An Open-Label, Multinational, Multicenter, Phase IIIB Study to Assess Safety of Rituximab Following Subcutaneous Administration in Patients With CD20+ DLBCL or CD20+ Follicular NHL Grade 1 to 3A
Phase: PHASE3
Conditions: Non-Hodgkin Lymphoma
Sponsor: Hoffmann-La Roche

Official Title: 
An Open-Label, Multinational, Multicenter, Phase IIIB Study to 
Assess Safety of Rituximab Following Subcutaneous Administration 
in Patients With CD20+ DLBCL or CD20+ Follicular NHL Grade 1 to 
3A 
NCT Number: 
NCT02406092 
Document Date: 
Protocol Version 3.1: 07-February-2016 

 
PROTOCOL 
TITLE:
AN OPEN-LABEL, MULTINATIONAL, 
MULTICENTER, PHASE IIIB STUDY TO ASSESS 
SAFETY OF RITUXIMAB FOLLOWING 
SUBCUTANEOUS ADMINISTRATION  IN 
PATIENTS WITH CD20+ DLBCL OR CD20+ 
FOLLICULAR NHL GRADE 1 TO 3A 
PROTOCOL NUMBER:
ML28964 
VERSION NUMBER:
3.1 
EUDRACT NUMBER:
 
IND NUMBER:
N/A 
TEST PRODUCT:
Rituximab (RO 45-2294) 
MEDICAL MONITOR:
 
SPONSOR:
Roche Algeria 
DATE FINAL:
See electronic date stamp below 
 
 
FINAL PROTOCOL APPROVAL 
Name: 
Signature: 
Date: 
 
  
  
 
 
 
 
Date 
 
 
 
 
 
 
Date 
 
 
 
CONFIDENTIAL STATEMENT 
 
This clinical study Mabrella program is being sponsored globally by F. Hoffmann-La 
Roche Ltd of Basel, Switzerland.  However, it may be implemented in individual 
countries by Roche’s local affiliates as daughter studies.  Thus the information 
contained in this document, especially any unpublished data, is the property of 
Roche Algeria spa. (or under its control) and therefore is provided to you in 
confidence as an investigator, potential investigator, or consultant, for review by you, 
your staff, and an applicable Ethics Committee or Institutional Review Board. It is 
understood that this information will not be disclosed to others without written 
authorization from Roche except to the extent necessary to obtain informed consent 
from persons to whom the drug may be administered. 

Rituximab – Roche North Africa (Algeria, Morocco &Tunisia) 
Mabrella ML28964 Daughter Protocol – V3.1 – 07 February 2016 
2 
TABLE OF CONTENTS 
1. 
BACKGROUND ........................................................................................... 20 
1.1 
Background on Non-Hodgkin’S Lymphoma ........................... 20 
1.1.1 
Epidemiology .......................................................................... 21 
1.1.2 
Current Management ............................................................. 22 
1.2 
Background on Rituximab ...................................................... 24 
1.2.1 
Rituximab IV ........................................................................... 25 
1.2.2 
Subcutaneous (SC) Rituximab ............................................... 32 
1.3 
Study Rationale and Benefit–Risk Assessment...................... 35 
2. 
OBJECTIVES .............................................................................................. 37 
2.1 
Primary Objective ................................................................... 37 
2.2 
Secondary Objectives ............................................................ 37 
2.3 
Patient-Reported Outcome Objectives ................................... 37 
2.4 
Healthcare ProfessIonal reported outcome 
objectıves ............................................................................... 37 
3. 
STUDY DESIGN .......................................................................................... 38 
3.1 
Description of Study ............................................................... 38 
3.1.1 
Overview ................................................................................ 38 
3.1.2 
Independent Review Committee ............................................ 41 
3.1.3 
Independent Data Monitoring Committee ............................... 41 
3.1.4 
Clinical Events Committee ..................................................... 41 
3.1.5 
Steering Committee ................................................................ 41 
3.2 
End of Study ........................................................................... 41 
3.3 
Rationale for Study Design ..................................................... 41 
3.3.1 
Rationale for Test Product Dosage ........................................ 41 
3.3.2 
Rationale for Patient Population and Analysis Group ............. 41 
3.3.3 
Rationale for Chemotherapy .................................................. 42 
3.3.4 
Rationale for Biomarker Assessments ................................... 42 
3.4 
Outcome Measures ................................................................ 42 
3.4.1 
Safety Outcome Measures ..................................................... 42 
3.4.2 
Efficacy Outcome Measures .................................................. 42 
3.4.3 
Exploratory Outcome Measures ............................................. 43 
3.4.4 
Pharmacodynamic and Pharmacokinetic Outcome 
Measures 43 

