clinical Study Protocol 
Protocol RI-01-006 
CONFIDENTIAL 
 
Version 5.0, Final 
 
 
 
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Brief 
Rationale 
CTCAE version 5.0, by treatment group 
and overall. TEAEs observed, based on 
the onset date, during the rituximab 
induction and maintenance will be 
summarised separately by treatment 
group. Drug-related TEAEs and SAEs, 
TEAEs leading to study discontinuation, 
and death will also be summarised by 
treatment group and overall. 
 
graded according to CTCAE version 5.0, by treatment 
group and overall. TEAEs observed, based on the 
onset date, during the rituximab induction and 
maintenance will be summarised separately by 
treatment group. Drug-related TEAEs and SAEs, 
TEAEs leading to study discontinuation, and death 
will also be summarised by treatment group and 
overall. 
 
belongs to 
addition of 
inter-current 
events. 
14. 
Section 9.4.7, Reporting 
Timeframes 
 
When all subjects have completed Week 
28 (or the EOS/ET Visit for subjects 
discontinued prior to Week 28), the 
primary endpoint (ORR at Week 28) will 
be analysed using centrally reviewed 
radiology assessments and a study report 
produced. Available safety data and other 
secondary and exploratory endpoints may 
also be reported at that time including 
ORR at Week 12. An addendum study 
report will be provided to applicable 
regulatory authority when all subjects 
have completed the study, including 
updated safety data and secondary 
endpoints for time to event endpoints. 
Further details will be provided in the 
SAP. 
When all subjects have completed Week 28 (or the 
EOS/ET Visit for subjects discontinued prior to Week 
28), the primary endpoint (BORR up to Week 28) will 
be analysed using centrally reviewed radiology 
assessments and a study report produced. Available 
safety data and other secondary and exploratory 
endpoints may also be reported at that time including 
ORR at Week 12 and Week 28. An addendum study 
report will be provided to applicable regulatory 
authority when all subjects have completed the study, 
including updated safety data and secondary endpoints 
for time to event endpoints. Further details will be 
provided in the SAP. 
Editorial 
changes based 
on the 
revisions made 
to other 
sections 
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Rationale 
15. 
General 
- 
Abbreviations, grammar/typo-error were corrected as 
applicable 
 
For better 
clarity. 
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Dr. Reddy’s Laboratories S.A. 
Clinical Study Protocol 
Protocol RI-01-006 
CONFIDENTIAL 
 
Version 5.0, Final 
 
 
 
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Table of Contents 
Title Page ........................................................................................................................................ 1 
Sponsor Signature Page .................................................................................................................. 2 
Key Study Personnel ....................................................................................................................... 3 
Protocol Amendment Summary of Changes Table ......................................................................... 5 
Table of Contents .......................................................................................................................... 14 
1 
Protocol Summary .................................................................................................................. 19 
1.1 
Synopsis .............................................................................................................................. 19 
1.2 
Schema ............................................................................................................................... 28 
1.3 
Schedule of Activities ......................................................................................................... 29 
2 
Introduction............................................................................................................................. 34 
2.1 
Study Rationale .................................................................................................................. 35 
2.2 
Background......................................................................................................................... 35 
2.2.1 
Rituximab ....................................................................................................................... 35 
2.2.2 
Follicular Lymphoma ..................................................................................................... 36 
2.2.3 
Efficacy of Rituximab in Low Tumour Burden Follicular Lymphoma .......................... 37 
2.2.4 
Dr. Reddy’s Rituximab (DRL_RI) ................................................................................. 38 
2.2.4.1 
Nonclinical Studies ..................................................................................................... 39 
2.2.4.2 
Clinical Studies ........................................................................................................... 39 
2.3 
Benefit/Risk Assessment .................................................................................................... 40 
3 
Objectives and Endpoints ....................................................................................................... 41 
4 
Study Design ........................................................................................................................... 43 
4.1 
Overall Design .................................................................................................................... 43 
4.1.1 
Description ..................................................................................................................... 43 
4.1.2 
Schedule of Assessments ................................................................................................ 45 
4.2 
Discussion of Study Design................................................................................................ 45 
4.3 
Scientific Rationale for Study Design ................................................................................ 46 
4.4 
Justification for Dose .......................................................................................................... 46 
4.5 
End of Study Definition...................................................................................................... 47 
4.5.1 
Telephone Assessments for Survival Follow-up ............................................................ 48 
4.5.2 
Early Termination of Study ............................................................................................ 48 
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4.5.3 
Definition of End of Study and Primary Completion Date ............................................ 49 
5 
Study Population ..................................................................................................................... 49 
5.1 
Inclusion Criteria ................................................................................................................ 49 
5.2 
Exclusion Criteria ............................................................................................................... 51 
5.3 
Screen Failures ................................................................................................................... 53 
6 
Study Intervention .................................................................................................................. 54 
6.1 
Identity of Study Treatments .............................................................................................. 54 
6.2 
Study Drugs Administered ................................................................................................. 54 
6.2.1 
Study Drug Infusion Preparation .................................................................................... 55 
6.2.2 
Pre-Medication for Study Drug Infusions ...................................................................... 55 
6.2.3 
Study Drug Administration ............................................................................................. 56 
6.3 
Preparation/Handling/Storage/Accountability ................................................................... 57 
6.3.1 
Packaging ....................................................................................................................... 57 
6.3.2 
Labelling ......................................................................................................................... 58 
6.3.3 
Storage ............................................................................................................................ 58 
6.4 
Measures to Minimise Bias: Randomisation and Blinding ................................................ 58 
6.4.1 
Procedure for Unblinding ............................................................................................... 59 
6.5 
Study Intervention Compliance .......................................................................................... 60 
6.6 
Study Treatment Accountability ......................................................................................... 60 
6.7 
Concomitant Therapy ......................................................................................................... 61 
6.8 
Dose Modification or Delays.............................................................................................. 62 
6.9 
Study medication access after the End of the Study ........................................................... 62 
6.10 Guidance for hepatitis B and hepatitis C seropositive subjects .......................................... 62 
7 
Discontinuation of Study Intervention and Subject Discontinuation ..................................... 64 
7.1 
Discontinuation of Study Intervention ............................................................................... 64 
7.1.1 
Temporary Discontinuation ............................................................................................ 64 
7.1.2 
Rechallenge .................................................................................................................... 64 
7.2 
Subject Discontinuation/Withdrawal from the Study ......................................................... 64 
7.3 
Loss of Subjects to Follow-Up ........................................................................................... 65 
8 
Study Assessments and Procedures ........................................................................................ 66 
8.1 
Study Assessments.............................................................................................................. 66 
8.1.1 
Screening (Day ˗35 to ˗1) ............................................................................................... 66 
8.1.2 
Treatment Period (Day 1 to Week 36) ............................................................................ 68 
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8.1.3 
Follow-up Period (Week 44 to Week 52) ....................................................................... 72 
8.1.4 
End of Study ................................................................................................................... 73 
8.2 
Efficacy Assessments ......................................................................................................... 73 
8.3 
Safety Assessments ............................................................................................................. 74 
8.3.1 
Physical Examinations .................................................................................................... 74 
8.3.2 
Vital Signs ...................................................................................................................... 75 
8.3.3 
Electrocardiograms ......................................................................................................... 75 
8.3.4 
Clinical Safety Laboratory Assessments ........................................................................ 76 
8.3.5 
Eastern Cooperative Oncology Group Performance Status ........................................... 77 
8.3.6 
Viral Disease Screening .................................................................................................. 77 
8.3.7 
Pharmacokinetic and Pharmacodynamic Assessments .................................................. 78 
8.3.8 
Immunogenicity Assessments ........................................................................................ 78 
8.3.9 
Histopathological Review of Diagnostic Tissue ............................................................. 78 
8.4 
Adverse Events and Serious Adverse Events ..................................................................... 78 
8.4.1 
Definitions ...................................................................................................................... 78 
8.4.2 
Time Period and Frequency for Collecting Adverse Events and Serious Adverse Events 
Information ..................................................................................................................... 82 
8.4.3 
Assessment of Intensity .................................................................................................. 83 
8.4.4 
Assessment of Causality ................................................................................................. 84 
8.4.5 
Suspected Unexpected Serious Adverse Reactions ........................................................ 86 
8.4.6 
Abnormal Laboratory Values/Vital Signs/Electrocardiograms ...................................... 86 
8.4.7 
Method of Detecting AEs and SAEs .............................................................................. 86 
8.4.8 
Follow-up of AEs and SAEs ........................................................................................... 86 
8.4.9 
Regulatory Reporting Requirements for Serious Adverse Events ................................. 87 
8.4.10 
Pregnancy ....................................................................................................................... 88 
8.4.11 
Death Events ................................................................................................................... 89 
8.5 
Study Conduct During the COVID-19 Pandemic .............................................................. 89 
8.5.1 
Contingency Measures Implemented During the COVID-19 Pandemic ....................... 89 
8.6 
Treatment of Overdose ....................................................................................................... 91 
9 
Statistical Considerations........................................................................................................ 92 
9.1 
Statistical Hypotheses ......................................................................................................... 92 
9.1.1 
General Principles .......................................................................................................... 92 
9.1.2 
Missing Data ................................................................................................................... 92 
9.1.3 
Demographic and Baseline Characteristics .................................................................... 93 
9.1.4 
Subject Disposition ......................................................................................................... 93 
9.2 
Sample Size Determination ................................................................................................ 93 
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9.3 
Populations for Analyses .................................................................................................... 94 
9.3.1 
Intent to Treat Population ............................................................................................... 94 
9.3.2 
Per Protocol Population .................................................................................................. 95 
9.3.3 
Safety Population ............................................................................................................ 95 
9.3.4 
Pharmacokinetic Analysis Population ............................................................................ 95 
9.3.5 
Pharmacodynamic Analysis Population ......................................................................... 95 
9.4 
Statistical Analyses ............................................................................................................. 96 
9.4.1 
Efficacy Analyses ........................................................................................................... 96 
9.4.1.1 
Analysis of Primary Efficacy Endpoint ...................................................................... 96 
9.4.1.2 
Analysis of Secondary Efficacy Endpoint .................................................................. 97 
9.4.1.3 
Analysis of Exploratory Endpoint .............................................................................. 98 
9.4.2 
Safety Analyses .............................................................................................................. 98 
9.4.3 
Subgroup Analysis .......................................................................................................... 99 
9.4.4 
Pharmacokinetics Assessment ........................................................................................ 99 
9.4.5 
Pharmacodynamics Assessment ................................................................................... 100 
9.4.6 
Immunogenicity Assessment ........................................................................................ 100 
9.4.7 
Reporting Timeframes .................................................................................................. 100 
9.4.8 
Other Analyses .............................................................................................................. 100 
9.5 
Interim Analyses ............................................................................................................... 101 
10 Supporting Documentation and Operational Considerations ............................................... 102 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .......................... 102 
10.1.1 
Regulatory and Ethical Considerations ........................................................................ 102 
10.1.2 
Financial Disclosure ..................................................................................................... 103 
10.1.3 
Informed Consent Process ............................................................................................ 103 
10.1.4 
Data Protection ............................................................................................................. 104 
10.1.5 
Data Quality Assurance ................................................................................................ 104 
10.1.5.1 
Quality Assurance Audits.......................................................................................... 105 
10.1.5.2 
Study Monitoring ...................................................................................................... 105 
10.1.6 
Data Monitoring Committee ......................................................................................... 106 
10.1.7 
Source Documents ........................................................................................................ 106 
10.1.8 
Study and Site Closure ................................................................................................. 107 
10.1.9 
Publication Policy ......................................................................................................... 107 
10.1.10 Protocol Approval and Amendment ............................................................................. 107 
10.1.11 Protocol Deviations ...................................................................................................... 108 
10.1.12 Liability and Insurance ................................................................................................. 108 
10.1.13 Access to Source Data .................................................................................................. 109 
10.1.14 Ann Arbor Staging - Cotswolds Recommendations ......................................................110 
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................................
............................................................................................................................111 
10.2 Appendix 2: Clinical Laboratory Tests..............................................................................112 
10.3 Appendix 3: Contraceptive Guidance and Collection of Pregnancy Information.............114 
10.4 Appendix 4: Genetics ........................................................................................................118 
10.5 Appendix 5: Abbreviations and Trademarks.....................................................................119 
10.6 Appendix 6: Protocol Amendment History...................................................................... 123 
10.7 Appendix 7: COVID-19 Related Screening Questionnaire.............................................. 148 
11 References............................................................................................................................. 150 
Investigator Agreement Page ...................................................................................................... 153 
List of Tables
Table 1–1 
Schedule of Assessments ...................................................................................... 30 
Table 8–1 
Eastern Cooperative Oncology Group Performance Status Definitions............... 77 
Table 10–1 
Ann Arbor Staging...............................................................................................110 
..............................................111 
 
................................................................................111 
Table 10-4 
Protocol Required Safety Laboratory Assessments .............................................112 
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1
Protocol Summary
1.1
Synopsis
Protocol Title: A Randomised, Double-blind, Parallel-group, Phase III Study to Compare the 
Efficacy, Safety, and Immunogenicity of Proposed Rituximab Biosimilar (DRL_RI) with 
MabThera® in Subjects with Previously Untreated, Stage II-IV, Cluster of Differentiation 
(CD)20-Positive, Low Tumour Burden Follicular Lymphoma
Sponsor Study No.: RI-01-006
Phase: III
Sponsor: Dr. Reddy’s Laboratories S.A.
Rationale: The evaluation of pharmacokinetics (PK), efficacy, and safety (including 
immunogenicity assessment) between a proposed biosimilar and the reference medicinal product 
(RMP) is an essential component of an efficient clinical study program collectively providing the 
evidence of biosimilarity. Results from a previous study 
 show that the 91% 
confidence interval (CI) for the test-to-reference ratios of all pre-specified primary and secondary 
PK endpoints were within the pre-specified window of 80.00% to 125.00% for the comparisons 
of proposed rituximab biosimilar (DRL_RI) to MabThera® and Rituxan®, and for the comparison 
of MabThera® to Rituxan®, demonstrating the PK similarity of the 3 products.
The primary objective of the current study is to demonstrate the equivalent efficacy of DRL_RI 
and MabThera® in subjects with cluster of differentiation 20 (CD20)-positive, low tumour burden 
follicular lymphoma (LTB-FL) in the first line treatment setting, as measured by overall response 
rate (ORR). While the use of rituximab monotherapy as first-line treatment of LTB-FL is not 
approved in the United States (US) or European Union (EU), it is frequently used and has the 
potential to replace watch and wait as the treatment of choice for asymptomatic, LTB-FL.
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Objectives and Endpoints 
Objective 
Endpoint 
Primary 
x To demonstrate the equivalent 
efficacy of DRL_RI and 
MabThera® in subjects with B-
lymphocyte antigen CD20-positive, 
LTB-FL, as measured by ORR up to 
Week 28, evaluated in accordance 
with published response criteria for 
malignant lymphoma 
x The primary endpoint is BORR (best overall 
response rate), defined as the proportion of 
subjects in each treatment group that achieve 
a best overall response of either complete 
response (CR), unconfirmed complete 
response (CRu) or partial response (PR) up 
to Month 7 (Week 28) based on central 
radiology review in accordance with the 
response criteria for malignant lymphoma. 13 
Secondary 
x To compare the ORR at Week 12 
and Week 28, CR at Week 28, CR 
as a best response up to week 28, 
duration of response (DOR), PFS 
and OS of DRL_RI with 
MabThera® in subjects with 
CD20-positive, LTB-FL 
x Overall response rate at Week 12 and Week 28 
based on central radiology review in accordance 
with published response criteria for malignant 
lymphoma.13 
x Complete Response (CR) rate at Month 7 
(Week 28). 
x CR rate as a best response up to Month 7 
(Week 28). 
x Duration of response defined as the time from 
date of the first documentation of tumour 
response (CR, CRu or PR) to the date of first 
documentation of PD or to death due to any 
cause up to 52 weeks/EOS. 
x Progression-free survival defined as the time 
from date of randomisation to the date of 
documented progressive disease (PD) or death 
due to any cause. 
x Overall survival defined as the time from date of 
randomisation to the date of death from any 
cause up to 52 weeks/End of Study (EOS). 
x To compare the safety, tolerability, 
and immunogenicity of DRL_RI 
with MabThera® in subjects with 
CD20-positive, LTB-FL. 
x Adverse events (AE), clinical laboratory values, 
vital signs, and electrocardiogram (ECG) 
x Anti-rituximab antibodies and their relationship 
with other outcome measures. 
 
 
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Exploratory
x
To compare ORR evaluated in 
accordance with the Lugano 
criteria 14 in subjects with 
CD20-positive, LTB-FL treated 
with either DRL_RI or MabThera®.
x
Overall response rate based on the Lugano 
criteria 14 for those subjects with available 
positron emission tomography (PET) data.
x
To explore the PK parameters of 
DRL_RI and MabThera®, using a 
population-PK modelling approach.
x
To explore the pharmacodynamic 
parameters of DRL_RI and 
MabThera®.
x
Pharmacokinetic parameters (e.g., clearance and 
volume of distribution) for DRL_RI and 
MabThera® will be derived using a population-
PK modelling approach.
x
Potential differences in pharmacodynamic 
parameters (e.g., area under the effect curve 
[AUEC] of circulating B-cells depletion) for 
DRL_RI and MabThera® will be investigated.
Overall Design:
This is a randomised, double-blind, parallel-group, equivalence, multicentre Phase III study. The 
study will consist of a Screening Period (Days ˗35 to ˗1), a 4-week Induction Treatment Period 
(Day 1 [Week 1] to Week 4), a Maintenance Treatment Period (Week 12 to Week 36) and Follow-
up Period (Week 44 and 52).
It is planned to randomise approximately 312 subjects as per the Blinded Sample Size 
Re-estimation (BSSR) result, (please refer Section 9.2) at approximately ≥130 study sites 
worldwide.
It is planned to randomise approximately 312 subjects with CD20-positive, LTB-FL will be 
randomised to receive either DRL_RI or MabThera®. Subjects will receive induction treatment 
consisting of a weekly intravenous (i.v) infusion for 4 weeks (375 mg/m2 of body surface area 
[BSA]) followed by maintenance treatment consisting of an i.v infusion (375 mg/m2 of BSA) every 
8 weeks starting at Week 12 until Week 36. After completion of the Maintenance Treatment Period, 
subjects will be followed up until 52 weeks after the first dose of study drug (at Weeks 44 and 52).
Randomisation will be stratified by low-, medium-, and high-risk subjects using the 
 
, as well as by tumour grade (1-2 Vs. 3a; i.e., 
subjects with Grade 1 tumours should be pooled with those with Grade 2 tumours, resulting in 2 
levels for this factor) and geographical area (USA, Europe and Asia Pacific region).
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Subjects will attend study visits every week (r2 days) during the Induction Treatment Period 
(Weeks 1 to 4), at Week 8 (r7 days), thereafter every 8 weeks (r7 days) from Week 12 until 
Week- 52 (EOS/Early termination [ET] Visit). Study procedures include physical examination, 
vital signs, Eastern Cooperative Oncology Group (ECOG) performance status, tumour 
assessments, clinical laboratory tests, serum lactate dehydrogenase (LDH) and β-2 microglobulin, 
coronavirus disease 2019 (COVID-19) testing at screening and as deemed appropriate by the 
Investigator at any time during the study, AEs, concomitant medication, immunogenicity, and PK 
and pharmacodynamic samplings for the subjects in the corresponding subset. 
All subjects completing the study (Week 52) will attend an EOS Visit. Subjects discontinuing the 
study before Week 52 for any reason will also attend an ET Visit. 
Subjects with a prior history of hepatitis B infection or with serological tests suggestive of previous 
hepatitis B infection will continue to receive hepatitis B virus (HBV) antiviral prophylaxis therapy 
for at least 12 months post last dose of rituximab in the study and will be monitored and reported 
for reactivation for up to 24 months following completion of rituximab therapy.  
Subjects prematurely discontinued from treatment, but wishing to continue in the study, will return 
for an ET Visit 8 weeks after the last dose of study drug. The post-treatment discontinuation 
follow-up for subjects wishing to continue in the study is detailed below: 
If the reason for study discontinuation is disease progression, the subjects will be contacted by 
telephone for information on survival, AEs, and concomitant medications every 8 weeks, for a 
total observation period of 52 weeks. 
If the reason for study discontinuation is different from disease progression, subjects will continue 
to attend scheduled tumour assessments (at which AE and concomitant medication information 
will also be collected) up to disease progression or Week 52, whichever occurs first. If these 
subjects subsequently experience disease progression, then they will continue to be followed up 
by telephone every 8 weeks from that point of identification and for a total observation period of 
52 weeks, as described for subjects discontinued from study drug due to disease progression. 
Clinical assessments will be performed before the start of each treatment cycle by the Investigator. 
Tumour assessments for the purpose of assessing subject eligibility (with central imaging 
confirmation) and medical care will be performed by the investigational site at Screening and 
Weeks 12, 28, and 52 (EOS/ET Visit). 
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Number of Subjects: 
Based on the observed pooled best overall response (BOR) rate, up to week 28, the revised total 
sample size obtained during the BSSR is approximately 312 subjects (156 per group) to be 
recruited.  
Diagnosis and Main Criteria for Inclusion: 
Inclusion Criteria 
A subject will be eligible for enrolment in the study if he/she meets all of the following criteria: 
1. Signed written informed consent. 
2. Male or female subjects aged ≥18 years of age. 
3. Histologically confirmed, Grade 1-3a, previously untreated, CD20-positive, LTB-FL as per 
Groupe D’Etude des Lymphomes Folliculaires (GELF) based criteria. Subjects must have 
sufficient tissue samples available for the central pathology review (Section 8.1.1), and a 
centrally-confirmed diagnosis prior to being randomised. Should a subject be eligible as per 
the central imaging review but not as per the Study Centre Review the subject will be 
considered eligible if confirmed both by the Investigator and the Medical Monitor. For any 
other disagreement in eligibility the subject will be considered ineligible. 
4. Ann Arbor Stage II to IV. 
5. ECOG status of 0 to 1. 
6. Low tumour burden follicular lymphoma defined as: 
x As per central radiological assessment, nodal or extranodal mass involvement with 
diameter measuring <7 cm 
x As per central radiological assessment, involvement of ≤3 nodal sites with diameter 
measuring >3 cm 
x Absence of systemic symptoms or B-symptoms* (asymptomatic) 
*B-symptoms defined as weight loss >10% within last 6 months, recurrent or 
continuous night sweats, intermittent or continuous fever recorded as axillary or oral 
temperature >38°C for at least 3 days 
x As per central radiological assessment, absence of splenomegaly (defined as spleen 
size higher than 16 cm by computed tomography [CT] scan) 
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x Absence of risk of vital organ compression based on clinical finding 
x Absence of leukemic phase (leukemic phase defined as a count >5,000/μL of 
circulating tumour cells) 
x Absence of clinically significant cytopenias (defined as a platelet count of 
<100,000/μL, haemoglobin <10 g/dL, or absolute neutrophil count <1,500/μL) 
x Absence of clinically significant serous effusion based on clinical examination and CT 
scan 
x Serum LDH not higher than the upper limit of normal (ULN) by local laboratory. 
7. Subject has at least 1 measurable tumour mass in 2 dimensions as per central radiological 
assessment, and the mass must be: 
x Nodal lesion >15 mm in the longest dimension; or 
x Nodal lesion >10 mm to ≤15 mm in the longest dimension and >10 mm in the 
shortest dimension; or 
x Extranodal lesion with both long and short dimensions ≥10 mm. 
8. Creatinine clearance ≥45 mL/min as calculated by the Cockcroft-Gault method. 
9. Aspartate transaminase, alanine transaminase, alkaline phosphatase values ≤3 × ULN, total 
or conjugated bilirubin values ≤1.5 × ULN. 
10. Life expectancy ≥3 months. 
11. Able to comply with the study protocol. 
12. If female subject, then subject should be non-pregnant, non-lactating. Adequate 
contraception or post-menopausal/non-childbearing status (e.g., women with cessation of 
menstruation for ≤ 2 years, peri-menopausal women with inconclusive menopausal 
evidences based on clinical assessment and medical history). Women of childbearing 
potential must practice effective birth control for the duration of the study and for 12 months 
after the last study drug dose. For this same duration, male subjects participating in the study 
should avoid passing the semen to female partners during sexual intercourse. 
Exclusion Criteria 
Subjects meeting any of the following criteria must not be enrolled in the study: 
1. Prior use of rituximab or any CD20 monoclonal antibody for any reason. 
2. Any contraindication to the use of rituximab. 
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3. Any prior therapy for follicular lymphoma (including but not limited to chemotherapy, 
radiotherapy). 
4. Subjects who, in the opinion of the Investigator, require additional concomitant treatment for 
lymphoma. 
5. Evidence of histologic transformation to high grade lymphoma or diffuse large B-cell 
lymphoma. 
6. Known Central Nervous System (CNS) involvement by lymphoma. (Note: CNS imaging is 
not required unless clinically indicated). 
7. Subjects on chronic supra-substitutive doses (defined as doses in excess of 7.5 mg per day of 
prednisone or prednisone equivalent for a period longer than 3 weeks) of systemic 
glucocorticoids. 
8. Prior malignancy (including recurrence) within 5 years of screening, other than non-melanoma 
skin cancer or intraepithelial cervical neoplasia, successfully treated more than 1 year before 
study inclusion. 
9. Subjects with known seropositivity for or history of active viral infection with human 
immunodeficiency virus (HIV). 
10. Subjects with positive serological test for hepatitis B surface antigen (HBsAg), hepatitis B core 
antibody (HBcAb) or hepatitis C virus (HCV) antibody can only be included in the study if 
any of the following is fulfilled. 18,19 
a. Subjects with a negative HBsAg and positive total HBcAb must have a HBV 
deoxyribonucleic acid (DNA) level <20 IU/mL (or 112 copies/mL) by polymerase 
chain reaction (PCR) to participate in the study. In addition, it is required for these 
subjects to follow consultation with a Hepatologist / relevant expert regarding 
initiation, monitoring, and use of HBV antiviral therapy and the subject must be 
willing to undergo PCR HBV DNA testing during treatment and agree to receive 
treatment as indicated. HBV DNA re-test will be performed as per the schedule of 
assessments (see Table 1–1) and further as needed, at the discretion of the Investigator.  
b. Subjects with a positive test because of HBV vaccination may be included (i.e., HBsAg 
negative, anti-HBs+, HBcAb–).  
c. Subjects positive for HCV antibody are eligible only if the PCR test for HCV 
ribonucleic acid (RNA) is negative.  
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11. 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 drug (Day 1). If latent TB is suspected based on clinical or epidemiological 
grounds, it should be further investigated using the tuberculosis testing as appropriate 
following local practice or investigator judgment. 
12. Subjects who have received a live vaccine within last 3 months or non-live vaccine within 4 
weeks of the first administration of study drug. [Note: A need may arise for trial subjects to 
receive vaccine against COVID-19 while being a part of the study. All such decisions will be 
taken at the discretion of the Investigator in consultation with the CRO / Sponsor after due 
consideration to subjects’ safety, national health policy of the respective country and overall 
need by the subject for such vaccine during the time of study participation].  
13. Subjects with an active uncontrolled infection requiring systemic treatment at Screening or 
history of documented recurrent clinically significant infection within 6 months of study 
inclusion (e.g., 2 or more viral, bacterial or fungal infections requiring in-patient treatment). 
14. Subjects with New York Heart Association (NYHA) class III or IV congestive heart failure or 
relevant arrhythmia or angina based on ECG with clinical judgment. 
15. Subjects with known hypersensitivity to rituximab or its excipients, or to proteins of murine or 
other foreign origin. 
16. History or presence of a medical condition or disease that in the Investigator's opinion would 
place the subject at an unacceptable risk for study participation. 
17. Participation in any clinical study or having taken any investigational therapy during the 
2-month period immediately preceding administration of the first dose of study drug. 
18. Lactating or pregnant female. 
19. Women of childbearing potential who do not consent to use highly effective methods of birth 
control (e.g., sterilisation, or other non-hormonal forms of contraception) during treatment and 
for at least 12 months after the last administration of study drug. True abstinence periodic 
abstinence (e.g., calendar ovulation, symptothermal, post-ovulation methods) and withdrawal 
are not acceptable methods of contraception. 
20. Subject has been previously randomised in this study. 
21. Subject likely not to be available to complete all protocol required study visits or procedures. 
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Treatment Groups and Duration: 
The study drug DRL_RI or MabThera® will be administered as an i.v infusion, at a dose of 
375 mg/m2 of BSA. Subjects will receive induction treatment consisting of weekly i.v infusions 
up to Week 4 followed by maintenance treatment consisting of an i.v infusion every 8 weeks from 
Week 12 up to Week 36. Subjects will be pre-medicated before each infusion with acetaminophen, 
diphenhydramine, and 100 mg i.v methylprednisolone or their equivalent to decrease the incidence 
and severity of acute infusion-related reactions (IRRs). 
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 every 30 minutes, to a maximum of 400 mg/hour. 
Subsequent Infusions: 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. 
Infusions should be administered under close medical supervision. The infusion should be 
interrupted, or the infusion rate slowed for infusion reactions. If symptoms improve, the infusion 
rate can be continued at one-half the previous rate. 
Whenever the infusion is interrupted, the stop time and restart time should be recorded (with date, 
hour and minutes) along with initial start and final end time. Rates of infusion throughout should 
be recorded. 
The preparation of rituximab infusion for dosing must be handled by the trained study personnel 
who is an unblinded team member and not part of any other study assessments. The study drugs 
should be kept in a secure area with access limited to authorised persons. 
An unblinded team shall be responsible for maintaining drug accountability logs and unblinded 
clinical site manager (CSM) will verify the same as part of monitoring visits. 
A separate unblinded team at the Contract Research Organisation (CRO) and site level will manage 
the shipping, inventory, storage, accountability and dosing preparation of the study drug. 
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1.2
Schema
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1.3 Schedule of Activities 
An overview of the protocol visits and procedures is provided in Table 1–1. Refer to Study 
Procedures and Assessments sections of the protocol for detailed information on each procedure 
and assessment required for compliance with the protocol. 
The Investigator may 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. Unscheduled visits (including reason) will be collected in the electronic case report 
forms (eCRF). 
The following priority order will be in effect when more than one assessment is required at a time 
point: 
1. 12-lead ECG 
2. Vital signs 
3. Pharmacokinetic blood sampling (subjects included in the PK and pharmacodynamic subset 
only) 
4. Pharmacodynamic blood sampling (subjects included in the PK and pharmacodynamic subset 
only) 
5. Blood sampling for safety assessments 
 