Rituximab – Roche North Africa (Algeria, Morocco &Tunisia) 
Mabrella ML28964 Daughter Protocol – V3.1 – 07 February 2016 
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3.4.5 
Pharmacoeconomic Outcome Measures ............................... 43 
3.4.6 
Patient-Reported Outcome (PRO) Measures ......................... 43 
3.4.7 
Healthcare Professional Reported Outcome 
Measures 43 
4. 
MATERIALS AND METHODS ..................................................................... 43 
4.1 
Patients .................................................................................. 43 
4.1.1 
Inclusion Criteria ..................................................................... 43 
4.1.2 
Exclusion Criteria ................................................................... 44 
4.2 
Method of Treatment Assignment and Blinding ...................... 45 
4.3 
Study Treatment ..................................................................... 45 
4.3.1 
Formulation, Packaging, and Handling ................................... 45 
4.3.2 
Dosage, Administration and Compliance ............................... 46 
4.3.3 
Investigational Medicinal Product Accountability .................... 47 
4.3.4 
Post-Trial Access to Rituximab SC ......................................... 47 
4.4 
Concomitant Therapy ............................................................. 47 
4.4.1 
Permitted Therapy .................................................................. 47 
4.4.2 
Prohibited Therapy ................................................................. 48 
4.4.3 
Prohibited Food ...................................................................... 49 
4.4.4 
Initiation of New Anti-lymphoma Treatment ............................ 49 
4.5 
Study Assessments ................................................................ 49 
4.5.1 
Description of Study Assessments ......................................... 49 
4.5.2 
Timing of Study Assessments ................................................ 52 
4.6 
Patient, Study, and Site Discontinuation ................................ 54 
4.6.1 
Patient Discontinuation ........................................................... 54 
4.6.2 
Study and Site Discontinuation............................................... 54 
5. 
ASSESSMENT OF SAFETY ....................................................................... 55 
5.1 
Safety Plan ............................................................................. 55 
5.1.1 
Adverse Events of Special Interest ......................................... 55 
5.1.2 
Interaction with Other Medicinal Products .............................. 55 
5.1.3 
Administration-Associated Reactions and their 
Management............................................................................................. 55 
5.2 
Safety Parameters and Definitions ......................................... 58 
5.2.1 
Adverse Events ...................................................................... 58 
5.2.2 
Serious Adverse Events (Immediately Reportable to 
the Sponsor) ............................................................................................. 59 

Rituximab – Roche North Africa (Algeria, Morocco &Tunisia) 
Mabrella ML28964 Daughter Protocol – V3.1 – 07 February 2016 
4 
5.2.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) ................................................. 59 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters .................................................................. 59 
5.3.1 
Adverse Event Reporting Period ............................................ 59 
5.3.2 
Eliciting Adverse Event Information ........................................ 60 
5.3.3 
Assessment of Severity of Adverse Events ............................ 60 
5.3.4 
Assessment of Causality of Adverse Events .......................... 61 
5.3.5 
Procedures for Recording Adverse Events ............................ 60 
5.4 
Immediate Reporting Requirements from Investigator 
to Sponsor .............................................................................. 65 
5.4.1 
Emergency Medical Contacts ................................................. 65 
5.4.2 
Reporting Requirements for Serious Adverse Events 
and Non-Serious Adverse Events of Special Interest ............................... 66 
5.4.3 
Reporting Requirements for Pregnancies .............................. 66 
5.5 
Follow-Up of Patients after Adverse Events ........................... 67 
5.5.1 
Investigator Follow-Up ............................................................ 67 
5.5.2 
Sponsor Follow-Up ................................................................. 67 
5.6 
Post-Study Adverse Events .................................................... 67 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and Ethics 
Committees ............................................................................ 68 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN........................ 68 
6.1 
Determination of Sample Size ................................................ 68 
6.2 
Summaries of Conduct of Study ............................................. 69 
6.3 
Summaries of PATIENT pOPULATION ................................. 69 
6.3.1 
Analysis Populations .............................................................. 69 
6.4 
Safety Analyses ...................................................................... 69 
6.5 
EFFICACY Analyses .............................................................. 70 
6.6 
Exploratory Analyses .............................................................. 70 
6.7 
Pharmacodynamic and Pharmacokinetic Analyses ................ 70 
6.8 
Pharmacoeconomic Analyses ................................................ 70 
6.9 
Patient-Reported Outcome Analyses ..................................... 70 
6.10 
Healthcare professıonal reported outcome analyses ............. 70 
6.11 
Interim Analyses ..................................................................... 70 
7. 
DATA COLLECTION AND MANAGEMENT ................................................ 70 

Rituximab – Roche North Africa (Algeria, Morocco &Tunisia) 
Mabrella ML28964 Daughter Protocol – V3.1 – 07 February 2016 
5 
7.1 
Data Quality Assurance .......................................................... 70 
7.2 
Electronic Case Report Forms ............................................... 70 
7.3 
Electronic Patient-Reported Outcome Data ........................... 72 
7.4 
Source Data Documentation .................................................. 72 
7.5 
Use of Computerized Systems ............................................... 72 
7.6 
Retention of Records .............................................................. 73 
8. 
ETHICAL CONSIDERATIONS .................................................................... 73 
8.1 
Compliance with Laws and Regulations ................................. 73 
8.2 
Informed Consent ................................................................... 73 
8.3 
Institutional Review Board or Ethics Committee ..................... 74 
8.4 
Confidentiality ......................................................................... 74 
8.5 
Financial Disclosure ............................................................... 74 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ...................................................................................... 74 
9.1 
Study Documentation ............................................................. 74 
9.2 
Site Inspections ...................................................................... 75 
9.3 
Publication of Data and Protection of Trade Secrets .............. 75 
9.4 
Protocol Amendments ............................................................ 75 
10. REFERENCES ............................................................................................ 76 
11. APPENDICES .............................................................................................. 80 
11.1 
Appendix 1 Schedule of Assessments ................................... 82 
11.2 
Appendix 2 Response Assessment According to the 
International Working Group Response Criteria ..................... 88 
11.3 
Appendix 3 Grading Systems and Scales .............................. 90 
11.3.1 
ECOG Performance status ..................................................... 90 
11.3.2 
International Prognostic Index (IPI) ........................................ 91 
11.3.3 
Follicular Lymphoma International Prognostic 
Index(FLIPI) .............................................................................................. 92 
11.4 
Appendix 4 Guidelines for Standard Rituximab SC 
Preparation and Administration .............................................. 93 
11.5 
Appendix 5 NCI Common Terminology Criteria for 
Adverse Events ...................................................................... 94 
11.6 
Appendix 6 rıtuxımab admınıstratıon Questıonnaıre 
(rasq-ıv and rasq-sc) .............................................................. 95 
11.7 
Appendıx 7 Healthcare ProfessIonal (HCP) 
questıonnaıre ....................................................................... 100 

Rituximab – Roche North Africa (Algeria, Morocco &Tunisia) 
Mabrella ML28964 Daughter Protocol – V3.1 – 07 February 2016 
6 
 
LIST OF TABLES 
Table 1 
Efficacy Summary of Phase III Randomized Controlled Trials of R-CHOP 
in Previously Untreated 
DLBCL……………………………………………………..25 
Table 2 
Efficacy Summary of Phase III Randomized Controlled Trials of Rituximab 
Plus Chemotherapy in Previously Untreated 
FL………………………….……27 
Table 3 
Safety Summary of Select Randomized Controlled Trials of R-CHOP in 
Previously Untreated 
DLBCL………………………………………………..……30 
Table 4 
Summary of Adverse Events from Stage 1 of Study 
BP22333……………….33 
Table 5 
Guidelines for Managing Specific Adverse Events related to R-CHOP 
treatment…………………………………………………………………………
…56 
Table 6 
Adverse Event Severity Grading 
Scale…………………………………………59 
 
LIST OF FIGURES 
Figure 1  
Study duration: Patients with CD20+ Follicular NHL…………………………….10 
Figure 2  
Study duration: Patients with CD20+ DLBCL…………………………………….10 
Figure 3  
Study duration: Patients with CD20+ Follicular NHL…………………………….40 
Figure 4  
Study duration: Patients with CD20+ DLBCL…………………………………….41 
 
 