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Table 1–1
Schedule of Assessments
Visit
Screening
Induction Treatment Period
Maintenance 
Treatment 
Period
Follow-up Period
Baseline
Week (Day)
± 2 days
Week
± 7 days
Week
± 7 days
Week
± 7 
days
EOS/ET1
Week
± 7 days
Timing
Days ˗35 to 
˗1
Days 0 to 12
2 (8)
3 (15)
4 (22)
8
12, 20, 28, 36
44
52
Baseline3
X
Informed consent4
X
Inclusion/exclusion criteria5
X
X
criteria
X
Histological confirmation of
diagnosis6
X
Medical, surgical and oncology
history including medications
X
Demographics
X
Physical examination7
X
X
X
X
X
X
X
X
X
Vital signs8
X
X
X
X
X
X
X
X
X
Pregnancy test9
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
X
X
X
X
Clinical laboratory tests10
X
X
X
X
X
X
X
X
X
LDH and β-2 microglobulin
X
X
X
X
X
X
X
X
X
TB screening11
X
Viral disease screening12
X
X12
X12
X12
12-Lead ECG
X
X
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Visit 
Screening 
Induction Treatment Period 
Maintenance 
Treatment 
Period 
Follow-up Period 
Baseline 
Week (Day) 
± 2 days 
Week 
± 7 days 
Week 
± 7 days 
Week 
± 7 
days 
EOS/ET1 
Week 
± 7 days 
Timing 
Days ˗35 to 
˗1 
Days 0 to 12 
2 (8) 
3 (15) 
4 (22) 
8 
12, 20, 28, 36 
44 
52 
CT Scan13 or [18F]FDG-PET/PET-
CT14 
X 
 
 
 
 
 
X13,14 
 
X 
Bone marrow biopsy15 
X 
 
 
 
 
 
X15 
 
X15 
Randomisation 
 
X16 
 
 
 
 
 
 
 
Study drug administration17 
 
X 
X 
X 
X 
 
X 
 
 
PK sampling18 
 
X 
X 
X 
X 
 
X18 
 
 
Pharmacodynamic sampling19 
 
X 
X 
X 
X 
 
X19 
X 
X 
Immunogenicity20 
 
X 
 
 
X 
X 
X20 
X 
X 
Adverse events including IRR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
COVID-19 testing21 
 
X 
 
 
 
 
 
 
 
COVID-19 related screening 
questionnaire 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Abbreviations: AE = adverse event; BAb = binding antibodies; COVID-19 = Coronavirus disease 2019; Ctrough = trough plasma concentration; CT = computed
tomography; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOS/ET = End of Study/Early Termination;
[18F]FDG-PET: fluorine-18-fluorodeoxyglucose positron emission tomography; FL = follicular lymphoma;a;
; HBV = hepatitis B virus; HCV = hepatitis C virus; IRR = infusion-related reactions; IWRS = ininter
terac
actitive web
eb resp
esponse systetem; LDH = lacta
lactatete
deh
ehydrogenase; NAb = neutralising antibodies; PET-CT = positron emission tomography - computed tomography; PK = pharmacokinetic; PR = partial response;
RNA = ribonucleic acid; RT-PCR = reverse transcription polymerase chain reaction; TB = tuberculosis.
1.
All subjects completing the study (Week 52) and those discontinuing the study at any time for any reason will attend the EOS Visit. Subjects experiencing 
disease progression will discontinue study drug and attend the ET Visit, which is to be scheduled 8 weeks after the last dose of study drug administration. 
These subjects will then be contacted by telephone for information on survival, AEs, and concomitant medications every 8 weeks, for a total observation period 
of 52 weeks. Subjects who wish to remain in the study but withdraw from the study drug for any reason other than disease progression will return for an ET 
Visit 8 weeks after the last dose of study drug and continue to attend scheduled tumour assessments (at which AE and concomitant medication information 
will also be collected) up to disease progression or Week 52, whichever occurs first. Note: if these subjects subsequently experience disease progression then 
they will continue to be followed up by telephone every 8 weeks from that point of identification and for a total observation period of 52 weeks, as described 
for subjects discontinued from study drug due to disease progression.
2.
Day 0 and Day 1 can be clubbed into one single day. However, randomisation in IWRS and administration of first dose of study medication should take place 
on the same day and this will be considered as Day 1.
3.
If the assessment is repeated before dosing, then latest values/observations will be considered as Baseline value/observation.
4.
Informed consent must be obtained prior to undergoing any study-specific procedure.
5.
All eligibility criteria must be met based on the screening assessment before a subject is randomised to study drug. Subjects that do not meet all requirements 
can be rescreened at the Investigator’s discretion, following discussion with the Sponsor/designee Medical Monitor.
6.
Subjects can be screened for the study based on a diagnosis of CD20-positive, low burden FL confirmed at the investigational site. Subjects must have sufficient 
tissue samples available for the central pathology review (obtained on or within 12 months prior to the screening date) and a centrally-confirmed diagnosis 
prior to being randomised.
7.
Complete physical examinations, including a thorough assessment of the lymph nodes, liver, and spleen, will be conducted at Screening and at the EOS/ET 
Visit. Physical examination evaluations at other study visits will be at the discretion of the Investigator, but should, at a minimum, include an assessment of 
the lymph nodes, liver, and spleen. Height will be recorded at screening only. Weight will be recorded at each study drug dosing visit.
8.
Temperature (oral, axillary, or tympanic), blood pressure, heart rate, and respiratory rate will be recorded at each time point. Vital signs will be monitored 
every 30 minutes (±5 minutes) during the course of the treatment administration and at end of infusion or more frequently as necessary.
9.
Women of childbearing potential will have a serum pregnancy test during Screening and urine or serum pregnancy tests on Day 1 prior to randomisation, and 
all subsequent study drug dosing visits. A serum pregnancy test will be repeated at EOS/ET Visit. Additional pregnancy tests should be performed whenever 
pregnancy is suspected or at the discretion of the Investigator. All tests will be performed by the local laboratory according to local practice.
10.
Clinical laboratory tests (haematology/coagulation/biochemistry/urinalysis) will be performed by local laboratories, prior to administration of study treatment.
11.
If latent TB is suspected based on clinical or epidemiological grounds, it should be further investigated using the tuberculosis testing as appropriate following 
local practice or Investigator judgment. 
12.
Hepatitis B surface antigen, hepatitis B core antibody, HBV DNA (as applicable), HCV antibody, HCV RNA (as applicable), and human immunodeficiency 
virus to be conducted by local laboratory. HBV DNA at Screening, Week 12 and all visits from Week 12 onwards (only for subjects with history of hepatitis B 
or hepatitis B serology suggestive of past hepatitis B infection). Additional monitoring/management of subjects who were HCV antibody positive (and HCV 
RNA negative) at Screening should be done in accordance with local practice and standard of care.
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13. Tumour assessments for the purpose of assessing subject eligibility (with central imaging confirmation) and medical care will be performed by the 
investigational site at Screening, Weeks 12, 28, and 52 (EOS/ET Visit) by reviewing CT scans (Neck, chest, abdomen, and pelvis) with contrast. Computed 
tomography scans obtained up to 6 weeks prior to the first administration of study drug may be used for determining study eligibility provided they are of 
adequate quality for subsequent central review. Tumour assessments may also be performed on the CT component of positron emission tomography - computed 
tomography (PET-CT) scans with contrast if the quality of the CT part of PET-CT is equivalent to that of a standard CT. The same modality (CT or PET-CT) 
should be consistently used throughout the study evaluations. All imaging performed for the study will be forwarded to the central imaging vendor for review 
and assessment of response for the primary and other efficacy endpoints. Disease assessments are to be performed as scheduled according to Table 1–1, 
regardless of treatment delays resulting from toxicity. Care must be taken in scheduling disease assessments to prevent the introduction of bias based on 
treatment delays. Assessments are NOT to be scheduled based on the previous imaging time point, but rather Day 1 should be used as the Baseline when 
calculating when the on-study tumour assessments are to be performed (with consideration of visit windows). 
14. Fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography ([18F] FDG-PET or PET-CT) scan will be obtained where available 
(according to study site standard of care) at Screening, Weeks 12, 28, and 52 (EOS/ET Visit). Positron emission tomography scans acquired up to 6 weeks 
prior to Day 1 may be used for screening provided they are of adequate quality for subsequent central imaging review. 
15. Bone marrow biopsies or aspirations performed up to 12 weeks prior to the first administration of study drug may be used. Additional bone marrow biopsies 
are required for any subject who has a response of CR at an evaluation point and either had a bone marrow examination positive for FL at Screening or shows 
new abnormalities in the peripheral blood counts or blood smear that clinically indicates a bone marrow evaluation is required. 
16. Before randomisation of the subject, all the Baseline assessments must be reviewed by the investigators for suitability of starting the study treatment. 
17. The study drug proposed rituximab biosimilar [DRL_RI] or MabThera® will be administered as an i.v infusion, at a dose of 375 mg/m2 of body surface area. 
Subjects will receive induction treatment consisting of a weekly i.v infusion for 4 weeks followed by maintenance treatment consisting of an i.v infusion every 
8 weeks up to Week 36. Subjects will be pre-medicated before each infusion with acetaminophen, diphenhydramine, and 100 mg i.v methylprednisolone or 
their equivalent to decrease the incidence and severity of acute IRRs. Randomisation in IWRS and administration of first dose of study medication should take 
place on the same day and this will be considered as Day 1 
18. Only for the subjects identified for the PK and pharmacodynamic evaluation: one PK sample will be taken prior to initiation of infusion (pre-dose or 
Ctrough) and a second sample immediately prior to the end of the infusion on Days 1, 8, 15, 22, and Week 12. 
19. Only for the subjects identified for the PK and pharmacodynamic evaluation: separate pharmacodynamic samples will be taken prior to initiation of 
infusion (pre-dose) and immediately prior to the end of the infusion on Day 1, prior to the initiation of infusion on Days 8, 15, 22, and at Weeks 12, 20, 28, 
and 36. Samples will also be collected at the Week 44 and 52 visits. 
20. Samples for detection of BAb and NAb will be collected before the administration of study drug infusion on Day 1 and Day 22. Additional samples for 
detection of BAb and NAb will be collected prior to study drug infusion at Weeks 8 and 28, as well as at the visits of Week 44 and Week 52 (EOS/ET Visit). 
21. COVID-19 testing (RT-PCR, Rapid Antigen test or test with similar nature antigen test but no antibody test) to be performed as close as possible but no more 
than 4 days before first dose administration. COVID-19 testing may be repeated at the discretion of the Investigator. Subjects should be randomised only after 
negative COVID-19 test result. 
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2 Introduction 
Rituximab is approved for use in B-cell non-Hodgkin’s Lymphoma (NHL), chronic lymphocytic 
leukaemia, rheumatoid arthritis (RA) in combination with methotrexate in adults with moderately-
to severely-active RA who have inadequate response to one or more tumour necrosis factor 
antagonist therapies, and granulomatosis with polyangiitis and microscopic polyangiitis in 
combination with glucocorticoids.1,2 Rituxan® is the commercially available innovator reference 
product in the United States (US); MabThera® is the commercially available innovator reference 
product in the European Union (EU). In Japan the commercially available product is Rituxan®. 
The proposed rituximab biosimilar (hereafter referred to as DRL_RI) is being developed as a 
potential biosimilar to Rituxan® and MabThera®. Rituximab, the innovator reference product 
approved in the EU (MabThera®) will be used as the selected reference medicinal product (RMP) 
for all study sites participating in this protocol. 
The term “biosimilar” refers to a biologic drug that is developed to be similar to an existing 
approved RMP. Biosimilars are intended to treat the same diseases as the RMP using the same 
dose and treatment regimen. Unlike generic versions of chemically-synthesised small molecule 
therapies, biosimilars are not structurally identical to their RMP. This is due to the purity, 
characteristics, and activity of a specific product being dependent on, and sensitive to changes in 
the process by which it was manufactured. Therefore, the aim is to create a product with no 
clinically meaningful differences between the proposed biosimilar and the RMP in terms of 
pharmacokinetics (PK), safety, immunogenicity, and efficacy. 
The demonstration of similarity in efficacy between a proposed biosimilar and the RMP is an 
essential component of a clinical study program that collectively provides the evidence of 
biosimilarity. The objective of the current study is to demonstrate equivalent efficacy of DRL_RI 
and MabThera® in subjects with B-lymphocyte antigen cluster of differentiation (CD)-20 positive, 
low tumour burden follicular lymphoma (LTB-FL) in the first-line treatment setting, as measured 
by overall response rate (ORR). 
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2.1 Study Rationale 
The evaluation of PK, efficacy, and safety (including immunogenicity assessment) between a 
proposed biosimilar and the RMP is an essential component of an efficient clinical study program 
collectively providing the evidence of biosimilarity. Results from a previous study 
(Study RI-01-003) show that the 91% confidence interval (CI) for the test to- reference ratios of 
all pre-specified primary and secondary PK endpoints were within the pre-specified window of 
80.00% to 125.00% for the comparisons of DRL_RI to -MabThera® and Rituxan®, and for the 
comparison of MabThera® to Rituxan®, demonstrating the PK similarity of the 3 products 
(Section 2.2.4.2). 
The primary objective of the current study is to demonstrate the equivalent efficacy of DRL_RI 
and MabThera® in subjects with CD20-positive, LTB-FL in the first line- treatment setting, as 
measured by ORR. While the use of rituximab monotherapy as first-line treatment of LTB-FL is 
not approved in the US or EU, it is frequently used 3,4,5 and has the potential to replace watch and 
wait as the treatment of choice for asymptomatic, LTB-FL. 
2.2 Background 
2.2.1 
Rituximab 
Rituximab is a genetically engineered chimeric murine/human monoclonal IgG1 kappa antibody 
directed against the CD20 antigen. It has an approximate molecular weight of 145 kilodaltons 
(kDa). Rituximab has a binding affinity for the CD20 antigen of approximately 8.0 nM.1,2 
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 
haematopoietic stem cells, pro-B-cells, normal plasma cells, or other normal tissue. This antigen 
does not internalise 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.2 
The fragment antigen-binding domain of rituximab binds to the CD20 antigen on B lymphocytes 
and the fragment crystallisable (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 
C1q 
binding, 
and 
antibody 
dependent 
cellular 
cytotoxicity (ADCC) mediated by one 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.2 
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Rituximab is approved for use in NHL, chronic lymphocytic leukaemia, RA, and granulomatosis 
with polyangiitis and microscopic polyangiitis. Further information is contained within both the 
Prescribing Information of Rituxan® and public information including the Summary of Product 
Characteristics (SmPC) for MabThera®.1,2 
2.2.2 
Follicular Lymphoma 
CD-20 positive, B-cell NHL is a heterogeneous group of malignancies with varying clinical 
outcomes.6 The risk of mortality from NHL depends on whether it is indolent or aggressive; 
indolent forms of NHL, such as follicular lymphoma (FL), have significantly better prognosis than 
more aggressive forms like diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma. 
Follicular lymphoma is the most common subtype of indolent NHL in the Western Hemisphere. 
With current therapy options, prognosis is favourable, with median overall survival (OS) 
exceeding 12 years. Recent advances in disease management and our understanding of the biology 
of FL have led to a dramatic change in the treatment landscape. Despite this progress, FL remains 
incurable with standard therapies.7 
Tumour grade is used to classify FL based on the number of centroblasts per high-power 
field (HPF). In general, cases harbouring a greater number of centroblasts behave more 
aggressively and are associated with a higher risk of transformation to DLBCL. Grade 1 
(<5 centroblasts/HPF) and Grade 2 (6 to 15 centroblasts/HPF) FL are combined in the World 
Health Organisation (WHO) classification given their similar clinical behaviour. Grade 3 FL can 
be further subdivided into 3a and 3b, with the latter distinguished by a lack of centrocytes. Despite 
a higher tumour grade, FL Grade 3a behaves like Grade 1-2 FL and as such should be approached 
in a similar fashion. FL Grade 3b represents a distinct entity characterised by a diffuse architectural 
pattern, frequent loss of CD10 expression, and absence of t (14;18) chromosomal translocation. 
Consequently, its clinical course and treatment mirror that of DLBCL.7 Subjects with Ann Arbor 
Stage II, III or IV of histological Grade 1, 2, or 3a with at least one measurable lesion 
(Section 10.1.14), will be enrolled in this study. 
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2.2.3 
Efficacy of Rituximab in Low Tumour Burden Follicular Lymphoma 
Despite much study and debate, a major issue that remains for newly diagnosed patients with 
asymptomatic, LTB-FL is whether therapy is indicated. While all available randomised data fail to 
demonstrate a survival benefit with early therapy compared with a watchful waiting approach, the 
success and tolerability of rituximab has challenged this treatment paradigm leading to earlier 
treatment with rituximab monotherapy, with or without rituximab maintenance8. Rituximab has a 
favourable side effect profile compared to chemotherapy; therefore, a study was conducted to 
compare watch and wait to immediate treatment with rituximab in subjects with LTB-FL.9 
Adult subjects with asymptomatic Stage II, III or IV FL (Grades 1 to 2 and 3a) were randomly 
assigned in a ratio of 1:1:1 to watch and wait (Arm A), rituximab 375 mg/m2 of body surface area 
(BSA) weekly for 4 weeks (rituximab induction; Arm B) or rituximab 375 mg/m2 of BSA weekly 
for 4 weeks followed by rituximab maintenance every 2 months for 2 years (from Month 3 to 
Month 25) (Arm C). The primary endpoints were time to initiation of new therapy (chemotherapy 
or radiotherapy) and effect on quality of life at Month 7 (i.e., 6 months after completion of 
rituximab induction). 
A total of 463 subjects were randomised (187 Arm A, 84 Arm B, and 192 Arm C) with 95% of 
subjects having low tumour burden (LTB) according to predefined criteria similar to the Groupe 
D’Etude des Lymphomes Folliculaires (GELF) criteria. The other 5% had raised lactate 
dehydrogenase (LDH) but fulfilled the remaining GELF criteria. Radiological response was 
assessed at Months 7, 13, and 25. 
There was a significant difference in the time to start of new treatment, with 46% (95% CI 39-53) 
of subjects in Arm A not needing treatment at 3 years compared with 88% (83-92) in Arm C 
(hazard ratio [HR] 0.21, 95% CI 0.14–0.31; p<0.0001). Seventy-eight percent (78%, 95% CI 69-
87) of subjects in Arm B did not need treatment at 3 years, which was significantly more than in 
Arm A (HR 0.35, 95% CI 0.22–0.56; p<0.0001), but no different compared with Arm C (HR 0.75, 
95% CI 0.41–1.34; p=0.33). 
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At Month 7, Arm A had an overall remission rate of 6%. Arm B had an ORR of 77%, with a 
complete response (CR) + unconfirmed complete response (CRu) of 47% and partial response 
(PR) of 30%. Arm C had a CR + CRu of 60% and a PR of 29% (ORR=88%). There were also 
differences observed in 3-year progression-free survival (PFS) between Arm B and the other 
2 arms with the highest PFS rate in Arm C, followed by Arm B, then Arm A. A statistically 
significant treatment difference was observed for the comparison between Arm C and Arm B 
(HR 0.53 [95% CI 0.32-0.87; p=0.011], and for the comparison between Arm B and Arm A 
(HR 0.55 [95% CI 0.37-0.83; p=0.0034]). These data indicate that initial treatment with rituximab 
significantly delays the need for new therapy.9 
Another study, RESORT, looked at the role of maintenance therapy in subjects with LTB-FL who 
received single agent rituximab.10 Subjects received weekly doses of rituximab (375 mg/m2 of 
BSA) for 4 weeks, and responders were randomised to maintenance rituximab (MR  single- dose 
rituximab every 3 months) or rituximab retreatment (RR - rituximab weekly for 4 weeks at disease 
progression). The primary endpoint was time to treatment failure (TTF). A total of 384 subjects 
enrolled. Complete response or PR was achieved in 274 subjects (71%), who were then 
randomised to MR (n=140) or RR (n=134). The mean number of rituximab doses/subject 
(including the 4 induction doses) was 15.5 (range 5 to 31) for MR and 4 (range 4 to 16) for RR. 
With a median follow-up of 3.8 years, TTF was 3.9 years for MR versus 3.6 years for RR 
(p-value=0.8). At 12 months post randomisation, there was no discernible difference in 
health -related quality of life and anxiety between the 2 arms. 
2.2.4 
Dr. Reddy’s Rituximab (DRL_RI) 
Dr. Reddy's Laboratories (DRL) is developing a proposed biosimilar version of the chimeric anti-
CD20 monoclonal antibody (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 kDa. Each of the heavy chains contains one 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 Rituxan® and MabThera® when compared by a battery of orthogonal 
analytical methods. The glycosylation variants (glycoforms) of DRL_RI are the same as those 
found in Rituxan® and MabThera®, and the proportions of each of the glycoforms are similar 
between the 3 proteins. 
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Further information can be found in the Investigators’ Brochure (IB) for DRL_RI.11
2.2.4.1
Nonclinical Studies
2.2.4.1.1
In Vitro Pharmacology
The comparison of in vitro functional activities of DRL_RI, Rituxan® and MabThera® was 
performed using multiple cell-based and binding assays. Batches of DRL_RI, Rituxan® and 
MabThera® were compared using Two One-Sided t-Test analyses. A difference of 20% in the mean 
relative binding or potency was deemed acceptable. The CDC and the ADCC activities and the 
binding of DRL_RI, Rituxan® and MabThera® to CD20, C1q, FcγRI, FcγRIIa, FcγRIIb, FcγRIII, 
and FcRn were found to be similar. Therefore, DRL_RI, Rituxan® and MabThera® are considered 
similar in terms of their in vitro functional characteristics. 11
2.2.4.2
Clinical Studies
The PK characteristics of DRL_RI, MabThera®, and Rituxan® were compared in a double -blind, 
randomised, 3 arm study 
 conducted in subjects with moderate to severe RA. 
The results of the study showed that the 91% CI for the test to- reference ratios of all pre-specified 
primary and secondary PK endpoints were within the pre-specified window of 80.00% to 125.00% 
for the comparisons of DRL_RI to -MabThera® and Rituxan®, and for the comparison of 
MabThera® to Rituxan®, 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 drug infusions, AUC from start to 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 drug. 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. The results also showed that the safety and immunogenicity profiles and 
CD20positive -Bcell- depletions as well as the proportion of subjects meeting the American 
College of Rheumatology (ACR)20, ACR50, and ACR70 improvement criteria from Baseline to 
Week 24 and the mean change from Baseline to Week 24 in Disease Activity Score 28-C-Reactive 
Protein (DAS28-CRP) were comparable across DRL_RI, MabThera®, and Rituxan®.12
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2.3 Benefit/Risk Assessment 
There is a substantial body of data related to the safety and efficacy of Rituxan®/MabThera® in 
subjects with B-cell NHL (Food and Drug Administration [FDA] Rituxan® prescribing 
information/European Medicines Agency [EMA] MabThera® SmPC).1,2 A comprehensive head-
to-head comparison of Dr. Reddy’s rituximab antibody, DRL_RI, to the US-approved Rituxan®, 
and the European RMP (MabThera®) has demonstrated that DRL_RI is similar to Rituxan® and 
the RMP (Section 2.2.4.2). Thus, the risk/benefit of DRL_RI is expected to be comparable to that 
of Rituxan®/MabThera®. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of DRL_RI may be found in the IB for DRL_RI.11 
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3 Objectives and Endpoints 
Objective 
Endpoint 
Primary 
To demonstrate the equivalent efficacy 
of DRL_RI and MabThera® in subjects 
with B-lymphocyte antigen 
CD20-positive, LTB-FL, as measured 
by ORR up to Week 28, evaluated in 
accordance with published response 
criteria for malignant lymphoma. 
The primary endpoint is BORR, defined as the 
proportion of subjects in each treatment group that 
achieve a best overall response of either CR, CRu or 
PR up to Month 7 (Week 28) based on central 
radiology review in accordance with the response 
criteria for malignant lymphoma. 13 
Secondary 
x To compare the ORR at Week 12 
and Week 28, CR at Week 28, CR 
as a best response up to week 28, 
duration of response (DOR), PFS 
and OS of DRL_RI with 
MabThera® in subjects with 
CD20-positive, LTB-FL. 
x Overall response rate at Week 12 and Week 28 
based on central radiology review in accordance 
with published response criteria for malignant 
lymphoma13. 
x Complete Response (CR) rate at Month 7 
(Week 28). 
x CR rate as a best response up to Month 7 
(Week 28). 
x Duration of response defined as the time from 
date of the first documentation of tumour 
response (CR, CRu or PR) to the date of first 
documentation of PD or to death due to any 
cause up to 52 weeks/EOS. 
x Progression-free survival defined as the time 
from date of randomisation to the date of 
documented progressive disease (PD) or death 
due to any cause. 
x Overall survival defined as the time from date of 
randomisation to the date of death from any 
cause up to 52 weeks/End of Study (EOS). 
x To compare the safety, tolerability, 
and immunogenicity of DRL_RI 
with MabThera® in subjects with 
CD20-positive, LTB-FL. 
x Adverse events, clinical laboratory values, vital 
signs, and electrocardiogram (ECG) 
x Anti-rituximab antibodies and their relationship 
with other outcome measures. 
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Objective 
Endpoint 
Exploratory 
x To compare ORR evaluated in 
accordance with the Lugano 
criteria 14 in subjects with 
CD20-positive, LTB-FL treated 
with either DRL_RI or MabThera®. 
x Overall response rate based on the Lugano 
criteria 14 for those subjects with available 
positron emission tomography (PET) data. 
x To explore the PK parameters of 
DRL_RI and MabThera®, using a 
population-PK modelling approach. 
x Pharmacokinetic parameters (e.g., clearance and 
volume of distribution) for DRL_RI and 
MabThera® will be derived using a population-
PK modelling approach. 
x To explore the pharmacodynamic 
parameters of DRL_RI and 
MabThera®. 
x Potential differences in pharmacodynamic 
parameters (e.g., area under the effect curve 
[AUEC] of circulating B-cells depletion) for 
DRL_RI and MabThera® will be investigated. 
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4
Study Design
4.1
Overall Design
4.1.1
Description
This is a Phase III, randomised, multicentre, double-blind, parallel-group study in subjects with 
previously untreated, Stage II-IV, CD20-positive, LTB-FL.
It is planned to randomise approximately 312 subjects (Please refer Section 9.2) at approximately 
≥130 study sites worldwide.
The study will enrol subjects with CD20-positive, LTB-FL who are asymptomatic for lymphoma 
specific B-symptoms. LTB-FL will be assessed according to the GELF based criteria.3,9
Subjects will receive induction treatment consisting of a weekly i.v infusion for 4 weeks 
(375 mg/m2 of BSA) followed by maintenance treatment consisting of an i.v infusion (375 mg/m2 
of BSA) every 8 weeks from Week 12 up to Week 36.15
Randomisation will be stratified by low-, medium-, and high-risk subjects using the 
 