Rituximab – Roche North Africa (Algeria, Morocco &Tunisia) 
Mabrella ML28964 Daughter Protocol – V3.1 – 07 February 2016 
7 
PROTOCOL ACCEPTANCE FORM 
TITLE:
AN OPEN-LABEL, MULTINATIONAL, 
MULTICENTER, PHASE IIIB STUDY TO ASSESS 
SAFETY OF RITUXIMAB FOLLOWING 
SUBCUTANEOUS ADMINISTRATION  IN 
PATIENTS WITH CD20+ DLBCL OR CD20+ 
FOLLICULAR NHL GRADE 1 TO 3A 
PROTOCOL NUMBER:
ML28964 
VERSION NUMBER:
3.1 
EUDRACT NUMBER:
{Number} 
IND NUMBER:
N/A 
TEST PRODUCT:
Rituximab (RO 45-2294) 
MEDICAL MONITOR:
 
SPONSOR:
Roche Algeria 
I agree to conduct the study in accordance with the current protocol. 
_______________________________________ 
Principal Investigator’s Name (print) 
_______________________________________ 
_________________________ 
Principal Investigator’s Signature 
 
 
 
 
 
 
Date 
Please return a copy of the form as instructed by your local study monitor. Please retain 
the original for your study files. 

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Rituximab – Roche North Africa (Algeria, Morocco &Tunisia) 
Mabrella ML28964 Daughter Protocol – V3.1 – 07 February 2016 
9 
This study will include adult patients with CD20+ DLBCL or CD20+ follicular NHL (grade 1 to 3a; 
NHL), who have already received at least one full dose of IV rituximab during first-line treatment, 
induction or maintenance.  
During administration of rituximab SC, patients will be assessed for safety and efficacy as detailed in 
the Schedule of Assessments (see Appendix 1). The Rituximab Administration Questionnaire 
(RASQ, Appendix 6) will be applied to patients and Healthcare Professional (HCP) Questionnaire 
(see Appendix 7) will be applied to health care professionals at the end of the study.  
Induction Therapy: 
NHL patients receiving Induction therapy prior to entry into the study must be eligible to receive at 
least four further cycles of rituximab SC (i.e. 4 additional months of Induction treatment). Patients 
with follicular NHL who will continue into Maintenance therapy (after staging at the end of Induction) 
can continue to receive rituximab SC during Maintenance (see below). 
Maintenance Therapy (patients with follicular NHL): 
NHL patients receiving Maintenance therapy prior to entry into the study must be eligible to receive 
at least six further cycles of rituximab SC (i.e. 12 additional months of Maintenance treatment). 
Patients who are continuing into Maintenance therapy following at least 4 (four) cycles of rituximab 
SC during Induction Therapy must also be eligible to receive at least six cycles of rituximab SC (i.e. 
12 additional months of Maintenance treatment). 
 

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Rituximab – Roche North Africa (Algeria, Morocco &Tunisia) 
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Endpoint and Analysis 
Safety will be assessed on the following safety parameters: AARs, including IIRRs, AEs, AEs of 
grade  3, SAEs, routine laboratory parameters, vital signs, concomitant medications, premature 
withdrawal from the study and from study medication due to AEs or ECOG performance status.  
The incidence of AARs AEs, AEs leading to premature discontinuation or interruption of study 
treatment, SAEs, grade  3 AEs will be estimated with 95%-Clopper-Pearson confidence intervals. 
The incidence of each AE will be summarized by the primary system-organ class and by preferred 
term. The incidence of deaths and cause of deaths will be listed and summarized. 
Laboratory parameters will be summarized and selected laboratory parameters may also be 
displayed graphically.  
Vital signs will be summarized over time. 
ECOG performance status will be summarized by frequency tables over time and percentage of 
patients in different categories will be presented by bar charts at different time points. 
Concomitant medication will be coded according to the WHO DRUG dictionary and tabulated in 
summary tables.  
All safety analyses will be based on the Safety population. 
The analysis of endpoints measured as a time to event (EFS, PFS, OS and DFS) is based on the 
survivor function, which is the probability of remaining event-free beyond a certain point in time.  The 
survivor function will be estimated using Kaplan-Meier methodology and summarized using the 
range, the 25th and 75th percentiles and median survival along with a 95% confidence interval for 
median survival.  
Endpoints resulting in an incidence rate (e.g. CR/CRu) will be summarized with a 95% Clopper-
Pearson confidence interval. 
Determination of Sample Size  
A sample size of 110 patients is deemed sufficient for this study. In this study, all planned statistical 
analysis will be exploratory in nature as the study will not be powered to address any pre-defined 
statements and only descriptive statistical evaluations will be carried out primarily for safety (and 
efficacy) parameters. Additionally, no published reference is available on administration-associated 
reactions (AARs) following multiple doses of subcutaneous (SC) rituximab during induction and/or 
maintenance therapy in patients with CD20+ follicular non-Hodgkin’s lymphoma (NHL) or CD20+ 
diffuse large B-cell lymphoma (DLBCL). However, with 110 patients a 95% Clopper-Pearson CI for 
the incidence of AARs will be no wider than +/- 9.7%. This width of interval is deemed sufficiently 
precise to draw valid conclusions around the incidence of ARRs. Additionally, enrolment of more 
than 110 patients within the specified indications could also be difficult in participating countries. 
Due to the fact of exploratory nature of the study, drop out patients will not be replaced. 
Interim Analyses  
Not applicable 
Study Procedures  
See Schedule of Assessments, Appendix 1 and Appendix 2.  
 