),), as well as by tumour grade (1-2 Vs. 
3a) and geographical area (USA, Europe and Asia-Pacific region).
Subjects will attend study visits every week (± 2 days) during the Induction Treatment Period 
(Weeks 1 to 4), at Week 8 (± 7 days), at Week 12 (± 7 days), thereafter every 8 weeks (± 7 days) 
up to Week 52 (EOS/Early Termination [ET] Visit). Study procedures include physical 
examination, vital signs, Eastern Cooperative Oncology Group (ECOG) performance status, 
tumour assessments, clinical laboratory tests, serum LDH and β-2 microglobulin, coronavirus 
disease 2019 (COVID-19) testing at screening and as deemed appropriate by the Investigator at 
any time during the study, AEs, concomitant medication, immunogenicity, and PK and 
pharmacodynamic samplings for the subjects in the corresponding subset.
All subjects completing the study (Week 52) will attend an EOS Visit. Subjects discontinuing the 
study before Week 52 for any reason will also attend an ET Visit. Subjects positive for hepatitis B 
at screening will be followed up to 24 months post last dose of rituximab in the study as outlined 
in Section 6.10. 
Subjects with a prior history of hepatitis B infection or serological tests suggestive of previous 
hepatitis B infection will continue to receive hepatitis B virus (HBV) antiviral prophylaxis therapy 
for at least 12 months post last dose of rituximab in the study and will be monitored and reported 
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for reactivation for up to 24 months following completion of rituximab therapy as outlined in 
Section 6.10. 
Subjects prematurely discontinued from treatment, but wishing to continue in the study, will return 
for an ET Visit 8 weeks after the last dose of study drug. The post-treatment discontinuation 
follow-up for subjects wishing to continue in the study is detailed below: 
x If the reason for study discontinuation is disease progression, the subjects will be contacted by 
telephone for information on survival, AEs, and concomitant medications every 8 weeks, for a 
total observation period of 52 weeks. 
x If the reason for study discontinuation is different from disease progression, subjects will 
continue to attend scheduled tumour assessments (at which AE and concomitant medication 
information will also be collected) up to disease progression or Week 52, whichever occurs 
first. If these subjects subsequently experience disease progression then they will continue to 
be followed up by telephone every 8 weeks from that point of identification and for a total 
observation period of 52 weeks, as described for subjects discontinued from study drug due to 
disease progression. 
Clinical assessments will be performed before the start of each treatment cycle by the Investigator. 
Tumour assessments for the purpose of assessing subject eligibility and medical care will be 
performed by the investigational site at Screening and Weeks 12, 28, and 52 (EOS/ET Visit). 
The primary endpoint is BORR, defined as the proportion of subjects in each treatment group that 
achieve a best overall response of either CR, CRu or PR up to Month 7 (Week 28, i.e., 6 months 
after completion of rituximab induction) based on central radiology review in accordance with the 
response criteria for malignant lymphoma.13 An exploratory analysis using the Lugano criteria14 
will also be performed as described in Section 3 and Section 9.4.1.3. 
Sparse PK sampling will be performed in a subset of approximately 90 subjects (approximately 45 
subjects per treatment group) (PK and pharmacodynamic subset) on Days 1, 8, 15, 22, and at Week 
12 (approximately 45 subjects per treatment group, these subjects will be included after they 
provide written consent for these evaluations) to facilitate a population-based PK approach using 
nonlinear mixed-effects modelling. At each of these visits, one sample will be taken prior to 
initiation of infusion (pre-dose or trough plasma concentration [Ctrough]) and a second sample will 
be taken immediately prior to the end of the infusion. Indicatively, Ctrough should be obtained within 
one hour prior to the start of infusion (but not after it has been started) and the sample prior to the 
end of infusion within 10 minutes prior to the end of infusion. In all cases the sampling time should 
be accurately recorded (date and time with hour and minutes). Should it not be possible to collect 
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the sample in the specified time frame, the sample should be anyway collected and the sampling 
date and time accurately (to hour and minutes) recorded.
The sampling date and time also needs to be accurately recorded for the samples obtained within 
the window period.
Separate samples for the pharmacodynamic marker, peripheral blood B-cell count, will be obtained 
in the same subset of subjects sampled for PK. These will be collected on the same days as the PK 
samples, as well as at Week 20, 28, 36, 44, and 52 visits, to facilitate a descriptive 
pharmacodynamic evaluation using the AUEC of B-cell depletion, B-cell counts at selected 
time-points, and optional population PK / pharmacodynamic modelling.
Samples for the evaluation of anti-rituximab antibodies (anti-drug antibodies [ADA]), including 
binding antibodies (BAb) and neutralising antibodies (NAb) will be obtained before the 
administration of study drug on Days 1 and 22. Additional samples for detection of BAb and NAb 
will be collected prior to study drug infusion at Weeks 8 and 28, as well as at the visits of Week 44 
and Week 52 (EOS/ET Visit). Analysis of BAb samples will follow a tiered approach of screening 
and confirmation. Samples that are confirmed positive for BAb will be further tested for titre and 
NAb determination using validated assays.
Safety endpoints are the incidence of reported AEs and changes in vital signs, clinical laboratory 
parameters and electrocardiogram (ECG) parameters.
4.1.2
Schedule of Assessments
An overview of the protocol visits and procedures is provided in Table 1–1. Refer to Section 8 for 
detailed information on each procedure and assessment required for compliance with the protocol.
The Investigator may 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. Unscheduled visits (including reason) will be collected in the electronic case report 
forms (eCRF).
4.2
Discussion of Study Design
This study is designed to demonstrate the equivalence of DRL_RI to MabThera® in subjects with 
previously untreated, Stage II-IV, CD20-positive, LTB-FL, as measured by ORR.
The study will enrol subjects with LTB-FL who are asymptomatic for lymphoma specific 
B-symptoms. LTB-FL will be assessed according to the GELF based criteria.9,16 
 