Rituximab – Roche North Africa (Algeria, Morocco &Tunisia) 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation
Definition
aaIPI
Age-adjusted International Prognostic Index 
AAR
Administration-associated reaction 
AE
adverse event 
ALT (SGPT)
alanine aminotransferase 
aPTT
Activated Partial Thromboplastin Time 
AST (SGOT)
aspartate aminotransferase 
BSA
body surface area 
BUN
blood urea nitrogen 
CEC
Clinical Events Committee 
CHO
Chinese hamster ovary 
CHOP
cyclophosphamide, oncovine (vincristine), doxorubicin, 
prednisone/prednisolone  
CHOP-21
CHOP given every 21 days  
CHOP-14
CHOP given every 14 days 
CHVP
cyclophosphamide, doxorubicin, etoposide, 
prednisone/prednisolone 
CI
confidence interval 
CLL
chronic lymphocytic leukaemia 
CR
complete response 
CRF
Case report form 
CRu
complete response unconfirmed 
CRO
contract research organization 
CT
Computed tomography  
CTCAE
Common Terminology Criteria for Adverse Events 
Ctrough
Minimal plasma concentration prior to next drug administration 
CVP
cyclophosphamide, vincristine, prednisone/prednisolone 
DFS
disease-free survival 
DLBCL
diffuse large B-cell lymphoma 
EC
Ethics Committee 
ECG
Electrocardiogram 
ECOG
Eastern Cooperative Oncology Group 
eCRF
electronic Case Report Form 
EDC
electronic data capture 

Rituximab – Roche North Africa (Algeria, Morocco &Tunisia) 
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Abbreviation
Definition
EFS
event-free survival 
EGSG
East German Study Group 
EU
FC
FC 28
European Union 
Fludarabine, cyclophosphamide 
FC given every 28 days 
FDA
Food and Drug Administration 
FDG-PET
[18F]deoxyglucose positron emission tomography 
FFS
failure-free survival 
FL
follicular lymphoma 
FLIPI
Follicular Lymphoma International Prognostic Index 
G-CSF
granulocyte colony-stimulating factor 
GELA
Groupe d’Etude des Lymphomes de l’Adulte  
GLSG
German Low-Grade Lymphoma Study Group 
HACA
human antichimeric antibody 
HAMA
human anti-mouse antibody 
HBV
hepatitis B virus  
HCV
hepatitis C virus  
HIPAA
Health Insurance Portability and Accountability Act 
HIV
Human Immunodeficiency Virus 
IB
Investigator’s Brochure 
ICF
informed consent form 
ICH
International Conference on Harmonisation 
IDMC
Independent Data Monitoring Committee 
IDSMB
Independent Data Safety Monitoring Board 
IFN
interferon- 
IMP
investigational medicinal product 
INR
International Normalized Ratio  
IPI
International Prognostic Index 
IRC
Independent Review Committee 
IRF
Independent Review Facility 
IRR
Infusion-related reaction 
IIRR
infusion/injection-related reaction 
ITT
Intent-to-treat  
IV
intravenous(ly) 