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.9,10,17 
13
13 
 
9,14
During the study, subjects will attend study visits every week (r2 days) during the Induction 
Treatment Period (Weeks 1 to 4), at Week 8 (r7 days), at Week 12 (± 7 days), thereafter every 
8 weeks (r7 days) up to Week 52 (EOS/ET Visit).
The dose of DRL_RI or MabThera® at 375 mg/m2 of BSA will be administered as an i.v infusion.
4.3
Scientific Rationale for Study Design
This study uses a double-blind design in order to avoid subjective influences in the study conduct 
and results evaluation. Random assignment is used to ensure balancing of external influences 
between the study arms.
The subject population and endpoint (BORR) have been chosen to provide an appropriate 
sensitivity to eventual differences in efficacy and safety of the DRL_RI and the reference product. 
The LTB-FL setting allows treatment with rituximab as a single agent, which maximises the 
sensitivity to differences in efficacy and safety between DRL_RI and the reference product due to 
the lack of interference by the effects of the concomitant therapies. The use of BORR as an 
endpoint also maximises sensitivity to differences in a reasonable time in this population, where 
the time to tumour growth is prolonged.
The current standard of care in advanced FL is rituximab in combination with chemotherapy. The 
indication for this study, anatomically defined, LTB, CD-20 positive FL, is a slow growing 
malignancy and rituximab monotherapy is an acceptable treatment option according to various 
treatment guidelines.3,4 The goal of treatment with rituximab monotherapy in LTB-FL is to relieve 
disease symptoms, to delay the time to treatments more difficult to tolerate such as chemotherapy, 
and to relieve anxiety related to disease.
Low tumour burden will be assessed according to the GELF based criteria.9,16A serum LDH level 
within normal limits will be required for enrolment as LDH is an important prognostic factor in 
FL.
4.4
Justification for Dose
The 375 mg/m2 of BSA is the dose of the RMP in clinical use for the treatment of follicular 
lymphoma. Thus, the same dose is maintained in order to allow a comparative evaluation of 
DRL_RI safety and efficacy with those of the reference product at the doses in current clinical use.
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4.5 End of Study Definition 
Subjects who complete the study or subjects who discontinue from the study early will attend an 
EOS/ET Visit. Subjects experiencing disease progression will discontinue study drug and attend 
the ET Visit, which is to be scheduled 8 weeks after the last dose of study drug administration. 
These subjects will then be contacted by telephone for information on survival, AEs, and 
concomitant medications (Section 4.5.1) every 8 weeks, for a total observation period of 52 weeks 
(Section 4.5.1). Subjects discontinued from study drug due to a reason other than disease 
progression will also attend the ET Visit scheduled 8 weeks after the last dose of study drug, and 
then will continue to attend scheduled tumour assessments (at which AE and concomitant 
medication information will also be collected) up to disease progression or Week 52, whichever 
occurs first, as described in Section 4.1.1. 
End of Study/Early Termination assessments are as follows: 
1. Clinical assessments will include the following: Physical examination (including weight), vital 
signs measurement (blood pressure, heart rate, respiration rate, and oral, axillary, or tympanic 
body temperature). 
2. Serum pregnancy test (human chorionic gonadotropin [hCG]) for women of childbearing 
potential. Female subjects with documented history of hysterectomy, bilateral oophorectomy, 
medically confirmed ovarian failure, or screening follicle stimulating hormone (FSH) test 
demonstrating post-menopausal status are exempted from pregnancy testing. 
3. ECOG performance status assessments. 
4. Clinical laboratory tests: Blood and urine samples will be taken for haematology, coagulation, 
biochemistry, and urinalysis. 
5. Serum LDH and β-2 microglobulin evaluation. 
6. 12-lead ECG (local ECG equipment with ECG to be read locally by a medically qualified and 
experienced ECG reader at the study site). 
7. Viral disease screening at the EOS Visit. 
8. Tumour assessments (using a computed tomography [CT] scan and, where available according 
to study site standard of care, a fluorine-18-fluorodeoxyglucose positron emission tomography 
[[18F] FDG-PET] or PET-CT scan) based on central radiology review in accordance with the 
response criteria for malignant lymphoma.13 
9. Samples for BAb and NAb will be obtained. 
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10. A pharmacodynamic sample will be obtained only in the subjects undergoing PK and 
pharmacodynamic assessments. 
11. Bone marrow biopsies are required for any subject who has a response of CR at an evaluation 
point and either had a bone marrow examination positive for FL at Screening or shows new 
abnormalities in the peripheral blood counts or blood smear that clinically indicates a bone 
marrow evaluation is required. 
12. Assess AEs. 
13. Review concomitant medications. 
14. COVID-19 questionnaire.  
4.5.1 
Telephone Assessments for Survival Follow-up 
The procedures will include the following: 
1. Check survival status. 
2. Record AEs and concomitant medications. 
4.5.2 
Early Termination of Study 
This study may be terminated prematurely at any time by DRL for medical, operational or ethical 
reasons at individual or all study sites. 
If the study is prematurely terminated or discontinued, the Sponsor/designee will promptly notify 
the Investigator, institutions and all competent regulatory authorities in writing outlining the 
reasons for the termination. The Investigator or Sponsor/designee 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. 
As directed by the Sponsor/designee, all study materials, except documents needed for archiving 
requirements, will be collected and all eCRFs completed to the greatest extent possible. 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. 
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4.5.3 
Definition of End of Study and Primary Completion Date 
End of Study is defined as the time at which all subjects enrolled in the study have been followed 
for 52 weeks unless lost to follow-up or the subject has died. The EOS is achieved at last subject 
last visit and when data from those visits have been reviewed by the Investigator or designee. 
Primary Completion Date is defined as the date that the final subject was examined or received an 
intervention for the purposes of final collection of data for the primary outcome, whether the 
clinical study concluded according to the pre-specified protocol or was terminated. For the 
purposes of analysis, the study will be unblinded to specified Sponsor/designee members (but not 
investigators or subjects) once all subjects have reached the primary endpoint through the end of 
Week 28 (or earlier termination of study drug), and the database is locked. 
For all those persons who will have access to the interim analysis unblinded data and results, will 
sign a confidentiality agreement in order to maintain study blind until the general unblinding 
happens after the final database lock. 
5 Study Population 
5.1 Inclusion Criteria 
A subject will be eligible for enrolment in the study if he/she meets all of the following criteria: 
1. Signed written informed consent. 
2. Male or female subjects aged ≥18 years of age. 
3. Histologically confirmed, Grade 1-3a, previously untreated, CD20-positive, LTB-FL as per 
GELF based criteria. Subjects must have sufficient tissue samples available for the central 
pathology review (Section 8.1.1), and a centrally -confirmed diagnosis prior to being 
randomised. Should a subject be eligible as per the central imaging review but not as per the 
Study Centre Review the subject will be considered eligible if confirmed both by the 
Investigator and the Medical Monitor (MM). For any other disagreement in eligibility the 
subject will be considered ineligible. 
4. Ann Arbor Stage II to IV (Section 10.1.14). 
5. ECOG status of 0 to 1. 
6. Low tumour burden follicular lymphoma defined as: 
x As per central radiological assessment, nodal or extranodal mass involvement with 
diameter measuring <7 cm 
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x As per central radiological assessment, involvement of ≤3 nodal sites with diameter 
measuring >3 cm 
x Absence of systemic symptoms or B-symptoms* (asymptomatic). 
*B-symptoms defined as weight loss >10% within last 6 months, recurrent or 
continuous night sweats, intermittent or continuous fever recorded as axillary or 
oral temperature >38°C for at least 3 days 
x As per central radiological assessment, absence of splenomegaly (defined as spleen 
size higher than 16 cm by CT scan) 
x Absence of risk of vital organ compression based on clinical finding 
x Absence of leukemic phase (leukemic phase defined as a count >5,000/μL of 
circulating tumour cells) 
x Absence of clinically significant cytopenias (defined as a platelet count of 
<100,000/μL, haemoglobin <10 g/dL, or absolute neutrophil count <1,500/μL) 
x Absence of clinically significant serous effusion based on clinical examination and 
CT scan 
x Serum LDH not higher than the upper limit of normal (ULN) by local laboratory. 
7. Subject has at least 1 measurable tumour mass in 2 dimensions as per central radiological 
assessment, and the mass must be: 
x Nodal lesion >15 mm in the longest dimension; or 
x Nodal lesion >10 mm to ≤15 mm in the longest dimension and >10 mm in the 
shortest dimension; or 
x Extranodal lesion with both long and short dimensions ≥10 mm. 
8. Creatinine clearance ≥45 mL/min as calculated by Cockcroft-Gault method. 
9. Aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) 
values ≤3 × ULN, total or conjugated bilirubin values ≤1.5 × ULN. 
10. Life expectancy ≥3 months. 
11. Able to comply with the study protocol. 
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12. If female subject, then subject should be non-pregnant, non-lactating. Adequate contraception 
or post-menopausal/non-childbearing status (e.g., women with cessation of menstruation for ≤ 
2 years, peri-menopausal women with inconclusive menopausal evidences based on clinical 
assessment and medical history). Women of childbearing potential must practice effective birth 
control for the duration of the study and for 12 months after the last study drug dose. For this 
same duration, male subjects participating in the study should avoid passing the semen to 
female partners during sexual intercourse. 
5.2 Exclusion Criteria 
Subjects meeting any of the following criteria must not be enrolled in the study. 
1. Prior use of rituximab or any CD20 mAb for any reason. 
2. Any contraindication to the use of rituximab. 
3. Any prior therapy for FL (including but not limited to chemotherapy, radiotherapy). 
4. Subjects who, in the opinion of the Investigator, require additional concomitant treatment for 
lymphoma. 
5. Evidence of histologic transformation to high grade lymphoma or DLBCL. 
6. Known Central Nervous System (CNS) involvement by lymphoma. (Note: CNS imaging not 
required unless clinically indicated). 
7. Subjects on chronic supra-substitutive doses (defined as doses in excess of 7.5 mg per day of 
prednisone or prednisone equivalent for a period longer than 3 weeks) of systemic 
glucocorticoids. 
8. Prior malignancy (including recurrence) within 5 years of screening, other than non-melanoma 
skin cancer or intraepithelial cervical neoplasia, which should have been successfully treated 
more than 1 year before study inclusion. 
9. Subjects with any of the following: known seropositivity for or history of active viral infection 
with human immunodeficiency virus (HIV). 
10. Subjects with positive serological test for hepatitis B surface antigen (HBsAg), hepatitis B core 
antibody (HBcAb) or hepatitis C virus (HCV) antibody can only be included in the study if 
any of the following is fulfilled.18,19 
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a. Subjects with a negative HBsAg and positive total HBcAb must have a HBV 
deoxyribonucleic acid (DNA) level <20 IU/mL (or 112 copies/mL) by polymerase 
chain reaction (PCR) to participate in the study. In addition, it is required for these 
subjects to follow consultation with a Hepatologist / relevant expert regarding 
initiation, monitoring, and use of HBV antiviral therapy and the subject must be 
willing to undergo PCR HBV DNA testing during treatment and agree to receive 
treatment as indicated. HBV DNA re-test will be performed as per the schedule of 
assessments (see Table 1–1) and further as needed, at the discretion of the Investigator.  
b. Subjects with a positive test because of HBV vaccination may be included (i.e., HBsAg 
negative, anti-HBs+, HBcAb–).  
c. Subjects positive for HCV antibody are eligible only if the PCR test for HCV 
ribonucleic acid (RNA) is negative.  
11. 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 drug (Day 1). If latent TB is suspected based on clinical or epidemiological 
grounds, it should be further investigated using the tuberculosis testing as appropriate 
following local practice or investigator judgment. 
12. Subjects who have received a live vaccine within last 3 months or non-live vaccine within 4 
weeks of the first administration of study drug. [Note: A need may arise for trial subjects to 
receive vaccine against COVID-19 while being a part of the study. All such decisions will be 
taken at the discretion of the Investigator in consultation with the CRO / Sponsor after due 
consideration to subjects’ safety, national health policy of the respective country and overall 
need by the subject for such vaccine during the time of study participation].. 
13. Subjects with an active uncontrolled infection requiring systemic treatment at Screening or 
history of documented recurrent clinically significant infection within 6 months of study 
inclusion (e.g., 2 or more viral, bacterial or fungal infections requiring in-patient treatment). 
14. Subjects with New York Heart Association (NYHA) class III or IV congestive heart failure or 
relevant arrhythmia or angina based on ECG with clinical judgment. 
15. Subjects with known hypersensitivity to rituximab or its excipients, or to proteins of murine or 
other foreign origin. 
16. History or presence of a medical condition or disease that in the Investigator's opinion would 
place the subject at an unacceptable risk for study participation. 
17. Participation in any clinical study or having taken any investigational therapy during the 
2-month period immediately preceding administration of the first dose of study drug. 
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18. Lactating or pregnant female. 
19. Women of childbearing potential who do not consent to use highly effective methods of birth 
control (e.g., sterilisation, or other non-hormonal forms of contraception) during treatment and 
for at least 12 months after the last administration of study drug. True abstinence periodic 
abstinence (e.g., calendar ovulation, symptothermal, post ovulation methods) and withdrawal 
are not acceptable methods of contraception. 
20. Subject has been previously randomised in this study. 
21. Subject likely not to be available to complete all protocol required study visits or procedures. 
5.3 Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently randomly assigned to study drug/entered in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond 
to queries from regulatory authorities. Minimal information includes demography, screen failure 
details (reason[s] for the screening failure), eligibility criteria, and any serious adverse events 
(SAEs). 
Individuals 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 MM. 
Subjects not included in the study due to latent TB (in the locations where TB screening is required) 
will also require rescreening after appropriate treatment has been administered as per local 
Guidance. 
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6
Study Intervention
6.1
Identity of Study Treatments
DRL_RI or MabThera® will be provided as study medication to the participating study sites.
6.2
Study Drugs Administered
This study is a randomised, double-blind, parallel-group, clinical study.
A computer-generated randomisation schedule will be used to assign subjects to the treatment 
groups. Subjects will be assigned a subject number in the order of their acceptance into the study. 
This identifying number will be retained throughout the study.
Following signing of informed consent, subjects will be registered into the study using an 
interactive web response system (IWRS) to receive a unique subject identification number. 
Randomisation will be performed using IWRS. Subjects will be randomised in a 1:1 ratio to one 
of the 2 study treatment arms taking into account stratification by low-, medium-, and high-risk 
subjects using the 
 index (
), 
), tumour grade (1-2 Vs. 3a; i.e., subjects with 
Grade 1 tumours should be pooled with those with Grade 2 tumours, resulting in 2 levels for this 
factor), and geographical area (USA, Europe and Asia-Pacific region):
x
Arm A: 
DRL_RI
x
Arm B: 
MabThera®
The study drug DRL_RI or MabThera® will be administered as an intravenous (i.v) infusion, at a 
dose of 375 mg/m2 of BSA.
Subject BSA will be calculated using an accepted formula. The Mosteller, Du Bois, and Haycock 
formulae are considered acceptable. The same formula should be used for the calculation of all 
doses administered to the same subject.
Mosteller formula20:
BSA(m2) = √([Height{cm} x Weight {kg}]/3600)
Du Bois formula21:
BSA(m2) = 0.007184 x Height (cm)0.725 x Weight (kg)0.425
Haycock formula22:
BSA(m2) = Weight (kg)0.5378 x Height (cm)0.3964 x 0.024265
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Subjects will receive induction treatment consisting of 4 weekly i.v infusions followed by 
maintenance treatment consisting of an i.v infusion every 8 weeks up to Week 36. Subjects will be 
pre-medicated before each infusion with an anti-pyretic and an antihistamine (e.g., paracetamol 
[acetaminophen] and diphenhydramine), and 100 mg i.v methylprednisolone or their equivalent to 
decrease the incidence and severity of acute IRRs. 
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 every 30 minutes, to a maximum of 400 mg/hour. 
Subsequent Infusions: 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. 
Infusions should be administered under close medical supervision. The infusion should be 
interrupted, or the infusion rate slowed for infusion reactions. If symptoms improve the infusion 
rate can be continued at one-half the previous rate. 
The schedule of dosing is presented in Section 1.2. 
6.2.1 
Study Drug Infusion Preparation 
Study drug (DRL_RI or MabThera®) solutions for infusion will be prepared by an unblinded 
pharmacist/authorised designee/unblinded qualified physician in this study. Unblinded 
pharmacist/authorised designee/unblinded qualified physician should use aseptic techniques 
appropriate to parenteral administration products. 
Study drug will be administered by i.v infusion by blinded study personnel. Study drug vials and 
prepared solutions should be inspected visually for particulate matter and discoloration prior to 
administration. Do not use vials if particulates or discoloration are present. 
6.2.2 
Pre-Medication for Study Drug Infusions 
All subjects should receive pre-medication with 100 mg i.v methylprednisolone or their equivalent 
to be completed at least 30 minutes prior to rituximab infusions to decrease the incidence rate and 
severity of acute IRRs. Pre-medication consisting of an anti-pyretic and an antihistamine (e.g., 
paracetamol [acetaminophen] and diphenhydramine), should always be administered before each 
infusion of rituximab. 
Acute IRRs are most often observed during the first infusion of rituximab. Any reduction in use of 
pre-medications during subsequent infusions must be in compliance with local labelling and 
regulation. 
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6.2.3 
Study Drug Administration 
Study drug (DRL_RI or MabThera®) will be administered by i.v infusion using the escalating 
infusion rate in accordance with the EMA approved labelling for MabThera®. The infusion rate 
must be well controlled to reduce the incidence of serious IRRs. 
Only qualified personnel who are familiar with procedures that minimise undue exposure to them 
and to the environment should undertake the preparation, handling, and safe disposal of study 
drugs. 
The study drug infusion must be administered in the presence of the Investigator/medically 
qualified study site staff (to enable compliance), and in an environment where full resuscitation 
facilities are immediately available. Vital signs will be monitored every 30 minutes during the 
course of the treatment administration and at the end of infusion or more frequently as necessary. 
The study drug will be administered at a dose of 375 mg/m2 of BSA. Subjects will receive 
induction treatment consisting of weekly i.v infusions for 4 weeks, followed by maintenance 
treatment consisting of an i.v infusion every 8 weeks from Week 12 up to Week 36. 
The instructions below should be followed in conjunction with the local product labelling if it 
differs from these instructions. An electronic infusion pump is required to be used. 
x 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 every 30 minutes, to a maximum of 
400 mg/hour. 
x Subsequent Infusions: 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. 
x Subjects should be closely monitored for the onset of cytokine release syndrome. Subjects who 
develop evidence of severe reactions, especially severe dyspnoea, 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 
relating to the infusion reaction. At this time, the infusion can be initially resumed at not more 
than one-half the previous rate. If the same severe adverse reactions occur for a second time, 
the decision to stop the treatment should be seriously considered on a case by case basis. 
x 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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Medication errors may result in this study from the administration of the wrong drug, by the wrong 
subject, at the wrong time, or at the wrong dosage strength.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, including:
x
Medication errors involving subject exposure to the study drug;
x
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, 
medication error should be captured on the medication error section of the AE page and, if 
applicable, any associated AE(s) captured on an AE eCRF page. All medication errors should be 
reported to the Sponsor’s designated safety services and MM within 24 hours of awareness as 
described in Section 8.4.2. Expedited reporting of medication error/infusion error to regulatory 
authorities will be based on the local regulatory requirements.
Whenever the infusion is interrupted, the stop time and restart time should be recorded (with date, 
hour and minutes) along with initial start and final end time. Rates of infusion throughout should 
be recorded.
6.3
Preparation/Handling/Storage/Accountability
6.3.1
Packaging
DRL_RI and MabThera® will be supplied as sterile, preservative-free, non-pyrogenic, single-use 
vials 
.
Each vial of DRL_RI will contain 100 mg unit dose of DRL_RI in 10 mL single-use vial or 500 mg 
unit dose of DRL_RI in 50 mL single-use vial.
Each vial of MabThera® will contain 100 mg unit dose of MabThera® in 10 mL single-use vial or 
500 mg unit dose of MabThera® in 50 mL single-use vial.
These rituximab concentrates for solution for infusion will be supplied packaged as blinded 
supplies in the external packaging (carton) for all products identified with a unique container 
number. The external packaging (carton) of DRL_RI 100 mg/10 mL and MabThera® 
100 mg/10 mL will appear identical. Similarly, the external packaging (carton) of DRL_RI 
500 mg/50 mL and MabThera® 500 mg/50 mL will appear identical.
Each blinded carton will contain 1 vial of study medication, either DRL_RI 100 mg/10 mL or 
MabThera® 100 mg/10 mL for the 10 mL vial size, or either DRL_RI 500 mg/50 mL or 
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MabThera® 500 mg/50 mL for the 50 mL vial size. Each carton will be packaged with a tamper-
resistant seal. The Sponsor/designee must be notified of any study medication in which the tamper-
resistant seal has been broken and this medication should not be used.
6.3.2
Labelling
Medication labels will comply with the legal requirements of each country and be printed in the 
local language (where applicable). They will not disclose the unblinded study drug information.
6.3.3
Storage
All drug supplies for this study must be stored according to labelled storage conditions (2ºC to 
8ºC). The Investigator, or an approved representative (e.g., unblinded pharmacist), will ensure that 
all study drug is stored in a secured (locked) area with restricted access, and in accordance with 
applicable regulatory requirements.
Drug should be stored in accordance with the drug label. Investigators and study site staff are 
reminded to check and record minimum and maximum temperatures daily (i.e., manually or by 
using alarm systems to alert of any excursions) and ensure that refrigerators and thermometers 
(periodically validated) and are working correctly as required for proper storage of study drugs. 
Any temperature excursions should be reported to the Sponsor/designee immediately.
The study drugs must be stored as indicated. Deviations from the storage requirements, including 
any actions taken, must be documented and reported to the Sponsor/designee immediately. Once 
a deviation is identified, the study drug must be quarantined and not used until the 
Sponsor/designee provides documentation of permission to use the study drug.
6.4
Measures to Minimise Bias: Randomisation and 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.
After written informed consent is obtained from an eligible subject, a unique subject number will 
be assigned to this subject. This number will be created and allocated by the IWRS, when the 
subject first enters the system at Screening.
The randomisation codes will be computer-generated and kept by a statistician independent from 
the project team. Randomisation will be stratified by low, medium, and high-risk subjects using 
 (
), as well as by tumour grade (1-2 Vs. 3a) and geographical area (USA, 
Europe and Asia-Pacific region).
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Randomisation methods will be fully described in the Randomisation Plan specification document. 
Subjects who are eligible for randomisation will be assigned a unique randomisation number at 
the Baseline (Day 0 to Day 1) Visit by IWRS. This randomisation number identifies which 
treatment will be allocated to the subject and will be used to identify randomised subjects during 
the study. Subjects who withdraw after randomisation are not to be replaced and their 
randomisation number will not be re-used. 
Dispensing of study drug will be coordinated by IWRS. The system will assign study drug 
corresponding to the randomisation arm. Due to the study drug not being identical in appearance, 
methods to maintain the blind of the study drug during dispensing and administration will be 
employed. 
6.4.1 
Procedure for Unblinding 
The study site Investigator and appropriate project team members will be authorised to access the 
emergency unblinding functionality within the IWRS. The system will require the user to confirm 
if it is medically necessary to break the randomisation code 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 drug 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 IWRS. If time allows, 
the Investigator may contact the Sponsor designee MM 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 
unblinded 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 the end of the study. Once a 
randomisation code has been broken for a subject, he/she must be withdrawn from the study. The 
Investigator must inform the Sponsor designee MM in writing within 24 hours. An SAE form 
should be completed and reported in accordance with Section 8.4.2. 
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6.5 Study Intervention Compliance 
Study drug will be administered under the supervision of the Investigator and study site personnel. 
At investigational site all activities related to handling of study drugs till administration to a subject 
should be performed by unblinded pharmacist/authorised designee/unblinded qualified physician. 
This person should be assigned by the Principal Investigator of a site and be responsible for: 
x receipt of study drugs, 
x storage of study drugs, 
x dispensing of study drugs, 
x preparation of study drugs for infusion, 
x accountability and reconciliation of study drugs, 
x preparation of study drugs for destruction (used, expired, not fit to use, unused after last subject 
last treatment). 
Unblinded pharmacist/authorised designee/unblinded qualified physician will provide study drug 
to other investigators at a site after its dilution (as required by applicable instruction) ready for 
administration by means of infusion system. 
Nobody except unblinded pharmacist/authorised designee/unblinded qualified physician among 
site’s staff should be in contact with vials of study drugs – that keeps blinded design of the study. 
Unblinded pharmacist/authorised designee/unblinded qualified physician may not be in direct 
contact (may not treat/administer study drug) subjects enrolled in the study. 
It is expected that at each investigational site there should be 2 unblinded pharmacist/authorised 
designee/unblinded qualified physician – to ensure appropriate handling of study drugs while 
absence of one of the unblinded person (e.g., due to vacation). 
Compliance will be monitored by study personnel at the study site by using the source documents 
and the eCRFs. The unblinded pharmacist/authorised designee/unblinded qualified physician 
responsible for drug preparation will keep accurate and complete dispensing and accountability 
forms showing the receipt and dispensation of the study drug. 
6.6 Study Treatment Accountability 
Records will be maintained of the delivery of study drugs to the study centres, the inventory at the 
study centres, the use of each subject and the return to the Sponsor/designee. 
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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 drug specified by the IWRS and that all study medication 
received from the Sponsor/designee is reconciled. 
6.7 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 screening are regarded as prior 
medication and must be documented as such in the eCRF. 
All medications still being taken by a subject at the time of signing the Informed Consent Form 
(ICF) and which continue to be taken during the study, as well as all medications started after 
signing of the ICF, are regarded as concomitant medication and must be documented as such in 
the eCRF. The use of concomitant therapy, including prescription and non-prescription drugs, non-
drug therapy, and dietary supplements and herbal preparations, is permitted as appropriate to treat 
AE or co-morbid conditions. Concomitant administration of any other experimental drug or a 
concomitant chemotherapy, anticancer hormonal therapy, radiotherapy, or immunotherapy is 
prohibited during study participation. This includes administration of rituximab not included in the 
protocol scheduled treatment. If a subject requires tumour targeting treatment for FL other than the 
protocol-defined treatment with rituximab monotherapy, including, but not restricted to, other 
immunotherapies, chemotherapy, and radiotherapy, this will be defined as disease progression. The 
date the concomitant treatment was initiated will be collected in the eCRF. 
Any other medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the subject is receiving at the time of enrolment or receives during 
the study must be recorded along with: 
x reason for use 
x dates of administration including start and end dates 
x dosage information including dose and frequency 
The MM should be contacted if there are any questions regarding concomitant or prior therapy. 
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During their participation in the study, subjects should not take any prescription or 
non-prescription drug without the permission of the Study Investigator. However, the permission 
of the Study Investigator should be waived for medical emergencies. 
6.8 Dose Modification or Delays 
Dose modification is not allowed in the study. All subjects will receive the recommended dose of 
375 mg/m2 of BSA. 
During the Induction Treatment Period, window period of ± 2 days from scheduled date of dosing 
will be allowed. The subsequent cycles would be administered so as to maintain a 7-day cycle, 
thus ensuring the 7-day gap between these dose administrations. 
During the Maintenance Treatment Period, window period of ± 7 days from scheduled date of 
dosing will be allowed. The subsequent cycles would be administered so as to maintain the 
required gap between successive doses. 
Any delays beyond what is mentioned above should be discussed in detail. If the out of window 
visit is on account of an adverse event or for safety related reasons, discussion with Medical 
Monitor (MM) is required, hence please contact your CRO MM under these circumstances. And 
if any social / other reasons lead to an out of window visit, then please document the reason for 
visit delay by adding a note/ short description in eCRF. Every out of window visit (irrespective of 
the reason) should be documented as a deviation. 
6.9 Study Medication Access after the End of the Study 
The study drug DRL_RI will not be available after the completion of the study. MabThera® can be 
procured from the market. 
6.10 Guidance for Hepatitis B and Hepatitis C Seropositive Subjects  
Subjects who show evidence of prior hepatitis B infection may participate in the study following 
consultation with a Hepatologist / relevant expert regarding monitoring and use of HBV antiviral 
therapy, and provided that subjects agree to receive and comply with HBV testing and hepatitis B 
prophylactic therapy as recommended by the Investigator, or treating Hepatologist, or relevant 
expert. HBV re-test will be performed as per schedule of assessment (see Table 1–1) and further 
at the discretion of the Investigator. 18,19 
Additional monitoring/management of subjects who had HCV antibody positive (and HCV RNA 
negative) at Screening should be done in accordance with local practice and standard of care. 
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Subjects will continue to receive HBV antiviral prophylaxis therapy for at least 12 months post 
last dose of rituximab in the study (i.e. 36 weeks, or earlier in case of ET), and will be monitored 
as recommended by hepatitis experts in accordance with local practice and guidelines. HBV 
reactivation will be monitored and reported for up to 24 months following completion of rituximab 
therapy. If any subject develops reactivation of HBV or any other significant infections while on 
rituximab, the Investigator should immediately discontinue study drug, consult with hepatitis 
experts, and institute appropriate treatment. For details and management of other infections, refer 
to the current marketed rituximab prescribing information. It will be the Investigator’s 
responsibility to ensure compliance to the antiviral treatment, regular follow-up for monitoring 
(i.e. laboratory tests, clinical examination, AE evaluation) with the Hepatologist / relevant expert 
of hepatitis B seropositive subjects and reporting of any reactivation events to the Sponsor 
immediately during and post study follow-up period of 24 months post last dose of rituximab. The 
investigator has to periodically update to the Sponsor about all such follow-up visits, treatment 
compliance with antiviral and other medications, tests results, and hepatitis B reactivation for up 
to 24 months post last study dose of rituximab. Detailed procedure and the needed documentation 
to ensure compliance to post study follow-up and measures will be outlined in an amended study 
agreement between the Sponsor / Designee and the Investigator. 
Post study period of 52 weeks, all safety related events to be reported directly to the Sponsor’s 
e mail address: pharmacovigilance@drreddys.com. 
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7 Discontinuation of Study Intervention and Subject Discontinuation 
7.1 Discontinuation of Study Intervention 
If new clinically significant findings occur, the Investigator should recheck that the continuation 
of the study intervention is allowed by the study protocol and is in the best interest of the subject. 
If the new findings met a protocol requirement for withdrawing the study intervention or the 
Investigator considers that the risk-benefit ratio of continuing the study intervention for the 
individual subject is not any longer favourable, the study intervention should be discontinued. 
Refer to the Schedule of Assessments for data to be collected at the time of study intervention 
discontinuation and follow-up and for any further evaluations that need to be completed. 
7.1.1 
Temporary Discontinuation 
Temporary discontinuations should only be done for legitimate medical reasons. 
7.1.2 
Rechallenge 
Based on the best interest of the subject, treatment may be restarted at the recommended dose of 
375 mg/m2 of BSA. 
7.2 Subject Discontinuation/Withdrawal from the Study 
Subjects may withdraw from the study at any time at their own request, or they may be withdrawn 
at any time at the discretion of the Investigator or Sponsor/designee for safety, behavioural, 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 or 
is lost to follow-up, every effort will be made to contact the subject. All attempts to contact the 
subject and information received during contact attempts must be documented in the subject’s 
medical record. In any circumstance, 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 52) Visit, if applicable, and follow-up with the subject regarding 
any unresolved AEs. The Investigator or sub-investigator will be responsible for reporting subject 
withdrawal to the Sponsor/designee. Subjects who withdraw after randomisation are not to be 
replaced and their randomisation number will not be re-used. If these subjects subsequently 
experience disease progression, then they will continue to be followed up as described in 
Section 4.1.1. 
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If a subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no additional data should be collected. The Sponsor/designee may retain and continue 
to use any data collected before such withdrawal of consent. 
Subjects shall be withdrawn during the course of the study when subject well-being is at risk, 
including but not limited to: 
x Unacceptable AE. 
x Subject is confirmed to be pregnant. 
Subjects who experience disease progression in accordance with published response criteria for 
malignant lymphoma 13 (per Investigator assessment) are expected to be withdrawn from study 
drug, to attend the ET Visit, and to be followed up by telephone for survival as described in 
Section 4.1.1. Subjects who wish to remain in the study but withdraw from the study drug for any 
reason other than disease progression will return for an ET Visit and continue to attend scheduled 
tumour assessments up to disease progression or Week 52, whichever occurs first. 
7.3 Loss of Subjects to Follow-Up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
x The site must attempt to contact the subject and reschedule the missed visit as soon as possible 
(and within the visit window, where one is defined) and counsel the subject on the importance 
of maintaining the assigned visit schedule and ascertain whether or not the subject wishes to 
and/or should continue in the study. 
x In cases in which the subject is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the subject (where possible, 3 telephone calls and, if 
necessary, a certified letter to the subject’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the subject’s medical record/eCRF. 
x Should the subject continue to be unreachable, he/she will be considered as have been lost to 
follow-up. 
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8 Study Assessments and Procedures 
8.1 Study Assessments 
For each study visit (except the Screening Visit) the subject will enter the study site in the morning 
and remain until approximately mid-afternoon. The designated study site personnel will take the 
appropriate blood samples from the subject, for various assessments, as indicated in the following 
sections. After the blood draws for the Baseline Visit (Day 0 to Day 1), subjects will receive the 
treatment i.v infusions in the presence of the designated study site personnel at each of the 
designated Induction Treatment Period (Weeks 1 to 4 [r2 days]) and Maintenance Treatment 
Period visits (Week 12 [r7 days], and every 8 weeks [r7 days] up to Week 36). Thereafter, subjects 
will continue to attend visits every 8 weeks (r7 days) in the Follow-up Period up to Week 52. A 
study physician will be available during treatment infusions to ensure subject safety in the event 
of an infusion-related reaction (IRR). 
Computed tomography scans are required to determine subject care by the Investigator and allow 
central vendor assessment of the primary endpoint (BORR) using criteria as outlined in Section 3. 
For modern imaging equipment, where the CT component attached to a PET-CT scanner is 
equivalent to that of a standard CT, a PET-CT scan is also suitable for assessment of the primary 
endpoint. The CT portion for such a combined PET-CT scan should be of diagnostic quality as a 
standalone CT scan in terms of i.v contrast, noise and anatomical coverage across all visits. The 
same modality (CT or PET-CT) for an individual subject should be consistently used throughout 
the study evaluations. PET scans alongside conventional CT scans provide both an indication of 
pathological metabolic activity and precise anatomic location of tumour tissue, and are required to 
assess BORR using the more recent Lugano criteria.14 Hence, where available as standard of care, 
all subjects should receive both PET and CT imaging to allow central vendor assessment of the 
primary and other efficacy endpoints. 
8.1.1 
Screening (Day ˗35 to ˗1) 
Subjects will undergo a Screening Visit at least 0 days, but not more than 35 days prior to the 
planned first day of blinded study drug. 
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 informed consent 
must be obtained from each subject prior to the conduct of any protocol-specific procedures. 
Screening procedures and assessments will be as follows: 
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The assessments are suggested to be conducted in the following chronological order.
1. Completion of a COVID-19 related screening questionnaire.
2. Obtain Informed Consent using a written ICF from the subject in accordance with local 
regulations.
3. Register screening of the subject using the IWRS.
4. Review subject eligibility (inclusion and exclusion criteria) with central confirmation of 
histopathology.
5. Assessment of subject stratification status based on n 
 criteria (
), 
), tumour 
grade, and geographical area.
6. Histological confirmation of diagnosis (subjects can be screened for the study based on a 
diagnosis of CD20-positive, low burden FL confirmed at the investigational site). Subjects 
must have sufficient tissue samples available for the central pathology review (obtained on or 
within 12 months prior to the screening date), and a centrally-confirmed diagnosis prior to 
being randomised.
7. Document medical and oncology history.
8. Document subject demographics.
9. Clinical assessments will include the following: Physical examination (including a thorough 
assessment of the lymph nodes, liver, spleen, height and weight), vital signs measurement 
(blood pressure, heart rate, respiration rate, and oral, axillary, or tympanic body temperature).
10. Serum pregnancy test (hCG) for women of childbearing potential. Female subjects with 
documented history of hysterectomy, bilateral oophorectomy, medically confirmed ovarian 
failure, or screening FSH test demonstrating post-menopausal status are exempt from 
pregnancy testing.
11. ECOG performance status assessments.
12. Clinical laboratory tests: Blood and urine samples will be taken for haematology, biochemistry, 
coagulation, and urinalysis.
13. Serum LDH and β-2 microglobulin evaluation.
14. TB screening (performed locally, if required by local regulation or practice).
15. Viral disease screening: HBsAg, HBcAb, HBV DNA (as applicable), HCV Ab, HCV RNA (as 
applicable), and HIV.
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16. 12-lead ECG (local ECG equipment with ECG to be read locally by a medically qualified and 
experienced ECG reader at the study site). 
17. Record prior and ongoing medications. 
18. Tumour assessments based on central radiology review of images from a CT scan and, where 
available according to study site standard of care, a [18F] FDG-PET or PET-CT scan. PET scans 
acquired up to 6 weeks prior to Day 1 may be used for screening provided they are of adequate 
quality for central imaging review. 
19. Bone marrow biopsy (if no previous biopsy within the last 12 weeks before dosing is available). 
Procedures can be performed locally. 
8.1.2 
Treatment Period (Day 1 to Week 36) 
Induction Treatment Period (Study Days 1, 8, 15, and 22 [Week 1 to Week 4 ± 2 days]) 
Subjects will attend study visits every week (r2 days) during the Induction Treatment Period at 
Weeks 1 to 4 ± 2 days. 
Samples for the evaluation of ADA including BAb and NAb will be obtained on Days 1 and 22 
before the start of the study drug infusion on the corresponding day. 
Subjects will be pre-medicated before each infusion with acetaminophen, diphenhydramine, and 
100 mg i.v methylprednisolone or their equivalent to decrease the incidence and severity of acute 
IRRs. 
Baseline Visit (Day 0 to Day 1, prior to randomisation and administration of study drug) 
Eligible subjects will return to the study site for the Baseline (Day 0 to Day 1) Visit. Subjects must 
satisfy inclusion/exclusion criteria in order to be eligible for randomisation. Before randomisation 
of the subject, all the baseline assessments must be reviewed by the investigators for suitability of 
starting study treatment. 
Baseline procedures and assessments are suggested to be conducted in the following chronological 
order: 
1. Completion of a COVID-19 related screening questionnaire. 
2. COVID-19 testing (RT-PCR, Rapid Antigen test or test with similar nature antigen test but no 
antibody test) to be performed as close as possible but no more than 4 days before first dose 
administration. Thus, COVID-19 testing may also be performed during the last few days of the 
screening window, ensuring maximum time gap of 4 days between first dose of the study drug 
and COVID-19 testing. 
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3. Re-review subject eligibility (inclusion and exclusion) criteria based on the screening 
assessment to ensure that the subject continues to be eligible for inclusion into the study. 
4. Clinical assessments will include the following: Physical examination (at discretion of the 
Investigator, but including weight), vital signs measurement (blood pressure, heart rate, 
respiration rate, and oral, axillary, or tympanic body temperature). 
5. Urine or serum pregnancy test for women of childbearing potential (performed locally, 
according to local practice). 
6. ECOG performance status. 
7. Clinical laboratory tests: Blood and urine samples will be taken for haematology, biochemistry, 
coagulation, and urinalysis. 
8. Serum LDH and β-2 microglobulin evaluation. 
9. Samples for immunogenicity assessments (BAb and NAb) prior to administration of study drug 
infusion. 
10. Randomise the subject in accordance with the IWRS. 
11. Randomisation in IWRS and administration of first dose of study medication should take place 
on the same day and this will be considered as Day 1. 
Baseline Visit (Day 0 to Day 1, following randomisation) 
Baseline procedures and assessments are suggested to be conducted in the following chronological 
order: 
1. Pharmacokinetic samples will be taken; one sample prior to initiation of infusion (pre-dose or 
Ctrough) and a second sample immediately prior to the end of the infusion (only in subjects 
undergoing PK and pharmacodynamic assessments). 
2. A separate pharmacodynamic sample will be taken prior to initiation of infusion and a second 
sample immediately prior to the end of the infusion (only in subjects undergoing PK and 
pharmacodynamic assessments). 
3. Study drug administration. 
4. Assess AEs. 
5. Record concomitant medications. 
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Study Days 8, 15 and 22 (Week 2 to Week 4 ± 2 days) 
The procedures and assessments for the Induction Treatment Period are as follows: 
1. Completion of a COVID-19 related screening questionnaire. 
2. Clinical assessments will include the following: Physical examination (at discretion of the 
Investigator, but including weight), vital signs measurement (seated blood pressure, heart rate, 
respiration rate, and oral, axillary, or tympanic body temperature). 
3. ECOG performance status. 
4. Urine or serum pregnancy test (performed locally, according to local practice). 
5. Clinical laboratory tests: Blood and urine samples will be taken for haematology, biochemistry, 
coagulation, and urinalysis. 
6. Serum LDH and β-2 microglobulin evaluation. 
7. Day 22 Only: Samples for BAb and NAb will be obtained before the infusion of study drug. 
8. Pharmacokinetic samples will be taken; one sample prior to initiation of infusion (pre-dose or 
Ctrough) and a second sample immediately prior to the end of the infusion on Days 8, 15, and 
22 (only in subjects undergoing PK and pharmacodynamic assessments). 
9. Separate pharmacodynamic samples will be taken prior to initiation of infusion (pre-dose, only 
in subjects undergoing PK and pharmacodynamic assessments) on Days 8, 15, and 22. 
10. Study drug administration. 
11. Assess AEs. 
12. Review concomitant medications. 
Week 8 ±7 days 
The procedures and assessments for Week 8 ±7 days are as follows: 
1. Completion of a COVID-19 related screening questionnaire. 
2. Clinical assessments will include the following: Physical examination (at the discretion of the 
Investigator), vital signs measurement (seated blood pressure, heart rate, respiration rate, and 
oral, axillary, or tympanic body temperature). 
3. ECOG performance status. 
4. Clinical laboratory tests: Blood and urine samples will be taken for haematology, biochemistry, 
coagulation, urinalysis, and pregnancy tests. 
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5. Serum LDH and β-2 microglobulin evaluation. 
6. Samples for BAb and NAb will be obtained. 
7. Assess AEs. 
8. Review concomitant medications. 
Maintenance Treatment Period (Week 12 to Week 36 ± 7 days) 
Subjects will attend the study visit at Week 12 ± 7 days, and thereafter every 8 weeks (r7 days) 
until Week 36. The subjects will attend the study site preferably from the morning until 
approximately mid-afternoon. 
The procedures and assessments for the Maintenance Treatment Period are as follows: 
1. Completion of a COVID-19 related screening questionnaire. 
2. Clinical assessments will include the following: Physical examination (at the discretion of the 
Investigator, but including weight), vital signs measurement (blood pressure, heart rate, 
respiration rate, and oral, axillary, or tympanic body temperature). 
3. ECOG performance status assessments. 
4. Urine or serum pregnancy test (performed locally, according to local practice). 
5. Clinical laboratory tests: Blood and urine samples will be taken for haematology, biochemistry, 
coagulation, and urinalysis. 
6. At Week 28 Only: Samples for BAb and NAb will be obtained before the infusion of study 
drug. 
7. Serum LDH and β-2 microglobulin evaluation. 
8. Viral disease screening: HBV DNA (as applicable) and HCV RNA (as applicable). 
9. At Week 12 and 28 only (Month 3 and Month 7, i.e. 2 and 6 months after completion of 
rituximab induction) tumour assessments (using a CT scan and, where available according to 
study site standard of care, a [18F]FDG-PET or PET-CT scan) based on central radiology 
review in accordance with the response criteria for malignant lymphoma.13 Subjects who have 
withdrawn from study drug for any reason other than disease progression will also undergo 
tumour assessment at Week 28. 
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10. Bone marrow biopsies are required for any subject who has a response of CR at an evaluation 
point and either had a bone marrow examination positive for FL at Screening or shows new 
abnormalities in the peripheral blood counts or blood smear that clinically indicates a bone 
marrow evaluation is required. 
11. Pharmacokinetic samples will be taken; one sample prior to initiation of infusion (pre-dose or 
Ctrough) and a second sample immediately prior to the end of the infusion at Week 12 (only in 
subjects undergoing PK and pharmacodynamic assessments). 
12. Separate pharmacodynamic samples will be taken prior to initiation of infusion (pre-dose, only 
subjects undergoing PK and pharmacodynamic assessments) at Weeks 12, 20, 28, and 36. 
13. Study drug administration. 
14. Assess AEs. 
15. Review concomitant medications. 
8.1.3 
Follow-up Period (Week 44 to Week 52) 
Week 44 ±7 days 
The procedures and assessments for Week 44 are as follows: 
1. Completion of a COVID-19 related screening questionnaire. 
2. Clinical assessments will include the following: Physical examination (at the discretion of the 
Investigator), vital signs measurement (seated blood pressure, heart rate, respiration rate, and 
oral, axillary, or tympanic body temperature). 
3. ECOG performance status. 
4. Clinical laboratory tests: Blood and urine samples will be taken for haematology, biochemistry, 
coagulation, and urinalysis. 
5. Serum LDH and β-2 microglobulin evaluation. 
6. Samples for BAb and NAb will be obtained. 
7. Viral disease screening: HBV DNA (as applicable) and HCV RNA (as applicable). 
8. A pharmacodynamic sample will be obtained only in the subjects undergoing PK and 
pharmacodynamic assessments. 
9. Assess AEs. 
10. Review concomitant medications. 
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8.1.4 
End of Study (Week 52 ± 7 Days)  
The procedures and assessments for Week 52 (± 7 days) are as follows: 
1. Completion of a COVID-19 related screening questionnaire. 
2. Clinical assessments will include the following: Physical examination (at the discretion of 
the Investigator), vital signs measurement (seated blood pressure, heart rate, respiration 
rate, and oral, axillary, or tympanic body temperature) and 12 lead ECG. 
3. ECOG performance status. 
4. Clinical laboratory tests: Blood and urine samples will be taken for haematology, 
biochemistry, coagulation, urinalysis, and serum pregnancy tests. 
5. Serum LDH and β-2 microglobulin evaluation. 
6. Samples for BAb and NAb will be obtained. 
7. A pharmacodynamic sample will be obtained only in the subjects undergoing PK and 
pharmacodynamic assessments. 
8. Viral disease screening: HBV DNA (as applicable) and HCV RNA (as applicable). 
9. Assess AEs. 
10. Review concomitant medications. 
11. At Week 52, tumour assessments (using a CT scan and, where available according to study 
site standard of care, a [18F]FDG-PET or PET-CT scan): based on central radiology review 
in accordance with the response criteria for malignant lymphoma.13 Subjects who have 
withdrawn from study drug for any reason other than disease progression will also undergo 
tumour assessment at Week 52. 
12. Bone marrow biopsies are required for any subject who has a response of CR at an 
evaluation point and either had a bone marrow examination positive for FL at Screening or 
shows new abnormalities in the peripheral blood counts or blood smear that clinically 
indicates a bone marrow evaluation is required. 
8.2 Efficacy Assessments 
The primary endpoint for efficacy is BORR, defined, as the proportion of subjects in each 
treatment group that achieve a best overall response of either CR, CRu or PR up to Month 7 (Week 
28) based on central radiology review in accordance with the response criteria for malignant 
lymphoma.13 This necessitates the use of bone marrow biopsies if bone marrow was involved at 
Screening or any abnormality occurred during treatment; combined PET-CT scans are not required 
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for this version of the response criteria, but are allowed if the CT portion has the slice thickness 
compatible with spiral CT scans. 
Disease assessments are to be performed as scheduled according to Table 1–1, regardless of 
treatment delays resulting from toxicity. Care must be taken in scheduling disease assessments to 
prevent the introduction of bias based on treatment delays. Failure to perform any of the required 
disease assessments will result in the inability to determine disease status for the impacted time 
point. A series of incomplete disease assessments will result in inability to determine disease 
response status and censoring of PFS back to the time of the last full assessment that did not show 
progression. Frequently off-schedule or incomplete disease assessments have the potential to 
weaken the conclusion of this clinical study. 
Assessments are NOT to be scheduled based on the previous imaging time point, but rather Day 1 
should be used as the baseline when calculating when the on-study tumour assessments are to be 
performed (with consideration of visit windows). The CT scans should be performed with contrast 
agents, unless contraindicated for medical reasons. If i.v contrast is medically contraindicated, 
imaging without contrast can be used. Depending on the adequacy for evaluation of disease, a 
combination of CT without contrast and magnetic resonance imaging should most often be used. 
Such cases will be reviewed by the medical team, and their inclusion in the Per Protocol (PP) 
Population will be discussed at the blinded data review meeting(s). 
Investigators will review the screening PET-CT or CT scans to determine subject eligibility 
(eligibility should be confirmed based on central radiology review) for the study. Investigators will 
review the post-treatment PET-CT or CT scans to determine and provide appropriate medical care 
to subjects. All [18F] FDG-PET and CT or PET-CT imaging data sets performed for the study will 
be transferred to a designated central imaging vendor to facilitate centralised quantitative response 
assessment of the primary and other efficacy endpoints. Details of the response assessment 
procedures are provided in the imaging charter. 
8.3 Safety Assessments 
The timing and frequency of safety assessments are described in Table 1–1. 
Safety variables include the following: 
8.3.1 
Physical Examinations 
A standard physical examination will be performed at every visit as indicated in Table 1–1. The 
following parameters and body systems will be examined and any abnormalities described: weight, 
height (at Screening), general appearance, skin (e.g., presence of rash), head, eyes, ears, nose, and 
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throat, lungs (auscultation), heart (e.g., auscultation for presence of murmurs, gallops, rubs), 
extremity exam for the presence of peripheral oedema, 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 drug should be recorded 
as AEs. 
8.3.2 
Vital Signs 
Vital signs, including heart rate, blood pressure, respiratory rate, and oral, axillary or tympanic 
body temperature, will be measured as detailed in Table 1–1 and in the event of an infusion 
reaction. 
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 5 minutes. The same arm and position should be used 
throughout the study, using an appropriate cuff size. All blood pressure readings should be 
measured after resting for at least 5 minutes. When the timing of these measurements coincides 
with blood collection, the blood pressure and heart rate should be obtained first. 
Vital signs are to be obtained prior to each study drug 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’s 
judgment. 
8.3.3 
Electrocardiograms 
The 12-lead ECG measurement will be done under medical supervision at Screening and 
Week 52/EOS/ET. Before recording, subjects should be resting in a quiet supervised setting with 
minimal stimulation (e.g., no television, loud music, computer games) and lie in a resting position 
for 10 minutes before ECG recording. 
Corrected QT interval (QTc) value (msec) will be calculated using the Fridericia formula, where: 
 
 
with QT measured in msec and RR in seconds. 
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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 pre-existing condition 
or if a pre-existing condition worsens in frequency or intensity. 
8.3.4 
Clinical Safety Laboratory Assessments 
Haematology, biochemistry, coagulation, and urinalysis will be conducted at Screening, on 
Weeks 1, 2, 3, 4, 8, 12, 20, 28, 36, 44, and 52. Serum pregnancy test will be conducted at Screening 
and EOS/ET. Urine or serum pregnancy tests will be conducted on Day 1 prior to randomisation, 
and all subsequent study drug dosing visits. 
Blood and urine samples for haematology, biochemistry, coagulation, urinalysis and pregnancy 
tests should be sent to the local laboratory for analysis. Local laboratory normal ranges will be 
collected prior to first subject first visit at each study site (and in case, any change to reference 
range during course of trial) 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/designated site personnel. 
The following parameters will be assessed: 
x Haematology: red blood cell count, total haemoglobin, haematocrit, white blood cell count 
with differential counts (specific leukocyte populations to be reported as counts; percentages 
are optional), platelets count. 
x Coagulation: prothrombin time. 
x Biochemistry: β-2 microglobulin, albumin, ALP, ALT, AST, blood urea nitrogen, calcium, 
chloride, creatinine, creatinine clearance (Cockroft Gault formula), gamma-glutamyl 
transpeptidase, LDH, phosphate, potassium, random serum glucose, sodium, total bilirubin, 
total protein, and uric acid. 
x Urinalysis (by dipstick or any other method): specific gravity, pH, protein, glucose, blood, 
ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase or leukocytes, microscopic 
examination (if blood or protein is abnormal). 
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x Other screening tests: FSH (as needed in women of non-childbearing potential only e.g., 
women with cessation of menstruation for ≤ 2 years, peri-menopausal women with 
inconclusive menopausal evidences based on clinical assessment and medical history), serum 
β-hCG, pregnancy test (for women of childbearing potential), serology (HIV antibody, 
hepatitis B surface antigen [HBsAg], hepatitis B core antibody, and HCV antibody), HBV 
DNA (as applicable) and HCV RNA (as applicable). If latent TB is suspected based on clinical 
or epidemiological grounds, it should be further investigated using the tuberculosis testing as 
appropriate following local practice or investigator judgment, and COVID -19 testing (as 
applicable). 
Blood and urine collection and sample preparation will be performed according to procedures from 
the local laboratories. 
8.3.5 
Eastern Cooperative Oncology Group Performance Status 
ECOG performance status will be graded according to the definitions presented in Table 8–1. 
Table 8–1 
Eastern Cooperative Oncology Group Performance Status 
Definitions 
Grade 
Eastern Cooperative Oncology Group Definition  
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
 
8.3.6 
Viral Disease Screening 
Subjects will be tested for HIV, hepatitis B, and hepatitis C to determine eligibility. 
HBsAg, HBcAb, HCV, and HIV are to be determined by each study site’s local laboratory. 
Screening for HIV infection is to be performed only if not prohibited by local regulations. 
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8.3.7
Pharmacokinetic and Pharmacodynamic Assessments
Pharmacokinetic and pharmacodynamic samples will be collected at time-points specified in 
Table 1–1. Pharmacokinetic and pharmacodynamic samples will be collected, processed and 
shipped as described in the central laboratory manual. All samples will be analysed by the 
designated analytical laboratory using a validated analytical method.
8.3.8
Immunogenicity Assessments
Blood samples for assessment of BAb and NAb will be collected at time-points specified in 
Table 1–1. BAb and NAb samples will be collected, processed and shipped as described in the 
central laboratory manual. All samples will be analysed by the designated analytical laboratory 
using a validated analytical method.
Analysis of BAb and NAb samples will follow a tiered approach of screening and confirmation. 
Samples that are confirmed positive for BAb will be further tested for titre and NAb determination 
using validated assays.
8.3.9
Histopathological Review of Diagnostic Tissue
To be eligible for this study, subjects must have tumour tissue available for review by a central 
pathology review committee. 
 
 
 
 
 The primary analysis for study outcome will be based on a 
centrally- confirmed- diagnosis documented at the time of randomisation.
8.4
Adverse Events and Serious Adverse Events
8.4.1
Definitions
The definitions for AEs and SAEs are given below. It is of the utmost importance that all staff 
involved in the study are familiar with the content of this section. The Principal Investigator is 
responsible for ensuring this.
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Adverse Event/Reaction 
An AE is defined as any untoward medical occurrence in a subject administered a pharmaceutical 
product, and which does not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavourable and unintended sign, symptom or disease temporally associated 
with the use of study drug, whether or not related to the study drug. 
Disease progression can be considered as a worsening of a subject’s condition attributable to the 
disease for which the study medication is being studied. It may be an increase in the severity of 
the disease under study and/or increases in the symptoms of the disease. The development of new, 
or progression of existing metastasis to the primary cancer under study should be considered as 
disease progression and not an AE. Events, which are unequivocally due to disease progression, 
should not be reported as an AE during the study. Progression of the malignancy under study, 
including signs and symptoms progression, should not be reported as a serious adverse event. 
Hospitalisation due to signs and symptoms of disease progression should not be reported as serious 
adverse event. However, all AEs (including disease progression) fulfilling any of the seriousness 
criteria are reportable as SAE for the study subjects from sites in India. 
Any relevant observations made at the Screening Visit (prior to signing the ICF) are to be recorded 
as a pre-existing condition; an AE will only be recorded if there is a worsening of the pre-existing 
condition during study conduct with regards to nature, severity, or frequency. An adverse drug 
reaction is an “untoward and unintended response to a study drug related to any dose 
administered”. 
All AEs judged by either the reporting Investigator or the Sponsor/designee as having a reasonable 
causal relationship to a medicinal product qualify as adverse reactions. The expression of 
“reasonable causal relationship” means to convey in general that there are facts or arguments meant 
to suggest a causal relationship. 
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Events Meeting the AE Definition  
x Any abnormal laboratory test results (haematology, biochemistry, or urinalysis) or other 
safety assessments (e.g., ECG, radiological scans, vital signs measurements), including 
those that worsen from baseline, considered clinically significant in the medical and 
scientific judgment of the Investigator (i.e., not related to progression of underlying disease). 
x Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
x New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
x Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
x Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming intent. 
Such overdoses should be reported regardless of sequelae. 
 
 
Events NOT Meeting the AE Definition  
x Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the subject’s condition. 
x The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s condition. 
x Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
x Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
x Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
 
 
Serious Adverse Event 
An SAE is defined as an AE that results in one of the following outcomes: 
x Results in death. 
Death is not an AE itself, but an outcome. The cause of the death is the AE which resulted 
in death. 
x Is life-threatening. 
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Life-threatening means that the subject was at immediate risk of death at the time of the 
SAE, it does not refer to a SAE that hypothetically might have caused death if it were more 
severe. 
x Requires in-patient hospitalisation or prolongs existing hospitalisation (This does not include 
prolonged hospitalisation for study purposes) 
Hospitalisation is defined as at least one 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 
hospitalisation due to pre-planned hospitalisations (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 hospitalisation due to unplanned complications. Following the initial discharge from 
hospital, subsequent hospitalisations are to be considered an SAE. “Social” hospitalisation, 
defined as administrative impossibility to discharge the subject is not necessarily an SAE. 
Complications that occur during hospitalisation 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. Hospitalisations due to diagnostic procedures which 
are not performed due to an AE are not regarded as SAE. 
x 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. 
x Is a congenital anomaly/birth defect 
x Is an important medical event 
Important medical events that may not result in death, be life-threatening or require 
hospitalisation may be considered an SAE, when based on appropriate medical judgment, 
they may jeopardise the subject or the subject may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. 
Treatment Emergent Adverse Event 
Treatment emergent adverse events (TEAEs) are defined as any AE occurring or worsening on or 
after the first dose of study medication. 
Infusion-Related Reactions 
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A pre-defined list of IRRs (using selected preferred terms from the Medical Dictionary for 
Regulatory Activities [MedDRA]) will be determined prior to unblinding. Details will be provided 
in the Statistical Analysis Plan (SAP).
8.4.2
Time Period and Frequency for Collecting Adverse Events and Serious 
Adverse Events Information
Any relevant observations (including laboratory data) made at the Screening Visit (prior to signing 
the ICF) are to be recorded as a pre-existing condition on the medical history page of the eCRF. 
For 
or 
 
 
 
 
 Those that were present both before and after signing the ICF should be 
recorded as medical history, and those with no past history should be considered as an AE/SAE.
The following variables will be recorded for each AE: verbatim/AE description, time and date for 
AE start and stop, severity, seriousness, causality rating, whether or not the AE caused the subject 
to discontinue, and the outcome. A new AE must be recorded if the severity of the AE changes.
SAEs and AEs will be recorded starting after signing of informed consent until EOS Visit or in 
case of early termination until ET Visit or week 52, whichever occurs later (unless subject 
withdrew consent or lost to follow-up at or after ET). All SAEs and AEs have to be recorded, 
whether or not considered causally related to the study drug or to the study procedure(s).
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation 
(e.g., hospital progress notes, laboratory, and diagnostics reports) related to the event. The 
Investigator will then record all relevant AE/SAE information in the eCRF. It is not acceptable for 
the Investigator to send photocopies of the subject’s medical records to the Sponsor or Sponsor’s 
designated safety services in lieu of completion of the AE/SAE in eCRF. There may be instances 
when copies of medical records for certain cases are requested by the Sponsor. In this case, all 
subject identifiers, with the exception of the subject number, will be blinded on the copies of the 
medical records before submission to the Sponsor.
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. In such cases, the diagnosis (not the individual signs/symptoms) will be 
documented as the AE/SAE.
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In case the eCRF is down or unavailable due to technical difficulties at the site, the Investigator 
will use the back-up paper SAE form to report SAEs within 24 hours via fax or via email to the 
Sponsor’s designated safety services. The paper SAE form and the contact details for reporting 
will be part of the site reference manual. 
All ongoing AEs/SAEs should be followed up until resolution or stabilisation or the EOS/ET Visit, 
whichever occurs first, with the exception of any ongoing drug-related AEs/SAEs, which should 
be followed until the AE/SAE is stabilised, resolved, or, in the Investigator's opinion, the AE/SAE 
is unlikely to resolve due to the subject's underlying condition. 
At any time after the EOS/ET Visit, if an Investigator learns of an SAE that can be reasonably 
related to study drug, he/she should promptly notify the Sponsor/designee. 
8.4.3 
Assessment of Intensity 
The Investigator will use the adjectives Mild, Moderate, Severe, Life-threatening, or Death to 
describe the maximum intensity of the AE. The US National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), version 5.0 will be used to grade severity. 23 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated. 
Moderate: minimal, local or non-invasive intervention indicated; limiting age appropriate 
instrumental Activities of Daily Living (ADL)*. 
Severe: or medically significant but not immediately life-threatening; hospitalisation or 
prolongation of hospitalisation indicated; disabling; limiting self-care ADL**. 
Life-threatening: urgent intervention indicated. 
Death: related to AE. 
Activities of Daily Living (ADL) 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
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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 met one of the criteria for SAEs, 
listed in Section 8.4.1.
8.4.4
Assessment of Causality
The Investigator is obligated to assess the relationship between study intervention and each 
occurrence of each 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. . 
 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 one 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:
x
Related: Reasonable possibility of a relatedness
x
Not related: No reasonable possibility of relatedness.
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, before 
reaching up to a decision on causality assessment:
x
Time relationship between study drug intake and event’s onset
x
Dechallenge
x
Rechallenge
x
Medical History
x
Study drug
x
Mechanism of action of study drug
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x Class effect 
x Concomitant treatments in use 
x Withdrawal of study drug 
x Lack of efficacy/worsening of existing condition 
x Erroneous treatment with study medication or concomitant medication 
x Protocol related process. 
Action taken with study drug due to the AE: 
x Dose not changed 
x Drug interruption 
x Drug withdrawn 
x Unknown 
x Not applicable 
Outcome: 
Each single AE must be rated by choosing one of the following: 
x Recovered/resolved 
x Recovering/resolving 
x Not recovered/not resolved 
x Recovered with sequelae/resolved with sequelae 
x Fatal 
x Unknown. 
The Investigator and the Sponsor (or Sponsor’s designated agent) will review each SAE report and 
the Sponsor/PAREXEL 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 
expectedness according to the reference document (IB or SmPC). Based on the Investigator and 
Sponsor’s assessment of the event, a decision will be made concerning the need for further action. 
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8.4.5 
Suspected Unexpected Serious Adverse Reactions 
Any AE that is serious, associated with the use of the study intervention, and unexpected 
(suspected unexpected serious adverse reaction [SUSAR]) has additional reporting requirements, 
as described below. 
x 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). 
x 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 as per local 
regulations. These updates will include information on SUSARs and other relevant safety findings. 
8.4.6 
Abnormal Laboratory Values/Vital Signs/Electrocardiograms 
Laboratory/vital signs/ECG abnormalities should be reported as an AE/SAE if any one of the 
following criteria is met: 
x Result is associated with signs/symptoms. 
x Requires additional diagnostic testing and/or interventions. 
x Leads to a change in dose, discontinuation of or interruption to the study drug. 
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. 
8.4.7 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the subject is the preferred method to inquire about AE occurrence. 
8.4.8 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilisation, until the event 
is otherwise explained, or the subject is lost to follow-up (as defined in Section 7.3). 
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The Investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the Sponsor to elucidate the nature 
and/or causality of the AE or SAE as fully as possible. This may include additional laboratory tests 
or investigations, histopathological examinations, or consultation with other health care 
professionals. If subject dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor with a copy of any post-mortem findings 
including histopathology. 
New or updated information will be recorded in the originally completed eCRF within 24 hours of 
receipt of the information. 
8.4.9 
Regulatory Reporting Requirements for Serious Adverse Events 
Investigators and other study site personnel must inform the Sponsor’s designated safety services 
of any SAE that occurs (whether or not attributable to the study drug) in the course of the study 
within one day (i.e., immediately but no later than 24 hours or as per local regulation) of when he 
or she becomes aware of it. 
Follow-up information on SAEs must also be reported to Sponsor’s designated safety services by 
the Investigator within 24 hours or as per local regulation. 
If a non-serious AE becomes serious, this and other relevant follow-up information must also be 
provided to the Sponsor’s designated safety services within 24 hours or as per local regulation as 
described above. 
All SAEs and pregnancies will be recorded in the eCRF. As soon as the SAE/pregnancy is recorded 
in the eCRF, a notification alert will be sent to the Sponsor’s designated safety services. A 
notification email of the event describing it in the e-mail text is not sufficient. Whenever required 
applicable local SAE reporting Form will be used (e.g., Appendix XI in India), in addition to eCRF 
update. 
Source documents relevant for the SAE should only 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. 
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. 
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Minimum criteria are identifiable subject (number), a suspect product (i.e., study drug or 
concomitant medication), an identifiable reporting source (Investigator/study site identification), 
and an event or outcome that can be identified as serious. The Investigator may change his/her 
opinion of causality in the light of follow-up information, amending the eCRF SAE page 
accordingly. The causality assessment is one of the criteria used when determining regulatory 
reporting requirements for SAEs.
When an SAE is discovered by the study site or is identified by a designated clinical research 
associate during study site visits, SAEs will be entered by the study site members into the eCRF, 
which contains specific questions for events regarded as serious. Designated personnel will receive 
the alert through automated e-mail notification.
The Sponsor/designee representative will work with the Investigator to compile all the necessary 
information and ensure that the appropriate Sponsor/designee representative receives a report 
within 24 hours for all SAEs.
The Sponsor/designee will bear responsibility of expedited and periodic reporting to the health 
authorities according to national requirements. The Investigator must comply with any applicable 
site-specific requirements related to the reporting of SAEs (particularly deaths and SUSARs) to 
the IEC/IRB that approved the study. 
 
 
8.4.10 Pregnancy
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study drug may have 
interfered with the effectiveness of a contraceptive medication. If a pregnancy is reported for a 
subject, no further study drug 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 in the eCRF. Follow-up should be performed 
up to delivery, after the examination of the newborn, and until 12 weeks of age, when follow-up 
information regarding the pregnancy and the outcome of the newborn should be entered in the 
eCRF.
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’s designated safety services via the eCRF.
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Pregnancy outcomes must be collected for the female partners of any males who took study drug 
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’s designated safety services using the reporting 
details provided in Section 8.4.2 within 24 hours of awareness. 
8.4.11 Death Events 
Should a death occur within the study period or within 16 weeks after the last administration of 
study drug an AE form and an SAE 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 
Sponsor’s designated safety services within 24 hours as described in Section 8.4.2. The report 
should contain a comment regarding the co-involvement of progression of disease, if appropriate, 
and should assign main and contributory causes of death. However, death due to disease 
progression to be reported as SAE from sites in India. 
8.5 Study Conduct During the COVID-19 Pandemic 
COVID-19 is a viral illness caused by the novel coronavirus (also called SARS-CoV-2) and has 
impacted most of the countries across the globe. It was declared as a global public health 
emergency by the WHO on 30 Jan 2020, and was declared as a pandemic on 11 Mar 2020. This 
pandemic has impacted the conduct of clinical trials in various ways. 
8.5.1 
Contingency Measures Implemented During the COVID-19 Pandemic 
In the current global outbreak of COVID-19, Dr. Reddy̓s Laboratories (DRL) has recognized 
the potential impact on the conduct of RI-01-006 study due to various reasons. Considering that 
the safety of study participant is paramount, DRL has initiated various contingency measures for 
the well-being of subjects and in order to ensure compliance with guidance issued by various 
regulatory agencies:24,25 
x COVID-19 protective measures: Recommendation to study sites to inform and encourage all 
study subjects to practice COVID-19 basic protective measures at all times. 
x COVID-19 testing and COVID-19 related screening questionnaire: 
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a. Each subject being randomized will undergo COVID-19 testing (preferably RT-PCR) 
and only subjects with confirmed negative test results will be administered the study 
drug. Additional testing for COVID-19 during the course of study may be performed 
at the discretion of the Investigator. All such test results will be documented 
appropriately in CRF. 
b. COVID-19 related screening questionnaire to rule out active COVID-19 infection as 
well as to evaluate further if potential study subjects are at risk of acquiring COVID-19 
at screening visit and during the study period. Study drug will be administered only in 
those subjects who are considered at no-risk by the Investigator based on this 
evaluation. 
x Inform Consent Document (ICD) amended to include possible risks related to COVID-19 and 
rituximab treatment. All ongoing subjects will undergo re-consent with a newer version of the 
ICD, after approval from a respective ethics committee (EC). All new subjects being screened 
will be asked to give their consent using the newer version of the ICD. 
x Advise study sites to prioritize subjects’ safety and priority care in the event of COVID-19 
infection. 
x The Investigator must stop rituximab treatment if any of the study subjects acquire COVID-19 
infection while in the study. Re-institution of therapy should be done after careful benefit risk 
assessment by the Investigator once the subject has been confirmed as cured of COVID-19 
with appropriate laboratory testing. 
x The Investigator is encouraged to do telephonic inquiry of study subjects to know about their 
overall well-being, adverse events, including suspected COVID-19 symptoms, concomitant 
medications etc. 
x COVID-19 events in the study are to be considered as “Events of Special Interest (EOSI)” 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 as an SAE. 
All details of remote monitoring, including discussion with sites on informed consent process, 
subject eligibility, review of central lab data, review of data entry, query resolution, pending 
actions, review of protocol deviations etc., have been captured in the monitoring plan, as 
applicable.  
Detailed information about the type of data to be collected, handling of missing data or 
assessments/procedures 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 
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deviations and additional safety contingency measures will be generated based on the available 
data, if required. Corresponding details will be mentioned in the SAP.
Based on the evolving COVID-19 pandemic, the Sponsor will revisit these contingency measures
for any further changes, or for their continuation/discontinuation, as needed, while ensuring subject
safety and trial data integrity throughout the conduct of the study.
8.6
Treatment of Overdose
A drug overdose is defined as the accidental or intentional use of a drug or medicine in an amount 
that is higher than the protocol-specified dose. Rounding off is unavoidable in the preparation of 
rituximab infusion solutions. Due to this reason, excess 
 
 for the subject will not be considered an overdose. Every overdose must 
be reported to the Sponsor’s designated safety services within 24 hours of awareness as described 
in Section 8.4.2, irrespective of whether the overdose was associated with an AE/SAE. Subjects 
who experience overdose should be closely monitored.
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9
 Statistical Considerations
9.1
Statistical Hypotheses
9.1.1
General Principles
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.
In general, continuous variables will be summarised 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.
 
 
An additional analysis may be performed based on country specific requests/ requirements by the 
relevant authorities.
An SAP will be prepared and finalised before the study data are unblinded.
The statistical analysis will be performed using SAS® version 9.4 or higher.
9.1.2
Missing Data
Imputation of missing data in the primary efficacy analysis is described in Section 9.4.1.1 Partial 
dates for start or stop date of AEs will be imputed in an appropriately conservative way. Detailed 
methods for handling missing data will be given in the SAP. For substantial missing assessments 
due to the COVID-19 pandemic additional sensitivity analyses will be performed to determine if 
there was an impact on the efficacy endpoints. Methods for handling missing data should outline 
the assumptions utilized and discuss if this method of choice may have an effect on the estimate 
of the treatment effect.
Other missing values will not be imputed, unless otherwise specified in each analysis section.
9.1.3
Inter-current events due to COVID-19
Handling (i.e., analysis and presentation) of intercurrent events and data/visit impacted due to 
COVID-19 pandemic will be described in the SAP. 
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The following events are considered as intercurrent events due to COVID-19 pandemic and any 
study data missing as an outcome of these events will be handled as missing data impacted due to 
COVID-19:
-
COVID-19 infection or death due to COVID-19 (as an Event of Special Interest)
-
Protocol deviation including missing assessment due to COVID-19 pandemic
-
Any other documented event which may interfere the study conduct and is reasonable 
related to COVID-19 pandemic 
Full details of the COVID-19 related intercurrent events definitions will be provided in SAP.
9.1.4
Demographic and Baseline Characteristics
Demographic and baseline characteristics will be analysed in a descriptive fashion and results will 
be presented overall and by treatment group.
9.1.5
Subject Disposition
The following will be summarised (overall and by treatment group where applicable):
x
Subjects screened
x
Subjects randomised
x
Subjects treated
x
Subjects in each analysis population
x
Subjects completing the study/withdrawing early (including withdrawal reason)
x
Subject allocation by study site
9.2
Sample Size Determination
Published data for rituximab treatment versus a "watch and wait" strategy in the first line treatment
of LTBFL (Ardeshna et al. 2014) revealed
led
 
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Based on the observed pooled best overall response (BOR) rate, up to week 28, the revised total 
sample size obtained in the BSSR is 312 subjects (156 per group) to be recruited.
9.3
Populations for Analyses
9.3.1
Intent to Treat Population
The Intent to Treat (ITT) Population will include all randomised subjects. The primary efficacy 
analysis will be based on the ITT Population.
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9.3.2 
Per Protocol Population 
The PP Population will include all subjects who are randomised into the study, receive at least one 
dose of study drug (sufficient compliance to be evaluated under blind conditions), have measurable 
disease at Baseline as confirmed by central review, have an at least one available valid response 
evaluation up to 7 months (± 4 weeks), and no major protocol deviations (such as administration 
of a forbidden treatment) that would significantly impact the primary efficacy endpoint. If the 
forbidden treatment was administered due to PD, the subject will be included in the PP Population 
as a non-responder. In the EMA analysis, both ITT and PP population will be considered as 
primary. 
Subjects will be considered to have a valid response evaluation if all required tests in accordance 
with published response criteria13 are available and have been obtained within ± 28 days of the 
scheduled date, and the central imaging reviewers consider all imaging at 3 months (Week 12) and 
7 months (Week 28) as properly evaluable for size comparison with the baseline images, and 
subjects have not received forbidden medications or other treatments for LTB-FL. 
Analysis of the PP Population may allow easier detection of any differences in treatment since the 
population includes only subjects who adhere to the protocol. Identification of the PP Population 
will be determined at one or several blinded data review meetings prior to unblinding. 
9.3.3 
Safety Population 
The Safety Population will include all subjects who have received at least one dose of study drugs. 
The Safety Population will be used for safety analysis. 
9.3.4 
Pharmacokinetic Analysis Population 
The PK Analysis Population will include all subjects in the PK and pharmacodynamic subset who 
have at least one available pre-dose sample and one quantifiable study drug concentration after 
initiation of treatment. 
Subjects will be considered included in the PK and pharmacodynamic subset if they participate in 
the PK and pharmacodynamic evaluations, have provided their written consent to participation and 
randomised to the study within the PK and pharmacodynamic subset. 
9.3.5 
Pharmacodynamic Analysis Population 
The Pharmacodynamic Analysis Population will include all subjects in the PK and 
pharmacodynamic subset and sampled for pharmacodynamics who have at least an available 
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pre -dose pharmacodynamic sample and an available pharmacodynamic sample obtained after the 
administration of the first dose of rituximab has started.
Subjects will be considered included in the PK and pharmacodynamic subset if they participate in 
the PK and pharmacodynamic evaluations, have provided their written consent to participation and 
randomised to the study within the PK and pharmacodynamic subset.
Subject evaluability for specific parameters will be decided under blinded conditions.
9.4
Statistical Analyses
The SAP will be developed and finalised prior to data base lock. Below is a summary of planned 
statistical analyses of the primary and secondary endpoints. Further details are presented in the 
SAP.
9.4.1
Efficacy Analyses
9.4.1.1
Analysis of Primary Efficacy Endpoint
The primary efficacy endpoint is the BORR i.e., the proportion of responders in each treatment 
arm who achieve a best overall response of either CR, CRu or PR up to Month 7 (Week 28) based 
on central radiology review in accordance with the response criteria for malignant lymphoma.13 
Subjects who are included in the ITT Population but do not have efficacy assessments will be 
assessed as non-responders. The estimated difference (DRL_RI minus MabThera®) and its 95% 
CI will be obtained using the test -based exact binomial confidence interval method.27, 28 
Equivalence will be concluded for FDA if the 90% CI and for EMA if the 95% CI of the BORR 
difference is completely contained within the pre-defined interval (-17%, 17%). 
 
. . Full details 
of the primary endpoint analysis including multiplicity considerations will be provided in the SAP.
Various sensitivity analyses will be conducted to confirm the robustness of the primary efficacy 
analysis result, including but not limited to:
x
 
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x
 
 
 
 
 
 
 
x
 
 
 
 
 
 
 
 
 
x
 
 
 
 
 
Additional details regarding sensitivity analyses for inter current events due to COVID-19 will be 
available in SAP.
9.4.1.2
Analysis of Secondary Efficacy Endpoint
Secondary efficacy endpoints include the following:
x
Overall response rate at Week 12 and Week 28 based on central radiology review in accordance 
with the response criteria for malignant lymphoma13.
x
CR rate at Month 7 (Week 28).
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x CR rate as a best response up to Month 7 (Week 28). 
x Duration of response defined as the time from date of the first documentation of tumour 
response (CR, CRu or PR) to the date of first documentation of PD or to death due to any cause 
up to 52 weeks/EOS. 
x Progression-free survival defined as the time from date of randomisation to the date of 
documented PD or death due to any cause. 
x Overall survival defined as the time from date of randomisation to the date of death from any 
cause up to 52 weeks/EOS. 
Time to event endpoints (PFS, OS, and DOR) will be summarised using Kaplan-Meier (K-M) 
survival curves. The K-M survival estimates, together with the number of subjects, percentage of 
subjects to experience the event, and the number and percentage of subjects censored will be 
summarised in a table by treatment group. The ORR at Week 12 and Week 28, CR at Month 7 
(week 28) and CR rate as a best response up to Month 7 (Week 28), duration of response defined 
as the time from date of the first documentation of tumour response (CR, CRu or PR) to the date 
of first documentation of PD or to death due to any cause up to 52 weeks/EOS, progression-free 
survival defined as the time from date of randomisation to the date of documented progressive 
disease (PD) or death due to any cause and overall survival defined as the time from date of 
randomisation to the date of death from any cause up to 52 weeks/End of Study (EOS) will be 
summarised by treatment group using frequency and percentage (including the 95% CI). 
More details of the analysis will be described in the SAP. 
9.4.1.3 
Analysis of Exploratory Endpoint 
The BORR will also be evaluated based on the Lugano criteria14 for those subjects with available 
PET data and summarised by treatment group using frequency and percentage (including the 95% 
CI). 
9.4.2 
Safety Analyses 
Safety will be reviewed throughout the study in a blinded manner by the study team. 
The safety endpoints will include the following: 
x Incidence of AEs, as assessed by the NCI CTCAE version 5.0. 
x Incidence of infusion reactions in each treatment group, where IRRs will be pre-defined. 
x Vital signs. 
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x
Clinical laboratory parameters.
x
12-lead ECG.
x
ECOG performance status.
x
Physical examination.
TEAEs including Events of Special Interest (COVID-19 infection or death due to COVID-19 
infection) will be described using descriptive statistics and coded according to the MedDRA 
(version 21.1 or latest) system organ class and MedDRA preferred term, graded according to 
CTCAE version 5.0, by treatment group and overall. TEAEs observed, based on the onset date, 
during the rituximab induction and maintenance will be summarised separately by treatment group. 
Drug-related TEAEs and SAEs, TEAEs leading to study discontinuation, and death will also be 
summarised by treatment group and overall.
Clinical safety laboratory data: clinical safety laboratory data will be presented by treatment group 
and overall. For each visit, the actual result and the change from baseline will be presented. Shift 
tables will be presented as appropriate.
Otherwise, safety data will be presented in tabular and/or graphical format and summarised 
descriptively, where appropriate. For continuous measurements (laboratory and vital signs data), 
change from baseline will be additionally summarised by treatment arm and visit. Subject listings 
will be produced for all safety endpoints.
The safety analysis will be based on the Safety Population and will be analysed according to the 
treatment they actually received. Detailed methods will be described in the SAP.
9.4.3
Subgroup Analysis
Subgroup analyses will be performed to examine efficacy and safety by 
 and other factors 
of interest. Detailed methods will be described in the SAP.
9.4.4
Pharmacokinetics Assessment
Using data from 
rom 
, a
, a population-PK model will be applied to 
the sparse PK data and potential differences in parameters such as clearance and volume of 
distribution for DRL_RI and RMP will be investigated using nonlinear mixed-effects modelling. 
Anti-drug antibodies status will be evaluated as a potential covariate in the population-PK model.
A separate analysis plan for the population-PK modelling will be developed and results will be 
provided in a separate population-PK report.
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9.4.5 
Pharmacodynamics Assessment 
Peripheral blood B-cell counts will be comparatively evaluated for potential differences in 
parameters such as the area under the B-cell depletion-time curve (depletion AUEC). 
Depletion is defined as Baseline (pre-dose at Visit 1) count minus the measured value. 
The AUEC will be calculated using the linear trapezoidal rule. Only the values up to the last value 
below the individual subject baseline count will be included in the AUEC calculation. 
Potential differences between DRL_RI and MabThera® in the AUEC will be investigated using a 
linear mixed-effects model with treatment as a fixed effect and subject as a random effect. 
On the basis of B-cell counts a population pharmacodynamics evaluation including population 
pharmacokinetics-pharmacodynamics evaluation might be performed which will be evaluated in 
a separate analysis plan.  
9.4.6 
Immunogenicity Assessment 
Immunogenicity data (BAb and NAb) will be summarised and analysed descriptively for each 
scheduled protocol assessment time point. 
9.4.7 
Reporting Timeframes 
When all subjects have completed Week 28 (or the EOS/ET Visit for subjects discontinued prior 
to Week 28), the primary endpoint (BORR up to Week 28) will be analysed using 
centrally-reviewed radiology assessments and a study report produced. Available safety data and 
other secondary and exploratory endpoints may also be reported at that time including ORR at 
Week 12 and Week 28. An addendum study report will be provided to applicable regulatory 
authority when all subjects have completed the study, including updated safety data and secondary 
endpoints for time to event endpoints. Further details will be provided in the SAP. 
Pharmacokinetic and pharmacodynamic endpoints will be reported as discussed in Section 9.4.4 
and Section 9.4.5. 
9.4.8 
Other Analyses 
Pharmacokinetic, pharmacodynamic, and biomarker exploratory analyses will be described in the 
SAP. The population-PK analysis and pharmacodynamic analyses are presented in Section 9.4.4 
and Section 9.4.5, respectively. 
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9.5 Interim Analyses 
There will be no interim analysis. 
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10 Supporting Documentation and Operational Considerations 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 Regulatory and Ethical Considerations 
x This study will be conducted in accordance with the protocol and with: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organisations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
o Applicable International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) 
Guidelines. 
o Applicable laws and regulations. 
x The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IEC/IRB by the Investigator and reviewed and 
approved by the IEC/IRB before the study is initiated. 
x Any amendments to the protocol will require IEC/IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study subjects. 
x The Investigator will be responsible for the following: 
x Providing written summaries of the status of the study to the IEC/IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IEC/IRB. 
x Notifying the IEC/IRB of SAE or other significant safety findings as required by 
IEC/IRB procedures. 
x Overall conduct of the study at the site and adherence to requirements of 21 Code of Federal 
Regulations (CFR), ICH GCP guidelines, the IEC/IRB, European regulation 536/2014 for 
clinical studies (if applicable), and all other applicable local regulations. 
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10.1.2 Financial Disclosure
Investigators will provide the Sponsor with sufficient, accurate financial information in accordance 
with local regulations to allow the Sponsor to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. 
 
 
10.1.3 Informed Consent Process
x
The Investigator or his/her representative will explain the nature of the study to the subject or 
his/her legally authorised representative and answer all questions regarding the study.
x
Subjects must be informed that their participation is voluntary. Subjects will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IEC/IRB or study centre.
x
The medical record must include a statement that written informed consent was obtained before 
the subject was enrolled in the study and the date the written consent was obtained. The 
authorised person obtaining the informed consent must also sign the ICF.
x
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study.
x
A copy of the ICF(s) must be provided to the subject or the subject’s legally authorised 
representative.
x
For subjects who are unable to read and write, the subject information sheet and ICF will be 
read to the subject in his/her native language in the presence of an impartial witness who is 
literate and not affiliated with the study. The subject having understood the information given 
to him/her in the presence of an impartial witness will thumbprint the ICF and the same will 
be countersigned by the impartial witness. If the subject or legally acceptable representative 
cannot read, then an impartial witness will witness and attest the entire consent process and 
will be required to sign the consent form. Confirmation of a subject’s informed consent must 
also be documented in the subject’s medical record prior to any testing under this protocol, 
including screening tests and assessments.
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.
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10.1.4 Data Protection 
x Subjects will be assigned a unique identifier by the Sponsor. Any subject records or datasets 
that are transferred to the Sponsor will contain the identifier only; subject names or any 
information which would make the subject identifiable will not be transferred. 
x The subject must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject. 
x The subject must be informed that his/her medical records may be examined by Clinical Site 
Manager (CSM) or Clinical Quality Assurance auditors or other authorised personnel 
appointed by the Sponsor, by appropriate IEC/IRB members, and by inspectors from regulatory 
authorities. 
10.1.5 Data Quality Assurance 
x All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (e.g., laboratory data). The Investigator 
is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF. 
x The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
x The Investigator must permit study-related monitoring, audits, IEC/IRB review, and regulatory 
agency inspections and provide direct access to source data documents. 
x The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
x Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorised site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of subjects are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements. 
x Records and documents, including signed ICF, pertaining to the conduct of this study must be 
retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be transferred to 
another location or party without written notification to the Sponsor. 
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x All data generated by the site personnel will be captured electronically at each study centre 
using eCRFs. Data from external sources (such as laboratory data) will be imported into the 
database or may be manually entered. Once the eCRF clinical data have been submitted to the 
central server at the independent data centre, corrections to the data fields will be captured in 
an audit trail. The reason for change, the name of the person who performed the change, 
together with the time and date will be logged to provide an audit trail. 
x If additional corrections are needed, the responsible monitor or data manager will raise a query 
in the eCRF. The appropriate staff at the study site will answer queries sent to the Investigator. 
The name of the staff member responding to the query, and time and date stamp will be 
captured to provide an audit trail. Once all source data verification is complete and all queries 
are closed, the monitor will freeze the eCRF page. 
x The specific procedures to be used for data entry and query resolution using the eCRF will be 
provided to study sites in a training manual. In addition, site personnel will receive training on 
the eCRF. 
10.1.5.1 Quality Assurance Audits 
Study centres, the study database and study documentation may be subject to a Quality Assurance 
audit during the course of the study by the Sponsor or CRO on behalf of the Sponsor. In addition, 
inspections may be conducted by regulatory bodies at their discretion. 
10.1.5.2 Study Monitoring 
The Sponsor has engaged the services of a CRO, to perform all monitoring functions within this 
clinical study. The CRO monitors will work in accordance with CROs’ SOPs and have the same 
rights and responsibilities as monitors from the Sponsor organisation. Monitors will establish and 
maintain regular contact between the Investigator and the Sponsor. 
Monitors will evaluate the competence of each study centre, informing the Sponsor about any 
problems relating to facilities, technical equipment or medical staff. During the study, monitors 
will check that written informed consent has been obtained from all subjects correctly and that 
data are recorded correctly and completely. Monitors are also entitled to compare entries in eCRFs 
with corresponding source data and to inform the Investigator of any errors or omissions. Monitors 
will also control adherence to the protocol at the study centre. 
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Monitoring visits will be conducted according to all applicable regulatory requirements and 
standards. Regular monitoring visits will be made to each study centre while subjects are enrolled 
in the study. The monitor will submit written reports after each monitoring visit to the clinical 
project manager/site visit report reviewer. On each occasion, contact with the Investigator will be 
made, regardless of whether it is by phone or in person. Telephone Contact Reports will be 
completed by monitors to document telephonic discussion with the sites. 
The Investigator will allocate adequate time for monitoring activities by the CRO. The Investigator 
will also ensure that the study monitor, other designee, or Quality Assurance Reviewer is given 
access to all the study-related documents and study-related facilities (e.g., pharmacy, diagnostic 
laboratory, etc.), and the study centre has adequate space to conduct the monitoring visit. 
10.1.6 Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will be established for the study, and operate 
according to procedures described in the DMC Charter. All meeting proceedings will be 
documented. 
10.1.7 Source Documents 
x Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
x Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
x A list of the normal ranges for all laboratory tests to be undertaken forms part of the 
documentation to be collated prior to study start. It is essential that all samples are analysed at 
the laboratories specified for this study. 
x The Investigator must maintain source documents, such as laboratory reports, X-rays, ECGs, 
consultation reports, and complete medical history and physical examination reports. 
x The Investigator/institution should maintain the study documents as specified in the ICH 
guidelines on GCP and as required by the applicable regulatory requirements. The 
Investigator/institution should take measures to prevent accidental or premature destruction of 
these documents. 
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10.1.8 Study and Site Closure 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies have 
been collected and a study site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are not 
limited to: 
x Failure of the Investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the Sponsor's procedures, or GCP guidelines 
x Inadequate recruitment of subjects by the Investigator 
x Discontinuation of further study intervention development 
10.1.9 Publication Policy 
The Sponsor shall retain the title and the right to publish all documentation, records, raw data, 
specimens or other work product generated pertaining to the study (“Data”) conducted by the site 
(site includes the Investigator and the Institution). The site shall maintain confidentiality and not 
disclose or divulge such “Data” to any third party. 
10.1.10 Protocol Approval and Amendment 
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 
must ensure that all ethical and legal requirements have been met before the first subject is enrolled 
in the study. In case of any changes implemented due to medical emergencies, the same needs to 
be promptly reported to the Sponsor and the IEC/IRB. 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, receive 
approval from the appropriate personnel, and receive IEC/IRB/Competent Authority approval 
prior to implementation (if appropriate). In the US: Following approval, the protocol 
amendment(s) will be submitted to the Investigational New Drug (IND) under which the study is 
being conducted. 
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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. 
10.1.11 Protocol Deviations 
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 Ethics Committee’s established 
procedures, will inform the Ethics Committee of protocol deviations. 
All instances where the requirements of the study protocol are not complied with, will be captured 
in the eCRF and the study monitor will prepare 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 clinical study 
report. 
10.1.12 Liability 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. The insurance 
will pay only when the Sponsor becomes legally obligated to compensate for the treatment; the 
Sponsor will cover the cost as per the local requirements. 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: 
x A serious GCP or protocol deviation by the Investigator, Sub-Investigator, or Site Team (except 
deviation medically necessary to avoid an immediate hazard to the study subjects). 
x Intentional act or negligence on the part of the Investigator, sub-investigator, or Site Team, or 
malpractice thereby. 
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x Injury caused by unlawful act or delinquency of a third party. 
x Injury caused by intentional act or negligence of the subject. 
x Hired person/Contracted person. 
For studies conducted in the US and Europe, the policy does not cover: 
x Bodily injury or property damage arising out of any human clinical study which has not been 
approved/placed on clinical hold/ordered to be discontinued by the governmental or regulatory 
authority having jurisdiction over the study (unapproved human clinical studies). 
x Bodily injury or property damage arising out of any human clinical study for which the 
governmental or regulatory authority having jurisdiction over the study has withdrawn 
approval (unapproved human clinical studies). 
For studies conducted in India and Rest of the World, (excluding non-admitted countries), coverage 
is on a legal liability basis depending on the local laws where the study is happening. Coverage 
will be for damages and or compensation or claimant’s costs and expenses in respect of any claim 
made by the research subjects for bodily injury arising out of any study conducted by or on behalf 
of the Insured in connection with the business. 
If compensation becomes necessary for a study-related injury, the study site will promptly notify 
the Sponsor and will co-operate with the Sponsor and its insurer (or their legal representatives) in 
their handling thereof. 
Any event/SAE is to be notified to the Sponsor or Sponsor’s designee on a promptly and timely 
basis. 
10.1.13 Access to Source Data 
During the study, a monitor will make site visits to review protocol compliance, compare eCRF 
entries and individual subject’s medical records, assess drug accountability, and ensure that the 
study is being conducted according to pertinent regulatory requirements. Electronic CRF entries 
will be verified with source documentation. The review of medical records will be performed in a 
manner to ensure that subject confidentiality is maintained. 
Checking of the eCRF entries for completeness and clarity, and cross-checking with source 
documents, will be required to monitor the progress of the study. Moreover, regulatory authorities 
of certain countries, IRBs, IECs, and/or the Sponsor’s Clinical Quality Assurance Group may wish 
to carry out such source data checks and/or on-site audit inspections. Direct access to source data 
will be required for these inspections and audits; they will be carried out giving due consideration 
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to data protection and medical confidentiality. The Investigator assures PAREXEL and the Sponsor 
of the necessary support at all times.
10.1.14 Ann Arbor Staging - Cotswolds Recommendations
Table 10–1
Ann Arbor Staging
Stage
Description
I
Involvement of a single lymphatic region (I), or localised involvement of a single 
extralymphatic organ or site (IE).
II
Involvement of 2 or more lymphatic regions on the same side of the diaphragm 
(II); or localised involvement of an extralymphatic organ or site and one or more 
lymph node regions on the same side of the diaphragm (IIE).
III
Involvement of 2 or more lymphatic regions on both sides of the diaphragm (III), 
which also may be accompanied either by localised involvement of extralymphatic 
organ or site (IIIE) or by involvement of the spleen (IIIS) or both (IIIE, S).
IV
Diffuse or disseminated involvement of one or more extralymphatic organ or 
tissue, with or without associated lymph node involvement. Bone marrow or liver 
involvement will always be considered as Stage IV.
Data source:
Ann Arbor Staging: Carbone PP, Kaplan HS, Musshoff K, et al. Report of the committee on Hodgkin's disease staging
classification. Cancer Res. 1971;31:1860-61.
Cotswolds Recommendations: Lister TA, Crowther D, Sutcliffe SB, et al. Staging for Hodgkin's disease. Report of a
committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J
Clin Oncol. 1989;7:1630-36 (Erratum; J Clin Oncol. 1990;8:1602)
 
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10.2 Appendix 2: Clinical Laboratory Tests 
x The tests detailed in Table 10-4 will be performed by the local laboratory. 
x Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Sections 5.1 and 5.2 of the protocol. 
x Additional tests may be performed at any time during the study as determined necessary by 
the Investigator or required by local regulations. 
Table 10-4 
Protocol Required Safety Laboratory Assessments 
Laboratory Assessments 
Parameters 
Haematology 
Haematocrit 
White blood cell with 
differential counts 
(neutrophils, lymphocytes, 
monocytes, eosinophils, and 
basophils)1 
 
Platelet count 
 
Red blood cell count 
 
Total haemoglobin 
Coagulation 
Prothrombin time 
 
Clinical Chemistry 
β-2 microglobulin 
Gamma-glutamyl 
transpeptidase 
 
Albumin 
Lactate dehydrogenase 
 
Alkaline phosphatase 
Phosphate 
 
Alanine aminotransferase 
Potassium 
 
Aspartate aminotransferase 
Random serum glucose 
 
Blood urea nitrogen 
Sodium 
 
Calcium 
Total bilirubin 
 
Chloride 
Total protein 
 
Creatinine 
Uric acid 
 
Creatinine clearance 
(Cockroft Gault formula) 
 
Routine urinalysis (by dipstick 
or any other method) 
Specific gravity 
Bilirubin 
 
pH 
Urobilinogen 
 
Protein 
Nitrite 
 
Glucose 
leukocyte esterase or 
leukocytes 
 
Blood 
Microscopic examination2 
 
Ketones 
 
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Laboratory Assessments 
Parameters 
Other Screening Tests 
Follicle stimulating hormone 
(as needed in women of 
non-childbearing potential 
only e.g., women with 
cessation of menstruation for 
≤ 2 years, peri-menopausal 
women with inconclusive 
menopausal evidences based 
on clinical assessment and 
medical history) 
Serology (HIV antibody, 
HBsAg, hepatitis B core 
antibody, and HCV antibody, 
HBV DNA [as applicable], 
HCV RNA [as applicable]) 
 
COVID-19 testing3: RT-PCR, 
Rapid Antigen test or test 
with similar nature antigen 
test 
 
Serum human chorionic 
gonadotropin (hCG) 
pregnancy test (as needed for 
women of childbearing 
potential) during Screening 
and EOS/ET visits. Serum or 
urine pregnancy tests on Day 
1 and all dosing visits 
If latent TB is suspected 
based on clinical or 
epidemiological grounds, it 
should be further investigated 
using the tuberculosis testing 
as appropriate following 
local practice or investigator 
judgment 
Abbreviations: COVID-19 = Coronavirus disease 2019; DNA = deoxyribonucleic acid; HBsAg = hepatitis B surface 
antigen; HBV = hepatitis C virus; HCV = hepatitis C virus; HIV= human immunodeficiency virus; TB = 
tuberculosis; RNA = ribonucleic acid; RT-PCR = reverse transcription polymerase chain reaction 
1. 
Specific leukocyte populations to be reported as counts; percentages are optional. 
2. 
Microscopic examination to be performed if blood or protein is abnormal. 
3. 
COVID-19 testing may be repeated at the discretion of the Investigator. 
Investigators must document their review of each laboratory safety report. 
Laboratory/analyte results that could unblind the study will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded. 
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10.3 Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
x Premenarchal 
x Premenopausal female with one of the following: 
a. Documented hysterectomy 
b. Documented bilateral salpingectomy 
c. Documented bilateral oophorectomy 
NOTE: Documentation can come from the site personnel’s review of the subject’s medical records, 
medical examination, or medical history interview. 
x Post-menopausal female 
x A post-menopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high FSH level in the post-menopausal range may be used to confirm 
a post-menopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, a 
single FSH measurement is insufficient. 
x Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-oestrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of post-menopausal status before study enrolment. 
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Contraception Guidance: 
Male Subjects: 
Male subjects with female partners of childbearing potential are eligible to participate if they agree 
to ONE of the following during the protocol-defined time frame in Section 5.1: 
x Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent. 
x Agree to use a male condom plus partner use of a contraceptive method with a failure 
rate of <1% per year as described in the table below when having penile-vaginal 
intercourse with a WOCBP who is not currently pregnant. 
In addition, male subjects must refrain from donating sperm for the duration of the study and for 
12 months after the last dose of study drug. 
Male subjects with a pregnant or breastfeeding partner must agree to remain abstinent from penile-
vaginal intercourse or use a male condom during each episode of penile penetration during the 
duration of the study and for 12 months after the last dose of study drug. 
Female Subjects 
Female subjects of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in the table below. 
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Highly Effective Contraceptive Methods That Are User Dependent1 
Failure rate of <1% per year when used consistently and correctly. 
Combined (oestrogen- and progestin-containing) hormonal contraception associated with 
inhibition of ovulation2 
x Oral 
x Intravaginal 
x Transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
x Oral 
x Injectable 
Highly Effective Contraceptive Methods That Are User Independent1 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation2 
x Intrauterine device (IUD) 
x Intrauterine hormone-releasing system (IUS) 
x Bilateral tubal occlusion 
Vasectomized Partner 
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used. 
NOTES: 
1 Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for subjects participating in clinical studies. 
2 Hormonal contraception may be susceptible to interaction with the study intervention, which may reduce the 
efficacy of the contraceptive method. In this case, 2 highly effective methods of contraception should be utilized 
during the treatment period and for at least 12 months after the last dose of study intervention. 
 
Pregnancy Testing 
x Woman of childbearing potential should only be included after a confirmed menstrual period 
and a negative highly sensitive serum pregnancy test. 
x Additional pregnancy testing should be performed at every dosing visit during the treatment 
period and at EOS/ET and whenever pregnancy is suspected or at the discretion of the 
Investigator. 
x Pregnancy testing will be performed whenever a menstrual cycle is missed or when pregnancy 
is otherwise suspected. 
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Collection of Pregnancy Information: 
Male subjects with partners who become pregnant 
x The Investigator will attempt to collect pregnancy information on any male subject’s female 
partner who becomes pregnant while the male subject is in this study. This applies only to male 
subjects who receive study drug. 
x After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and submit 
it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The female partner 
will also be followed to determine the outcome of the pregnancy. Information on the status of 
the mother and child will be forwarded to the Sponsor. Generally, the follow-up will be no 
longer than 12 weeks following the estimated delivery date. Any termination of the pregnancy 
will be reported regardless of foetal status (presence or absence of anomalies) or indication for 
the procedure. 
Female subjects who become pregnant 
x The Investigator will collect pregnancy information on any female subject who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate form 
in the eCRF and submitted to the Sponsor within 24 hours of learning of a subject’s pregnancy. 
The subject will be followed to determine the outcome of the pregnancy. The Investigator will 
collect any follow-up information on the subject and the neonate and the information will be 
forwarded to the Sponsor. Generally, follow-up will not be required for longer than 12 weeks 
beyond the delivery date. Any termination of the pregnancy will be reported, regardless of 
foetal state (presence or absence of anomalies) or indication for the procedure. 
x While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous abortion 
is always considered to be an SAE and will be reported as such. Any post-study pregnancy-
related SAE considered reasonably related to study intervention by the Investigator will be 
reported to the Sponsor as described in Section 8.4.2. While the Investigator is not obligated 
to actively seek this information in former study subjects, he or she may learn of an SAE 
through spontaneous reporting. 
x Any female subject who becomes pregnant while participating in the study will discontinue 
study intervention or will be withdrawn from the study. 
 
 
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10.4 Appendix 4: Genetics 
Not applicable. 
 
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10.5 Appendix 5: Abbreviations and Trademarks 
Abbreviation 
Definition 
18[F]FDG-PET 
Fluorine-18-fluorodeoxyglucose positron emission tomography 
ACR 
American College of Rheumatology 
ADA 
Anti-Drug Antibodies 
ADCC 
Antibody-Dependent Cellular Cytotoxicity 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Concentration-Time Curve 
AUC0-t 
Area Under the Concentration-Time Curve From Time Zero To The 
Last Quantifiable Time Point 
AUEC 
Area Under the Effect Curve 
BAb 
Binding Antibodies 
BORR 
Best Overall Response Rate 
BSA 
Body Surface Area 
CD 
Cluster of Differentiation 
CDC 
Complement-Dependent Cytotoxicity 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
Cmax 
Maximum Serum Concentration 
CNS 
Central Nervous System 
COVID-19 
Coronavirus disease 2019 
CR 
Complete Response 
CRO 
Contract Research Organisation 
CRu 
Unconfirmed Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
Trough Plasma Concentration 
DLBCL 
Diffuse Large B-Cell Lymphoma 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic Acid 
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Abbreviation
Definition
DOR
Duration Of Response
DRL
Dr. Reddy's Laboratories
DRL_RI
Proposed Rituximab Biosimilar
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EMA
European Medicines Agency
EOS
End Of Study
ET
Early termination
EU
European Union
Fc
Fragment Crystallisable
FDA
Food and Drug Administration
FL
Follicular Lymphoma
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GELF
Groupe D’Etude des Lymphomes Folliculaires
HBcAb
Hepatitis B Core Antibody
HBsAg
Hepatitis B Surface Antigen
HBV
Hepatitis B Virus
hCG
Human Chorionic Gonadotropin
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
HPF
High-Power Field
HR
Hazard Ratio
HRT
Hormonal Replacement Therapy
i.v
Intravenous
IB
Investigators’ Brochure
ICF
Informed Consent Form
ICH
The
International
Council
for
Harmonisation
of
Technical
Requirements for Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRRs
Infusion-Related Reactions
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CCI
CCI
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Abbreviation 
Definition 
ITT 
Intent To Treat 
IWRS 
Interactive Web Response System 
kDa 
Kilodaltons 
K-M 
Kaplan-Meier 
LDH 
Lactate Dehydrogenase 
LTB 
Low Tumour Burden 
LTB-FL 
Low Tumour Burden Follicular Lymphoma 
mAb 
Monoclonal Antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
Medical Monitor 
MR 
Maintenance Rituximab 
NAb 
Neutralising Antibodies 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NHL 
Non-Hodgkin’s Lymphoma 
NK 
Natural Killer 
NYHA 
New York Heart Association 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PR 
Partial Response 
QTc 
Corrected QT Interval 
RA 
Rheumatoid Arthritis 
RMP 
Reference Medicinal Product 
RNA 
Ribonucleic acid 
RR 
Rituximab Retreatment 
RT-PCR 
Reverse transcription polymerase chain reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SmPC 
Summary of Product Characteristics 
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Abbreviation 
Definition 
SOPs 
Standard Operating Procedures 
SUSAR 
Suspected Unexpected Serious Adverse Event 
TAT 
Turn Around Time 
TB 
Tuberculosis 
TEAE 
Treatment Emergent Adverse Event 
TTF 
Time to Treatment Failure 
ULN 
Upper Limit of Normal 
US 
United States 
WHO 
World Health Organisation 
WOCBP 
Woman Of Childbearing Potential 
 
 
 
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10.6 Appendix 6: Protocol Amendment History 
DOCUMENT HISTORY 
Document 
Version 
Date 
Amendment 3 
Protocol Version 4 
04 Nov 2020 
Amendment 2 
Protocol Version 3 
04 Dec 2019 
Amendment 1 
Protocol Version 2 
04 Jan 2019 
Original Protocol 
Protocol Version 1 
25 Oct 2018 
 
Amendment 1, 04 Jan 2019 
Overall Rationale for the Amendment: 
The protocol was amended based on protocol review non hold comments from the United States 
Food and Drug Administration (US FDA). One exclusion criterion was added to exclude patients 
with Central Nervous System involvement by lymphoma. Reference to statistical analysis plan 
was provided for detailed algorithm for sample size re-estimation and simulations to show that the 
type-I error rate will be maintained. The method to estimate difference (DRL_RI minus 
MabThera®) and its 95% Confidence Interval (CI) was updated to use exact Binomial method 
(Garner W, 2016; and Chan IS, Zhang Z, 1999); accordingly, the references were updated. In 
addition, a few edits were made for better clarity. The updates made to the protocol as presented 
in a tabular fashion below to reflect the changes made to the text in the previous version of the 
protocol (Version 1). 
Amendment 2, 04 Dec 2019 
Overall Rationale for the Amendment 
The protocol was amended based on protocol review and recommendations by the Regulatory 
Authorities (United States Food and Drug Administration, US FDA). Other administrative 
changes/edits towards more clarity have also been made. These changes from the previous version 
of the protocol, are summarized in a tabulated manner below. 
 
 
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Amendment 3, 04 Nov 2020 
Overall Rationale for the Amendment 
This amendment allows for study inclusion of subjects with past history of hepatitis B or hepatitis 
B serology suggestive of past hepatitis B infection while ensuring that the management practices 
for this condition are in line with current scientific guidelines. 
The protocol is also being amended to reflect contingency measures implemented by the Sponsor 
in the wake of the COVID-19 pandemic.  
A few administrative and minor technical edits towards more clarity have also been made. 
The changes from the previous version of the protocol are summarised in a tabulated manner 
below. 
 
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Amendment 1, 04 Jan 2019 
S. 
No 
Section 
Number and 
Name 
Previous Protocol Text (Version 1) 
Current Protocol Text (Version 2) 
Brief Rationale 
1 
Sections 1.1 
(synopsis) and 
5.2; Exclusion 
Criteria 
- 
Criterion # 6: Known Central Nervous System (CNS) involvement 
by lymphoma. (Note: CNS imaging is not required unless 
clinically indicated.) 
Addition of 
exclusion 
criterion based on 
protocol review 
non-hold 
comments from 
US FDA. 
2 
Section 8.4.9; 
Regulatory 
Reporting 
Requirements 
for Serious 
Adverse 
Events 
- 
Whenever required applicable local SAE reporting Form will be 
used (e.g., Appendix XI in India), in addition to eCRF update 
Added text for 
better clarity 
3 
Section 9.2; 
Sample Size 
Determination 
Full details will be provided in the SAP. 
Full details will be provided in the SAP, especially the detailed 
algorithm for sample size re-estimation and simulations to show 
that the type-I error rate is maintained 
Addition of text 
based on protocol 
review non-hold 
comments from 
US FDA. 
4 
Section 
9.4.1.1; 
Analysis of 
Primary 
Efficacy 
Endpoint 
The estimated difference (DRL_RI minus 
MabThera®) and its 95% CI will be 
obtained using the stratified Miettinen and 
Nurminen method. 23 
The estimated difference (DRL_RI minus MabThera®) and its 
95% CI will be obtained using the test-based exact Binomial 
confidence interval method. 23, 24 
Change in text 
based on protocol 
review non-hold 
comments from 
US FDA. 
5 
Section 9.4.2; 
Safety 
Analyses  
MedDRA (Version 21.1) 
MedDRA (Version 21.1 or latest) 
Addition of text 
for using latest 
available version 
for Medical 
dictionary  
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S. 
No 
Section 
Number and 
Name 
Previous Protocol Text (Version 1) 
Current Protocol Text (Version 2) 
Brief Rationale 
6 
Section 10.1.8; 
Publication 
policy 
The Sponsor shall retain the title and the 
right to publish all documentation, 
records, raw data, specimens or other 
work product generated pertaining to the 
study (“Data”) conducted by the site (site 
includes the Investigator and the 
Institution) as defined in the applicable 
protocol or study plan or study agreement. 
The Sponsor shall retain the title and the right to publish all 
documentation, records, raw data, specimens or other work 
product generated pertaining to the study (“Data”) conducted by 
the site (site includes the Investigator and the Institution). 
Edited text for 
better clarity. 
7 
Section 11; 
References 
Point 23- Miettinen O and Nurminen M. 
(1985) Comparative analysis of two rates 
Stat Med.;Apr-Jun;4(2):213-226. 
Garner W. (2016). Constructing Confidence intervals for the 
differences of Binomial proportions in SAS. Available at: 
https://www.lexjansen.com/wuss/2016/127_Final_Paper_PDF.pdf. 
Accessed on 04 Jan 2019 
Change in 
reference based 
on protocol 
review non-hold 
comments from 
US FDA. 
8 
Section 11; 
References 
- 
Chan IS, Zhang Z. Test-based exact confidence intervals for the 
difference of two binomial proportions. Biometrics. 
1999;55(4):1202-9 
Added new 
reference based 
on protocol 
review non-hold 
comments from 
US FDA. 
 
Amendment 2, 04 Dec 2019 
S. No. 
Section 
number and 
Name 
Previous Protocol V2.0 dated 04 January 2019 
Current Protocol V3.0 dated 04 December 2019 
Brief Rationale 
1. 
Synopsis 
- 
Changes made in various sections of the protocol 
have been reflected in Synopsis 
Changes made in various 
sections of the protocol 
have been reflected in 
the Synopsis. 
 
Please refer to the 
section “Synopsis” in the 
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S. No. 
Section 
number and 
Name 
Previous Protocol V2.0 dated 04 January 2019 
Current Protocol V3.0 dated 04 December 2019 
Brief Rationale 
revised protocol version 
3.0 for details. 
2. 
Section 1.2; 
Schema 
Screening period -4 weeks  
Screening period -5 weeks 
For administrative 
reasons considering 
longer turnaround time 
(TAT) of central 
histopathology lab 
evaluation report. 
3. 
Table 1-1; 
Timing for the 
screening 
Day -28 to -1 
Day -35 to -1 
For administrative 
reasons considering 
longer turnaround time 
(TAT) of central 
histopathology lab 
evaluation report. 
4. 
Table 1-1; 
footnote no.2 
Day 0 and Day 1 can be clubbed into one single 
day. 
Day 0 and Day 1 can be clubbed into one single 
day.  However, randomisation in IWRS and 
administration of first dose of study medication 
should take place on the same day and this will 
be considered as Day 1. 
For better clarity towards 
implementation. 
5. 
Table 1-1; 
footnote no.5  
All eligibility criteria must be met before a subject 
is randomised to study drug. Subjects that do not 
meet all requirements can be rescreened at the 
investigator’s discretion, following discussion 
with the Sponsor/designee Medical Monitor 
All eligibility criteria must be met based on the 
screening assessment before a subject is 
randomised to study drug. Subjects that do not 
meet all requirements can be rescreened at the 
investigator’s discretion, following discussion 
with the Sponsor/designee Medical Monitor 
Added for better clarity 
and in the interest of 
subject safety. 
6. 
Table 1-1; 
footnote no.6  
Subjects can be screened for the study based on a 
diagnosis of CD20-positive, low burden FL 
confirmed at the investigational site. Subjects 
must have sufficient tissue samples available for 
the central pathology review (obtained on or 
within 6 months prior to the screening date) and a 
centrally-confirmed diagnosis prior to being 
randomised. 
Subjects can be screened for the study based on a 
diagnosis of CD20-positive, low burden FL 
confirmed at the investigational site. Subjects 
must have sufficient tissue samples available for 
the central pathology review (obtained on or 
within 12 months prior to the screening date) and 
a centrally-confirmed diagnosis prior to being 
randomised. 
Added in the interest of 
subject, invasive nature 
of procedure and 
indolent course of 
disease under study. 
7. 
Table 1-1; 
footnote no.8 
Temperature, blood pressure, pulse rate, and 
respiratory rate will be recorded at each time 
point. Vital signs will be monitored every 
Temperature, blood pressure, pulse rate, and 
respiratory rate will be recorded at each time 
point. Vital signs will be monitored every 
For better 
implementation and 
clarity. 
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S. No. 
Section 
number and 
Name 
Previous Protocol V2.0 dated 04 January 2019 
Current Protocol V3.0 dated 04 December 2019 
Brief Rationale 
30 minutes during the course of the treatment 
administration and at end of infusion or more 
frequently as necessary. 
30 minutes (±5 minutes) during the course of the 
treatment administration and at end of infusion or 
more frequently as necessary. 
8. 
Table 1-1; 
footnote no.11 
Tuberculosis testing (QuantiFERON®-TB Gold-
in-Tube test - QFT-GIT or QuantiFERON®-TB 
Gold Plus) is requested only if it is required by 
local regulations or practice 
If latent TB is suspected based on clinical or 
epidemiological grounds, it should be further 
investigated using the tuberculosis testing as 
appropriate following local practice or 
investigator judgment.  
For better clarity towards 
implementation. 
9. 
Table 1-1; 
footnote no.13 
Tumour assessments for the purpose of assessing 
subject eligibility (with central imaging 
confirmation) and medical care will be performed 
by the investigational site at Screening, Weeks 12, 
28, and 52 (EOS/ET Visit) by reviewing CT scans 
(Neck, chest, abdomen, and pelvis) with contrast. 
Computed tomography scans obtained up to 
4 weeks prior to the first administration of study 
drug may be used for determining study eligibility 
provided they are of adequate quality for 
subsequent central 
review……………..Assessments are NOT to be 
scheduled based on the previous imaging time 
point, but rather Day 1 should be used as the 
Baseline when calculating when the on-study 
tumour assessments are to be performed (with 
consideration of visit windows). 
Tumour assessments for the purpose of assessing 
subject eligibility (with central imaging 
confirmation) and medical care will be performed 
by the investigational site at Screening, Weeks 12, 
28, and 52 (EOS/ET Visit) by reviewing CT scans 
(Neck, chest, abdomen, and pelvis) with contrast. 
Computed tomography scans obtained up to 
6 weeks prior to the first administration of study 
drug may be used for determining study eligibility 
provided they are of adequate quality for 
subsequent central review………Assessments are 
NOT to be scheduled based on the previous 
imaging time point, but rather Day 1 should be 
used as the Baseline when calculating when the 
on-study tumour assessments are to be performed 
(with consideration of visit windows). 
For implementing  
uniformity of timings of 
imaging modalities 
allowed for the purpose 
of eligibility. 
10. 
Table 1-1; 
footnote 15 
Bone marrow biopsies or aspirations performed up 
to 6 weeks prior to the first administration of study 
drug may be used. Additional bone marrow 
biopsies are required for any subject who has a 
response of CR at an evaluation point and either 
had a bone marrow examination positive for FL at 
Screening or shows new abnormalities in the 
peripheral blood counts or blood smear that 
clinically indicates a bone marrow evaluation is 
required. 
Bone marrow biopsies or aspirations performed up 
to 12 weeks prior to the first administration of 
study drug may be used. Additional bone marrow 
biopsies are required for any subject who has a 
response of CR at an evaluation point and either 
had a bone marrow examination positive for FL at 
Screening or shows new abnormalities in the 
peripheral blood counts or blood smear that 
clinically indicates a bone marrow evaluation is 
required. 
In the interest of subject 
considering invasive 
nature of the 
biopsies/aspirations and 
indolent nature of the 
disease under study. 
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11. 
Table 1-1; 
footnote 16 
All the baseline assessments must be reviewed by 
the investigators for final eligibility assessment 
before randomisation of the subject 
Before randomisation of the subject, all the 
baseline assessments must be reviewed by the 
investigators for suitability of starting the study 
treatment. 
For better clarity. 
12. 
Section 2.2. 
Background; 
subsection 
2.2.3 Efficacy 
of Rituximab 
in Low 
Tumour 
Burden 
Follicular 
Lymphoma 
A total of 463 subjects were randomised (187 Arm 
A, 84 Arm B, and 192 Arm C) with 95% of 
subjects having low tumour burden (LTB) 
according to the Groupe D’Etude des Lymphomes 
Folliculaires (GELF) criteria. 
A total of 463 subjects were randomised (187 Arm 
A, 84 Arm B, and 192 Arm C) with 95% of 
subjects having low tumour burden (LTB) 
according to predefined criteria similar to the 
Groupe D’Etude des Lymphomes Folliculaires 
(GELF) criteria. 
For better clarity. 
13. 
A secondary 
objective in the 
Section 3; 
Objectives and 
endpoints 
To compare the PFS, ORR at Week 12, OS and 
duration of response (DOR) of DRL_RI with 
MabThera® in subjects with CD20-positive, 
LTB-FL. 
To compare the ORR at Week 12, CR at 28 
weeks duration of response (DOR), PFS and OS 
of DRL_RI with MabThera® in subjects with 
CD20-positive, LTB-FL. 
Added to comply with 
Regulatory Authority 
advice. 
14. 
Secondary 
endpoint in the 
Section 3; 
Objectives and 
endpoints 
- 
Complete Response (CR) rate at Month 7 
(Week 28). 
Added to comply with 
Regulatory Authority 
advice. 
15. 
Secondary 
endpoint in the 
Section 3; 
Objectives and 
endpoints 
x 
Progression-free survival defined as the time 
from date of randomisation to the date of 
documented progressive disease (PD) or death 
due to any cause. 
x 
Overall response rate at Week 12 based on 
central radiology review in accordance with 
published response criteria for malignant 
lymphoma 13. 
x 
Overall survival defined as the time from date 
of randomisation to the date of death from any 
cause up to 52 weeks/End of Study (EOS). 
x 
Overall response rate at Week 12 based on 
central radiology review in accordance with 
published response criteria for malignant 
lymphoma13. 
x 
Complete Response (CR) rate at Month 7 
(Week 28). 
x 
Duration of response defined as the time from 
date of the first documentation of tumour 
response (CR, CRu or PR) to the date of first 
documentation of PD or to death due to any 
cause up to 52 weeks/EOS. 
Rearrangement of the 
secondary endpoints to 
follow the chronological 
order in which they are 
determined in the Study. 
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x
Duration of response defined as the time from
date of the first documentation of tumour
response (CR, CRu or PR) to the date of first
documentation of PD or to death due to any
cause up to 52 weeks/EOS.
x
Adverse events, clinical laboratory values,
vital signs, and electrocardiogram (ECG)
x
Anti-rituximab antibodies and their
relationship with other outcome measures.
x
Progression-free survival defined as the time
from date of randomisation to the date of
documented progressive disease (PD) or death
due to any cause.
x
Overall survival defined as the time from date
of randomisation to the date of death from any
cause up to 52 weeks/End of Study (EOS).
x
Adverse events, clinical laboratory values,
vital signs, and electrocardiogram (ECG)
x
Anti-rituximab antibodies and their
relationship with other outcome measures.
16.
Section 4.1.1;
Description
The study will enrol subjects with CD20-positive,
LTB-FL who are asymptomatic for lymphoma
specific B-symptoms. LTB-FL will be assessed
according to the GELF criteria.3
The study will enrol subjects with CD20-positive,
LTB-FL who are asymptomatic for lymphoma
specific B-symptoms. LTB-FL will be assessed
according to the GELF based criteria.3, 9
For better clarity.
17.
Section 4.1.1;
Description
Randomisation will be stratified by low, medium,
and high-risk subjects using the
(
,
), as
well
ell as by tumour grad
ade an
and geo
eograp
aphical
ical ararea
ea.
Randomisation will be stratified by low, medium,
and high-risk subjects using the
(
,
), as
well
ell as by tumour grad
ade (1
(1-2 Vs.
Vs. 3a) an
and
geographical area (USA, Europe and Asia-
Pacific region).
For better clarity and to
further specify the
randomization strata.
18.
Section 4.2;
Schedule of
assessments
The study will enrol subjects with LTB-FL who
are asymptomatic for lymphoma specific
B-symptoms. LTB-FL will be assessed according
to the GELF criteria. 9,16
The study will enrol subjects with LTB-FL who
are asymptomatic for lymphoma specific
B-symptoms. LTB-FL will be assessed according
to GELF based criteria. 9, 16
For better clarity.
19.
Section 4.3;
Scientific
rationale for
study design
Low tumour burden will be assessed according to
the GELF criteria.9,16A serum LDH level within
normal limits will be required for enrolment as
LDH is an important prognostic factor in FL.
Low tumour burden will be assessed according to
GELF based criteria. 9, 16A serum LDH level
within normal limits will be required for
enrolment as LDH is an important prognostic
factor in FL.
For better clarity.
20.
Section 5.1;
inclusion
criterion 3
Histologically confirmed, Grade 1-3a, previously
untreated, CD20-positive, LTB-FL as per GELF
criteria. Subjects must have tissue available for the
Histologically confirmed, Grade 1-3a, previously
untreated, CD20-positive, LTB-FL as per
GELF-based criteria. Subjects must have tissue
For better clarity.
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central pathology review and a 
centrally-confirmed diagnosis prior to being 
randomised. 
available for the central pathology review and a 
centrally-confirmed diagnosis prior to being 
randomised. 
21. 
Section 5.1; 
inclusion 
criterion 4 
Ann Arbor Stage II to IV of histological Grade 1, 
2, or 3a (Section 10.1.14). 
Ann Arbor Stage II to IV (Section 10.1.14). 
Deleted repetitive text. 
22. 
Section 5.1; 
inclusion 
criterion 6 
As per central radiological assessment, 
involvement of <3 nodal sites with diameter 
measuring >3 cm 
As per central radiological assessment, 
involvement of ≤3 nodal sites with diameter 
measuring >3 cm 
To add clarity and to 
ensure the inclusion 
criteria are in alignment 
with those in the 
reference documents 
from which the design 
data (and thus the 
study’s statistical 
assumptions) were 
obtained. 
23. 
Section 5.2; 
exclusion 
criterion 8 
Prior malignancy other than non-melanoma skin 
cancer or intraepithelial cervical neoplasia, 
successfully treated more than 1 year before study 
inclusion. 
Prior malignancy (including recurrence) within 
5 years of screening, other than non-melanoma 
skin cancer or intraepithelial cervical neoplasia, 
which should have been successfully treated 
more than 1 year before study inclusion. 
Added clarity with 
respect to prior 
malignancies. 
24. 
Section 5.2 
exclusion 
criterion 10 
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 drug (Day 1). Tuberculosis testing 
(QuantiFERON®-TB Gold-in-Tube test - QFT-
GIT or QuantiFERON®-TB Gold Plus) is 
requested only if it is required by local regulations 
or practice. 
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 drug (Day 1). If latent TB is suspected 
based on clinical or epidemiological grounds, it 
should be further investigated using the 
tuberculosis testing as appropriate following 
local practice or investigator judgment. 
To add clarity for better 
implementation. 
25. 
Section 5.2 
exclusion 
criterion 19 
Subject has been previously enrolled and/or 
randomised in this study. 
Subject has been previously randomised in this 
study. 
For better clarity. 
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26.
Section 6.2;
study drugs
administered
Subjects will be randomised in a 1:1 ratio to one
of the 2 study treatment arms taking into account
stratification by low-, medium-, and high-risk
subjects using the
index (
),
tumour grade, and geo
eograp
aphical ararea
ea:
Subjects will be randomised in a 1:1 ratio to one
of the 2 study treatment arms taking into account
stratification by low-, medium-, and high-risk
subjects using the
index (
),
tumour grade(1-2 Vs.
Vs. 3a), and geo
eograp
aphical
ical ararea
ea
(USA, Europe and Asia-Pacific region):
For better clarity and to
elaborate on the
randomization strata.
27.
Section 6.4;
Measures to
minimise bias:
Randomisation
and Blinding
The randomisation codes will be
computer-generated and kept by a statistician
independent from the project team. Randomisation
will be stratified by low, medium, and high-risk
subjects using
(
), as well as
by tumour grad
ade an
and geo
eograp
aphical
ical ararea
ea.
The randomisation codes will be
computer-generated and kept by a statistician
independent from the project team. Randomisation
will be stratified by low, medium, and high-risk
subjects using
(
), as well as
by tumour grad
ade (1
(1-2 Vs.
Vs. 3a) an
and geo
eographical
area (USA, Europe and Asia-Pacific region).
For better clarity and to
elaborate on the
randomization strata.
28.
Section 6.8;
Dose
modification
or delays
Any delays beyond what is mentioned above
should be discussed with Contract Research
Organisation (CRO) Medical Monitor.
Any delays beyond what is mentioned above
should be discussed in detail. If the out of window
visit is on account of an adverse event or for
safety related reasons, discussion with Medical
Monitor (MM) is required, hence please contact
your CRO MM under these circumstances. And if
any social / other reasons lead to an out of window
visit, then please document the reason for visit
delay by adding a note/ short description in eCRF.
Every out of window visit (irrespective of the
reason) should be documented as a deviation.
More detailed provided
for better clarity.
29.
Section 8.1.1
8.1.1
Screening (Day ˗28 to ˗1)
Subjects will undergo a Screening Visit at least 0
days, but not more than 28 days prior to the
planned first day of blinded study drug.
8.1.1
Screening (Day ˗35 to ˗1)
Subjects will undergo a Screening Visit at least 0
days, but not more than 35 days prior to the
planned first day of blinded study drug.
For administrative
reasons considering long
turnaround time (TAT)
of central histopathology
lab evaluation report.
30.
Section 8.1.1
(In
chronological
order of the
assessments)
5. Histological confirmation of diagnosis (subjects
can be screened for the study based on a diagnosis
of CD20-positive, low burden FL confirmed at the
investigational site). Subjects must have sufficient
tissue samples available for the central pathology
5. Histological confirmation of diagnosis (subjects
can be screened for the study based on a diagnosis
of CD20-positive, low burden FL confirmed at the
investigational site). Subjects must have sufficient
tissue samples available for the central pathology
Added in the interest of
the subject considering
invasive nature of
procedure and indolent
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review (obtained on or within 6 months prior to 
the screening date), and a centrally-confirmed 
diagnosis prior to being randomised. 
review (obtained on or within 12 months prior to 
the screening date), and a centrally-confirmed 
diagnosis prior to being randomised. 
nature of disease under 
study. 
31. 
Section 8.1.1  
(In 
chronological 
order of the 
assessments) 
18. Bone marrow biopsy (if no previous biopsy 
within the last 6 weeks before dosing is available). 
Procedures can be performed locally. 
18. Bone marrow biopsy (if no previous biopsy 
within the last 12 weeks before dosing is 
available). Procedures can be performed locally. 
For better 
implementation of the 
study procedures. 
32. 
Section 8.1.2 
Treatment 
period 
Eligible subjects will return to the study site for 
the Baseline (Day 0 to Day 1) Visit. Subjects must 
satisfy inclusion/exclusion criteria in order to be 
eligible for randomisation. All the baseline 
assessments must be reviewed by the investigators 
for final eligibility assessment before 
randomisation of the subject. 
Eligible subjects will return to the study site for 
the Baseline (Day 0 to Day 1) Visit. Subjects must 
satisfy inclusion/exclusion criteria in order to be 
eligible for randomisation. Before randomisation 
of the subject, all the baseline assessments must 
be reviewed by the investigators for suitability of 
starting study treatment. 
For better clarity. 
33. 
Section 8.1.2 
Treatment 
period 
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. 
Baseline procedures and assessments should be 
conducted in chronological order as follows: 
1. Re-review subject eligibility (inclusion 
and exclusion) criteria based on the 
screening assessment to ensure that the 
subject continues to be eligible for 
inclusion into the study. 
For better 
implementation and 
clarity. 
34. 
Section 8.3.2; 
Vital Signs 
Vital signs are to be obtained prior to each study 
drug infusion, every 30 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’s judgment. 
Vital signs are to be obtained prior to each study 
drug 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’s judgment. 
For better 
implementation and 
clarity. 
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35. 
Section 8.3.4; 
Clinical safety 
laboratory 
assessments 
Other screening tests: FSH (as needed in women 
of non-childbearing potential only), serum β-hCG, 
and urine pregnancy test (for women of 
childbearing potential), serology (HIV antibody, 
hepatitis B surface antigen [HBsAg], hepatitis B 
core antibody, and HCV antibody). TB screening 
(QuantiFERON®-TB Gold-in-Tube test - QFT-
GIT or QuantiFERON®-TB Gold Plus) is 
requested only if it is required by local regulations 
or practice. 
Other screening tests: FSH (as needed in women 
of non-childbearing potential only e.g., women 
with cessation of menstruation for ≤ 2 years,  peri-
menopausal women with inconclusive menopausal 
evidences based on  clinical assessment and 
medical history), serum β-hCG, and urine 
pregnancy test (for women of childbearing 
potential), serology (HIV antibody, hepatitis B 
surface antigen [HBsAg], hepatitis B core 
antibody, and HCV antibody). If latent TB is 
suspected based on clinical or epidemiological 
grounds, it should be further investigated using 
the tuberculosis testing as appropriate 
following local practice or investigator 
judgment. 
To add clarity for better 
implementation. 
36. 
Section 9.1.1; 
General 
principles 
- 
An additional analysis may be performed based 
on country specific requests/requirements by 
the relevant Authorities 
For better clarity. 
37. 
Section 9.4.1.2;  x 
Progression-free survival defined as the time 
from date of randomisation to the date of 
documented PD or death due to any cause. 
x 
Overall response rate at Week 12 based on 
central radiology review in accordance with 
the response criteria for malignant 
lymphoma.13 
x 
Overall survival defined as the time from date 
of randomisation to the date of death from any 
cause up to 52 weeks/EOS. 
x 
Duration of response defined as the time from 
date of the first documentation of tumour 
response (CR, CRu or PR) to the date of first 
documentation of PD or to death due to any 
cause up to 52 weeks/EOS 
Secondary efficacy endpoints include the 
following: 
x 
Overall response rate at Week 12 based on 
central radiology review in accordance with 
the response criteria for malignant 
lymphoma.13 
x 
Complete Response (CR) rate at Month 7 
(Week 28). 
x 
Duration of response defined as the time from 
date of the first documentation of tumour 
response (CR, CRu or PR) to the date of first 
documentation of PD or to death due to any 
cause up to 52 weeks/EOS. 
Addition of secondary 
end point as detailed in 
change no. 13 above and 
the rearrangement of the 
endpoints to follow the 
chronological order in 
which they are 
determined in the Study 
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x 
Progression-free survival defined as the time 
from date of randomisation to the date of 
documented PD or death due to any cause. 
x 
Overall survival defined as the time from date 
of randomisation to the date of death from 
any cause up to 52 weeks/EOS. 
38. 
Section 10.1.6 
Data 
monitoring 
committee 
- 
Section 10.1.6 Data Monitoring Committee 
An independent Data Monitoring Committee 
(DMC) will be established for the study, and 
operate according to procedures described in 
the DMC Charter. All meeting proceedings will 
be documented.  
Added to reflect set up of 
DMC for the study. 
The numbers of 
subsequent subsection 
numbers till 10.1.14 are 
changed. 
39. 
Table 10.4 
Parameters for 
other 
screening tests 
Follicle stimulating hormone (as needed in women 
of non-childbearing potential only. 
Serum or urine human chorionic gonadotropin 
(hCG) pregnancy test (as needed for women of 
childbearing potential) 
Follicle stimulating hormone (as needed in women 
of non-childbearing potential only e.g. women 
with cessation of menstruation for ≤ 2 years, 
peri-menopausal women with inconclusive 
menopausal evidences based on clinical 
assessment and medical history) 
Serum or urine human chorionic gonadotropin 
(hCG) pregnancy test (as needed for women of 
childbearing potential) 
To add clarity for better 
implementation. 
40. 
Table 10-4 
Parameters for 
other 
screening tests 
TB screening (QuantiFERON®-TB Gold-in-Tube 
test - QFT-GIT or QuantiFERON®-TB Gold Plus) 
is requested only if it is required by local 
regulations or practice 
If latent TB is suspected based on clinical or 
epidemiological grounds, it should be further 
investigated using the tuberculosis testing as 
appropriate following local practice or 
investigator judgment. 
To add clarity for better 
implementation. 
41. 
Section 10.5 
Appendix 5 
Abbreviations 
and 
trademarks 
- 
DMC- Data Monitoring Committee 
TAT- Turn Around Time 
List of abbreviations 
updated. 
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S. No.
Section number and Name
Previous Protocol V3.0 dated
04 December 2019
Current Protocol V4.0 dated 04 November 2020
Brief Rationale
1.
Key Study Personnel;
Medical Monitors
To align with updated
list of medical
monitors.
2
Synopsis
-
Changes made in various sections of the protocol have
been reflected in Synopsis
Changes made in
various sections of the
protocol have been
reflected in the
Synopsis.
Please refer to Section
1.1 Synopsis in the
revised protocol
version 4.0 for details.
3
Table 1-1; Viral disease
screening
Screening
Screening, Week 12, 20, 28, 36, Week 44, and Week
52
For subjects with
history of hepatitis B
requiring HBV DNA
and subjects with
history of Hepatitis C
requiring HCV RNA at
Screening.
4
Table 1-1; footnote no.9
Women of childbearing
potential will have a serum
pregnancy test during
screening and a urine
pregnancy test on Day 1 prior
to randomisation, and all
subsequent study drug dosing
visits.
Women of childbearing potential will have a serum
pregnancy test during Screening and urine or serum
pregnancy tests on Day 1 prior to randomisation, and all
subsequent study drug dosing visits.
Edited for improved
clarity and
implementation.
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5 
Table 1-1; footnote no.12 
Hepatitis B surface antigen, 
hepatitis B core antibody, 
hepatitis C virus, and/or 
human immunodeficiency 
virus to be conducted by local 
laboratory 
Hepatitis B surface antigen, hepatitis B core antibody, 
HBV DNA (as applicable), HCV RNA (as 
applicable), hepatitis C virus, and/or human 
immunodeficiency virus to be conducted by local 
laboratory. HBV DNA at Screening, Week 12 and all 
visits from Week 12 onwards (only for subjects with 
history of hepatitis B or hepatitis B serology 
suggestive of past hepatitis B infection). Additional 
monitoring/management of subjects who were HCV 
antibody positive (and HCV RNA negative) at 
Screening should be done in accordance with local 
practice and standard of care. 
To allows for study 
inclusion of subjects 
with past history of 
hepatitis B or hepatitis 
B serology suggestive 
of past hepatitis B 
infection and subjects 
with history of 
hepatitis C while 
ensuring that the 
management practices 
for this condition are 
in line with current 
scientific guidelines. 
6 
Table 1-1; COVID-19 
testing 
- 
Baseline 
For adherence with 
contingency measures 
implemented during 
the COVID-19 
pandemic. 
7 
Table 1-1; COVID-19 
related screening 
questionnaire 
- 
Every Visit 
For adherence with 
contingency measures 
implemented during 
the COVID-19 
pandemic. 
8 
Table 1-1; footnote no.21 
- 
COVID-19 testing (RT-PCR, Rapid Antigen test or 
test with similar nature antigen test but no antibody 
test) to be performed as close as possible but no 
more than 4 days before first dose administration. 
COVID-19 testing may be repeated at the discretion 
of the Investigator. Subjects should be randomised 
only after negative COVID-19 test result. 
For adherence with 
contingency measures 
implemented during 
the COVID-19 
pandemic in the 
interest of subject 
safety. 
9 
Section 3 Objectives and 
Endpoints; Secondary 
endpoints 
Anti-DRL_RI antibodies 
Anti-rituximab antibodies 
Updated to reflect the 
actual assessment and 
better clarity. 
10 
Section 4.1.1 Description 
- 
coronavirus disease 2019 (COVID-19) testing at 
screening and as deemed appropriate by the Investigator 
at any time during the study. 
For consistency and 
clarity. 
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Subjects with a prior history of hepatitis B infection or 
serological tests suggestive of previous hepatitis B 
infection will continue to receive hepatitis B virus 
(HBV) antiviral prophylaxis therapy for at least 12 
months post last dose of rituximab in the study and will 
be monitored and reported for reactivation for up to 24 
months following completion of rituximab therapy. 
11 
Section 4.5 End of Study 
Definition 
Clinical assessments will 
include the following: Physical 
examination (including 
weight), vital signs 
measurement (blood pressure, 
heart rate, respiration rate, and 
oral body temperature). 
Clinical assessments will include the following: 
Physical examination (including weight), vital signs 
measurement (blood pressure, heart rate, respiration 
rate, and oral, axillary, or tympanic body temperature). 
For consistency and 
clarity. 
12 
Section 5.1 Inclusion 
Criteria; Inclusion criterion 
no.3 
Histologically confirmed, 
Grade 1-3a, previously 
untreated, CD20-positive, 
LTB-FL as per GELF based 
criteria. Subjects must have 
tissue available for the central 
pathology review and a 
centrally-confirmed diagnosis 
prior to being randomised. 
Should a subject be eligible as 
per the central imaging review 
but not as per the Study Centre 
Review the subject will be 
considered eligible if 
confirmed both by the 
Investigator and the Medical 
Monitor (MM). For any other 
disagreement in eligibility the 
subject will be considered 
ineligible. 
Histologically confirmed, Grade 1-3a, previously 
untreated, CD20-positive, LTB-FL as per GELF based 
criteria. Subjects must have sufficient tissue samples 
available for the central pathology review ( 
Section 8.1.1), and a centrally-confirmed diagnosis 
prior to being randomised. Should a subject be eligible 
as per the central imaging review but not as per the 
Study Centre Review the subject will be considered 
eligible if confirmed both by the Investigator and the 
Medical Monitor (MM). For any other disagreement in 
eligibility the subject will be considered ineligible. 
Updated for clarity and 
consistency with rest 
of the protocol. 
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13 
Section 5.2 Exclusion 
Criteria; Exclusion 
criterion no.9 
Subjects with any of the 
following: known 
seropositivity for or history of 
active viral infection with 
human immunodeficiency 
virus (HIV). 
Subjects with any of the following: known 
seropositivity for or history of active viral infection with 
human immunodeficiency virus (HIV), hepatitis B 
surface antigen (HBsAg) positive or hepatitis B core 
antibody positive, hepatitis C virus (HCV) antibody 
positive. 
Separate exclusion 
criterion (no.10) for 
known seropositivity 
or history of active 
hepatitis B and 
hepatitis C infections 
was created. 
14 
Section 5.2 Exclusion 
Criteria; Exclusion 
criterion no.10 
- 
Subjects with positive serological test for hepatitis B 
surface antigen (HBsAg), hepatitis B core antibody 
(HBcAb) or hepatitis C virus (HCV) antibody can 
only be included in the study if any of the following 
is fulfilled. 
x 
Subjects with a negative HBsAg and positive 
total HBcAb must have a HBV 
deoxyribonucleic acid (DNA) level <20 
IU/mL (or 112 copies/mL) by polymerase 
chain reaction (PCR) to participate in the 
study. In addition, it is required for these 
subjects to follow consultation with a 
hepatologist / relevant expert regarding 
initiation, monitoring, and use of HBV 
antiviral therapy and the subject must be 
willing to undergo PCR HBV DNA testing 
during treatment and agree to receive 
treatment as indicated. HBV DNA re-test 
will be performed as per the schedule of 
assessments (ref. table no. 1-1) and further 
as needed, at the discretion of the 
Investigator. 
x 
Subjects with a positive test because of HBV 
vaccination may be included (i.e., HBsAg 
negative, anti-HBs+, HBcAb–). 
x 
Subjects positive for HCV antibody are 
eligible only if the PCR test for HCV 
ribonucleic acid (RNA) is negative. 
To allows for study 
inclusion of subjects 
with past history of 
hepatitis B or hepatitis 
B serology suggestive 
of past hepatitis B 
infection and subjects 
with history of 
hepatitis C while 
ensuring that the 
management practices 
for this condition are 
in line with current 
scientific guidelines. 
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15 
Section 5.2 Exclusion 
Criteria; Exclusion 
criterion no.12  
Subjects who have received a 
live vaccine within last or non-
live vaccine within 4 weeks of 
the first administration of 
study drug. 
Subjects who have received a live vaccine within last 3 
months or non-live vaccine within 4 weeks of the first 
administration of study drug. [Note: A need may arise 
for trial subjects to receive vaccine against 
COVID-19 while being a part of the study. All such 
decisions will be taken at the discretion of the 
Investigator in consultation with the CRO / Sponsor 
after due consideration to subjects’ safety, national 
health policy of the respective country and overall 
need by the subject for such vaccine during the time 
of study participation]. 
Updated for adherence 
with contingency 
measures implemented 
during the COVID-19 
pandemic. 
16 
Section 6 Study 
Intervention 
Section 6.9 The End of the 
Study 
Section 6.9 Study medication access after the End of 
the Study 
Sub-heading updated 
for clarity. 
17 
Section 6 Study 
Intervention 
Section 6.10 Management of 
Hepatitis Reactivation and 
Other Infections during 
Rituximab Therapy 
Section 6.10 Guidance for hepatitis B and hepatitis C 
seropositive subjects  
Sub-heading updated 
for clarity. 
18 
Section 6.10 Guidance for 
hepatitis B and hepatitis C 
seropositive subjects 
- 
Subjects who show evidence of prior hepatitis B 
infection may participate in the study following 
consultation with a Hepatologist / relevant expert 
regarding monitoring and use of HBV antiviral 
therapy, and provided that subjects agree to receive 
and comply with HBV testing and hepatitis B 
prophylactic therapy as recommended by the 
Investigator, treating hepatologist, or relevant 
expert. HBV re-test will be performed as per 
schedule of assessment (see Table 1–1) and further at 
the discretion of the Investigator. 
Additional monitoring/management of subjects who 
had HCV antibody positive (and HCV RNA 
negative) at Screening should be done in accordance 
with local practice and standard of care. 
Subjects will continue to receive HBV antiviral 
prophylaxis therapy for at least 12 months post last 
dose of rituximab in the study (i.e. 36 weeks, or 
earlier in case of ET), and will be monitored as 
recommended by hepatitis experts in accordance 
Added to ensure safety 
of subjects who show 
evidence of prior 
hepatitis B and 
hepatitis C infection as 
per the management 
practices for this 
condition in line with 
the current scientific 
guidelines. 
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with local practice and guidelines. HBV reactivation 
will be monitored and reported for up to 24 months 
following completion of rituximab therapy. If any 
subject develops reactivation of HBV or any other 
significant infections while on rituximab, the 
Investigator should immediately discontinue study 
drug, consult with hepatitis experts, and institute 
appropriate treatment. For details and management 
of other infections, refer to the current marketed 
rituximab prescribing information. 
It will be the Investigator’s responsibility to ensure 
compliance to the antiviral treatment, regular 
follow-up for monitoring (i.e. laboratory tests, 
clinical examination, AE evaluation) with the 
Hepatologist / relevant expert of Hepatitis B 
seropositive subjects and reporting of any 
reactivation events to the Sponsor immediately 
during and post study follow up period of 24 months 
post last dose of rituximab. The investigator has to 
periodically update to the Sponsor about all such 
follow-up visits, treatment compliance with antiviral 
and other medications, tests results, and Hepatitis B 
reactivation for up to 24 months post last study dose 
of rituximab. Detailed procedure and the needed 
documentation to ensure compliance to post study 
follow up and measures will be outlined in an 
amended study agreement between the Sponsor / 
Designee and the Investigator. 
Post study period of 52 weeks, all safety related 
events to be reported directly to the Sponsor’s e mail 
address- pharmacovigilance@drreddys.com. 
19 
Section 8.1 Study 
Assessments 
- 
Completion of a COVID-19 related screening 
questionnaire. 
Added to each visit for 
adherence with 
contingency measures 
implemented during 
the COVID-19 
pandemic. 
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20 
Section 8.1 Study 
Assessments 
Clinical assessments will 
include the following: Physical 
examination (including a 
thorough assessment of the 
lymph nodes, liver, spleen, 
height and weight), vital signs 
measurement (blood pressure, 
heart rate, respiration rate, and 
oral temperature). 
Clinical assessments will include the following: 
Physical examination (including a thorough assessment 
of the lymph nodes, liver, spleen, height and weight), 
vital signs measurement (blood pressure, heart rate, 
respiration rate, and oral, axillary, or tympanic body 
temperature). 
Added to each visit for 
clarity. 
21 
Section 8.1.1 Screening 
(Day -35 to -1) 
The proposed chronological 
order of the assessments below 
should be followed. 
The proposed chronological order of the assessments 
below suggested to be conducted in the following 
chronological order should be followed. 
Edited for clarity. 
22 
Section 8.1.1 Screening 
(Day -35 to -1); assessment 
no.14 
Viral disease screening: 
hepatitis B surface antigen 
(HBsAg), hepatitis B core 
antibody (anti-HBc), HCV, 
and/or HIV. 
Viral disease screening: hepatitis B surface antigen 
(HBsAg), HBcAbhepatitis B core antibody (anti-HBc), 
HBV DNA (as applicable), HCV RNA (as 
applicable), HCV, and HIV. 
Added for improved 
implementation and 
clarity. 
23 
Section 8.1 Study 
Assessments; Maintenance 
Treatment Period, Follow-
up Period, and End of 
Study 
- 
Viral disease screening: HBV DNA (as applicable) 
and HCV RNA (as applicable). 
Added for improved 
implementation and 
clarity. 
24 
Section 8.1.2 Treatment 
Period; Baseline Visit 
Baseline procedures and 
assessments should be 
conducted in chronological 
order as follows: 
Baseline procedures and assessments suggested should 
to be conducted in the following chronological order as 
follows: 
Edited for improved 
clarity and 
implementation. 
25 
Section 8.1.2 Treatment 
Period; Baseline Visit 
(Day 0 to Day 1, prior to 
randomization and 
administration of the study 
drug) 
- 
COVID-19 testing (RT-PCR, Rapid Antigen test or 
test with similar nature antigen test but no antibody 
test) to be performed as close as possible but no 
more than 4 days before first dose administration. 
Thus, COVID-19 testing may also be performed 
during the last few days of the screening window, 
ensuring maximum time gap of 4 days between first 
dose of the study drug and COVID-19 testing. 
For clarity and 
adherence with 
contingency measures 
implemented during 
the COVID-19 
pandemic and in the 
interest of subject 
safety. 
26 
Section 8.1.2 Treatment 
Period; Baseline Visit 
(Day 0 to Day 1, prior to 
Urine pregnancy test 
(performed locally, according 
to local practice). 
Urine or serum pregnancy test (performed locally, 
according to local practice). 
Added for improved 
implementation and 
clarity. 
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randomization and 
administration of the study 
drug) 
27 
Section 8.1.2 Treatment 
Period; Study Days 8, 15 
and 22 (Week 2 to Week 
4 ± 2 days) 
Urine pregnancy test 
(performed locally, according 
to local practice). 
Urine or serum pregnancy test (performed locally, 
according to local practice). 
Added for improved 
implementation and 
clarity. 
28 
Section 8.1.2 Treatment 
Period; Week 12 to Week 
36 ± 7 days 
Urine pregnancy test 
(performed locally, according 
to local practice). 
Urine or serum pregnancy test (performed locally, 
according to local practice). 
Added for improved 
implementation and 
clarity. 
29 
Section 8.1.4 End of Study; 
Clinical laboratory tests: 
Blood and urine samples will 
be taken for haematology, 
biochemistry, coagulation, 
urinalysis, and pregnancy 
tests. 
 
Clinical laboratory tests: Blood and urine samples will 
be taken for haematology, biochemistry, coagulation, 
urinalysis, and serum pregnancy tests. 
 
Added for improved 
implementation and 
clarity. 
30 
Section 8.3.2 Vital Signs 
Vital signs, including heart 
rate, blood pressure, 
respiratory rate, and oral or 
tympanic body temperature, 
will be measured as detailed in 
Table 1–1 and in the event of 
an infusion reaction. 
Vital signs, including heart rate, blood pressure, 
respiratory rate, and oral, axillary or tympanic body 
temperature, will be measured as detailed in Table 1–1 
and in the event of an infusion reaction. 
Added for improved 
implementation and 
clarity. 
31 
Section 8.3.4 Clinical Safety 
Laboratory Assessments 
Urine pregnancy test will be 
conducted on Day 1 prior to 
randomisation, and all 
subsequent study drug dosing 
visits. 
 
Urinalysis (by dipstick): 
specific gravity, pH, protein, 
glucose, blood, ketones, 
bilirubin, urobilinogen, nitrite, 
leukocyte esterase. 
Urine or serum pregnancy tests will be conducted on 
Day 1 prior to randomisation, and all subsequent study 
drug dosing visits. 
 
 
Urinalysis (by dipstick or any other method): specific 
gravity, pH, protein, glucose, blood, ketones, bilirubin, 
urobilinogen, nitrite, leukocyte esterase or leukocytes. 
Added for improved 
implementation and 
clarity. 
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32 
Section 8.5 Study Conduct 
During the COVID-19 
Pandemic 
- 
Coronavirus disease 2019 (COVID-19) is a viral 
illness caused by the novel coronavirus (also called 
SARS-CoV-2) and has impacted most of the 
countries across the globe. It was declared as a 
global public health emergency by the WHO on 
30 Jan 2020. and declared as a pandemic on 
11 Mar 2020. This pandemic has impacted the 
conduct of clinical trials in various ways. 
For clarity and 
adherence with 
contingency measures 
implemented during 
the COVID-19 
pandemic. 
33 
Section 8.5.1 Contingency 
Measures Implemented 
During the COVID-19 
Pandemic 
- 
In the current global outbreak of coronavirus 
disease 2019 (COVID-19), Dr. Reddy’s Laboratories 
(DRL) has recognized the potential impact on the 
conduct of RI-01-006 study due to various reasons. 
Considering that the safety of trial participant is 
paramount, DRL has initiated various contingency 
measures for the well-being of subjects and in order 
to ensure compliance with guidance issued by 
various regulatory agencies: 
x 
COVID-19 protective measures: 
Recommendation to study sites to inform 
and encourage all study subjects to practice 
COVID-19 basic protective measures at all 
times. 
x 
COVID-19 testing and COVID-19 related 
screening questionnaire: 
o 
Each subject being randomized will 
undergo COVID-19 testing 
(preferably RT PCR) and only 
subjects with confirmed negative 
test results will be administered the 
study drug. Additional testing for 
COVID-19 during the course of 
study may be performed at the 
discretion of the Investigator. All 
such test results will be documented 
appropriately in CRF. 
o 
COVID-19 related screening 
questionnaire to rule out active 
For clarity and 
adherence with 
contingency measures 
implemented during 
the COVID-19 
pandemic. 
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COVID-19 infection as well as to 
evaluate further if potential study 
subjects are at risk of acquiring 
COVID-19 at screening visit and 
during the study period. Study drug 
will be administered only in those 
subjects who are considered at no-
risk by the Investigator based on 
this evaluation. 
x 
Inform Consent Document (ICD) amended 
to include possible risks related to 
COVID-19 and rituximab treatment. All 
ongoing subjects will undergo re-consent 
with a newer version of the ICD, after 
approval from a respective ethics committee 
(EC). All new subjects being screened will 
be asked to give their consent using the 
newer version of the ICD. 
x 
Advise study sites to prioritize subjects’ 
safety and priority care in the event of 
COVID-19 infection. 
x 
The investigator must stop rituximab 
treatment if any of the study subjects 
acquire COVID-19 infection while in the 
study. Re-institution of therapy should be 
done after careful benefit risk assessment by 
the Investigator once the subject has been 
confirmed as cured of COVID-19 with 
appropriate laboratory testing. 
x 
The Investigator is encouraged to do 
telephonic inquiry of study subjects to know 
about their overall well-being, adverse 
events, including suspected COVID-19 
symptoms, concomitant medications etc. 
x 
COVID-19 events in the study are to be 
considered as “Events of Special Interest 
(EOSI)” and all relevant detailed 
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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 as an
SAE.
All details of remote monitoring, including
discussion with sites on informed consent process,
subject eligibility, review of central lab data, review
of data entry, query resolution, pending actions,
review of protocol deviations etc., have been
captured in the monitoring plan, as applicable.
Detailed information about the type of data to be
collected, handling of missing data or
assessments/procedures 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 and
additional safety contingency measures will be 
generated based on the available data, if required.
Corresponding details will be mentioned in the SAP.
Based on the evolving COVID-19 pandemic, the
Sponsor will revisit these contingency measures for
any further changes, or for their
continuation/discontinuation, as needed, while
ensuring subject safety and trial data integrity
throughout the conduct of the study.
34
Section 9.2 Sample Size
Determination
.
For better
administrative
flexibility.
35
Section 9.4.5
Pharmacodynamics
Assessment
-
On the basis of B-cell counts a population
pharmacodynamics evaluation including population
pharmacokinetics-pharmacodynamics evaluation
Added for clarity.
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might be performed which will be evaluated in a 
separate analysis plan. 
36 
Section 10.2 Appendix 2: 
Clinical Laboratory Tests 
- 
Changes made in various sections of the protocol have 
been reflected in Appendix 2. 
Changes made in 
various sections of the 
protocol have been 
reflected in the 
Appendix 2. 
 
Please refer to Section 
10.2 Appendix 2: 
Clinical Laboratory 
Tests s in the revised 
protocol version 4.0 
for details. 
37 
Section 10.6 Appendix 6: 
Protocol Amendment 
History 
- 
Moved previous summary of changes table to this 
section 
Moved previous 
summary of changes 
table to this section. 
38 
Section 10.7 Appendix 7: 
COVID-19 Related 
Screening Questionnaire 
- 
COVID-19 related screening questionnaire was 
inserted in Appendix 7. 
For adherence with 
contingency measures 
implemented during 
the COVID-19 
pandemic in the 
interest of subject 
safety. 
39 
Whole document 
- 
Abbreviations, administrative information, editorial 
changes, and/or style or formatting revisions were 
made. 
For improving clarity 
and consistency 
throughout the 
protocol. 
 
 
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10.7 Appendix 7: COVID-19 Related Screening Questionnaire 
Study # RI-01-006 
COVID-19 Related Screening Questionnaire 
______________________________________________________________________________________________ 
Please complete this form at Screening, Baseline and every subsequent study visit before every dosing (please refer 
schedule of assessment in protocol). 
Please send completed form to the PAREXEL CRA/Medical Monitor along with Patient Enrollment Form for 
screening visit only. For subsequent visits, please keep completed form along with Patient’s source documents for 
the visit. 
Patient ID / Initials: ____________ / __________ 
Visit No. (Tick applicable): Screening / Wk 1 / Wk 2 / Wk 3 / Wk 4 / Wk 8 / Wk 12 / Wk 20 / Wk 28 / Wk 36 / 
Wk 44 / Wk 52 / Early Termination/ Unscheduled visit 
Date of Visit: _______/ ________/ _________ 
 
Q. No. 
Questions 
Responses 
1 
Does the patient have any COVID-19 signs / symptoms?  
 
 Yes / 
 No 
2 
Have any of the patient’s close contacts been diagnosed with COVID-19 in the last 
two months / since last visit? 
 
 Yes / 
 No 
3 
Considering the age of the patient and co-morbidities (if any), do you believe 
rituximab treatment will pose an additional risk to the patient related to COVID-
19? 
 
 Yes / 
 No 
4 
Looking at the overall COVID-19 pandemic in your country and city, do you see 
any challenges with the protocol mandated weekly dosing and compliance with 
other study procedures (e.g., hospital visits, investigations, imaging etc.)? 
 
 Yes / 
 No 
5 
Do you foresee any challenges in the availability of the study team for conducting 
ongoing patient visits? 
 
 Yes / 
 No 
6 
If tests are available, has the patient tested for COVID-19 at screening?  
(RT-PCR, Rapid Antigen test or test with similar nature antigen test but no 
antibody test) 
If tested, Name of Test - __________________ 
Result of the COVID-19 testing 
  
 Yes / 
 No 
 
 Positive 
 
 Negative  
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If any response to the above questions (No. 1 - 5) is YES or Positive for question No. 6, we request you to put 
temporary hold on your decision to screen / randomize / dose the patient and contact your site CRA or Medical 
Monitor. 
 
Investigator Name and Title (print): 
 
Signature: 
Date:      /     /      (DD/MMM/YYYY) 
 
 
 
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11 References 
1 Rituxan® 
(rituximab) 
Prescribing 
Information. 
Available 
at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/103705s5460lbl.pdf. 
Accessed 
Oct 30, 2020. 
2 MabThera® (rituximab): Summary of Product Characteristics (SmPC). January 3, 2014. 
Available at: https://www.ema.europa.eu/en/documents/product-information/mabthera-epar-
product-information_en.pdf. Accessed Oct 30, 2020. 
3 Lymphomas. NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkin's 
Lymphomas. Version 3, 2017. Available at: 
https://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed Oct 16, 2017. 
4 Dreyling M, Ghielmini M, Rule S, Salles G, Vitolo U, et al. Newly diagnosed and 
relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment 
and follow-up. Annals of Oncol. 2016; 27 (Supplement 5): v83-v90. 
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7 Riedell PA, Kahl BS. How to refine Treatment Choice in Follicular Lymphoma: From 
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Grade Follicular Lymphoma. Curr Hematol Malig Rep. 2016;218-223. 
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a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky 
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10 Kahl BS, Hong F. Williams ME, et al. Results of Eastern Cooperative Oncology Group 
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11 Investigator’s Brochure for DRL_RI. 
12 Study RI-01-003 Clinical Study Report. A Double-blind, Randomized, Parallel Group 
Study Comparing the Pharmacokinetics, Pharmacodynamics, Safety, Efficacy, and 
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Immunogenicity of Three Anti-CD20 Monoclonal Antibodies in Patients with Moderate to 
Severe Active, Seropositive Rheumatoid Arthritis with an Inadequate Response to 
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16 Brice P, Bastion Y, Lepage E, Brousse N, Haїoun C, Moreau P, et al. Comparison in Low-
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19 NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas. Version 4, 2020. 
Available at: https://www.nccn.org/professionals/physician_gls. Accessed Aug 14, 2020. 
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weight be known. Arch Intern Med. 1916;17:836-871. 
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66. 
23 Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Available at 
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_Reference_5x7.pdf. Accessed May 01, 2018. 
24 Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) 
pandemic, EMA, Version 3 (28/04/2020). Reference the most up-to-date version, see 
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https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf  
25 FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 
Public Health Emergency, March 2020, Updated on September 21, 2020. Reference the most 
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health-emergency. 
26 FDA Briefing Document Oncology Drugs Advisory Committee October 10, 2018. BLA 
761088. CT-P10, A Proposed Biosimilar to US-Rituxan (rituximab). Applicant: Celltrion, Inc. 
Available 
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OncologicDrugsAdvisoryCommittee/UCM622649.pdf%20Accessed%2023%20October%20
2018. 
27 Garner W. (2016). Constructing Confidence intervals for the differences of Binomial 
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28 Chan IS, Zhang Z. Test-based exact confidence intervals for the difference of two binomial 
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29 FDA 
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and 
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Accessed Mar 07, 2018.  
 
 
 
 
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Investigator Agreement Page 
Declaration of the Investigator 
Title: A Randomised, Double-blind, Parallel-group, Phase III Study to Compare the Efficacy, 
Safety, and Immunogenicity of Proposed Rituximab Biosimilar (DRL_RI) with MabThera® in 
Subjects with Previously Untreated, Stage II-IV, Cluster of Differentiation (CD) 20-Positive, Low 
Tumour Burden Follicular Lymphoma. 
All documentation for this study that is supplied to me and that has not been previously published 
will be kept in the strictest confidence. This documentation includes this study protocol, 
Investigator's Brochure, electronic case report form, and other scientific data. 
The study will not be commenced without the prior written approval of a properly constituted 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB). No changes will be 
made to the study protocol without the prior written approval of the Sponsor and the IEC or IRB, 
except where necessary to eliminate an immediate hazard to the participants. 
I have read and understood and agree to abide by all the conditions and instructions contained in 
this protocol version 5.0 dated 27 Oct 2021. 
Responsible Investigator of the local study centre 
 
 
_____________________________________ 
_____________________ 
Signature 
 
 
 
 
 
Date 
_____________________________________ 
Name (block letters) 
_____________________________________ 
Title (block letters) 
_____________________________________ 
Institution (block letters) 
_____________________________________ 
Phone number 
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