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Abbreviation
Definition
IWG
International Working Group 
LDH
lactate dehydrogenase  
LPLV
last patient, last visit 
MCP
mitoxantrone, chlorambucil, prednisone/prednisolone 
MedDRA
Medical Dictionary for Regulatory Activities 
MInT
MabThera international trial  
MRI
magnetic resonance imaging 
NCI
National Cancer Institute 
NCI CTCAE
National Cancer Institute Common Terminology Criteria for 
Adverse Events  
NHL
Non-Hodgkin’s Lymphoma 
NIMP
Non-investigational medicinal product 
ORR
overall response rate 
OS
overall survival 
PD
progressive disease (disease progression)  
PD
pharmacodynamics 
PET
positron emission tomography 
PFS
progression-free survival 
PK
Pharmacokinetic 
PML
Progressive Multifocal Leukoencephalopathy 
PR
partial response 
PRO
patient-reported outcome 
PT
Prothrombin Time 
RBC
red blood cell count  
RCR
Roche Clinical Repository 
R-CHOP
rituximab plus CHOP chemotherapy 
RCT
randomized controlled trial 
R-CVP
rituximab plus CVP chemotherapy 
R-CHVP
R-FC
rituximab plus CHVP chemotherapy 
Rituximab plus FC chemotherapy 
rHuPH20
recombinant human hyaluronidase 
SAE
serious adverse event 
SAP
Statistical Analysis Plan 
SC
subcutaneous(ly) 
SD
stable disease 

Rituximab – Roche North Africa (Algeria, Morocco &Tunisia) 
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Abbreviation
Definition
SEER
Surveillance, Epidemiology, and End Results 
SPD
sum of the products of the greatest diameters 
SUSAR
Suspected Unexpected Serious Adverse Reactions 
SWT
Satisfaction with Therapy  
TLS
Tumour lysis syndrome 
TNLT
time to next lymphoma treatment 
TTF
time to treatment failure 
TTP
time to tumour progression 
ULN
upper limit of normal 
WBC
White blood cell 
WHO
World Health Organization 

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1. 
BACKGROUND 
1.1 
BACKGROUND ON NON-HODGKIN’S LYMPHOMA 
Non-Hodgkin’s lymphoma (NHL), a heterogeneous group of lymphoproliferative 
malignancies, is one of the leading causes of cancer death in the United States (US) 
and Europe. NHL accounted for 3.2% of new cancer cases and 2.8% of cancer 
deaths in Europe in 2006, making it the 8th leading cause of new cancer cases and 
the 10th leading cause of cancer deaths (Ferlay et al, 2007).  
In Northen Africa, tha age adjusted incidence rate of NHL is 8.4 per 100,000. It’s 
ranked the 3rd cancer of most common cancer in males and females. NHL represent 
the 5th leading cause of cancer deaths in males and the 4th leading cause of cancer 
deaths in women (Globocan 2008).  Among North African countries, Egypt has the 
highest incidence rate of lymphoma, mainly NHL; which is higher than even the 
United States (Ferlay J, et al, 2010). In Morocco, Lymphoma represents 4% of all 
cancers among both Men and women, it’s ranked 5th cancer, with an increasing 
incidence over the last 3 decades. In the following North African countries (Algeria, 
Morocco and Tunisia), the incidence of NHL is higher in males than females 
(Lamchahab M, Quessar A, Maghrebian congress 2012). As with other lymphoid 
neoplasms, its aetiology remains largely unknown, although risk factors include 
certain infections as well as treatments and diseases that cause severe 
immunosuppression. NHL has been classified into two types: aggressive (i.e. fast 
growing) and indolent (i.e. slow growing) (Landis et al. 1999). Categorizing the 
various lymphoid neoplasms has proven to be enormously challenging and has 
resulted in the evolution of numerous classification schemes over the past 50 years. 
In 2001, the World Health Organization (WHO) introduced a new system for 
classifying haematopoietic neoplasms, which, in addition to morphology, 
incorporates immunophenotype, cytogenetic and molecular features, clinical 
behaviour, and some known aspects of aetiology and pathogenesis into the 
definition of each disease subtype (Jaffe et al. 2001). Indolent NHL comprises a 
group of incurable, generally slow-growing lymphomas that are highly responsive to 
initial therapy and are characterized by a relapsing and progressive course. Diffuse 
large B-cell lymphoma (DLBCL) is the most common histologic subtype of NHL 
(Swerdlow S et al, 2008). 
Follicular lymphoma (FL) is the most common of the indolent NHLs (Friedberg, 
2008), accounting for 20-25% of all lymphomas. The disease generally manifests 
with hypertrophy of peripheral and deep lymph nodes and splenomegaly, together 
with bone marrow infiltration. FL is characterized by initial responsiveness to therapy 
followed by repeated relapses and sometimes with histological progression into high-
grade NHL (Horning, 1993). In the WHO classification the histology is further 
classified into grade 1, 2 or 3 FL, depending on the percentage of large cells seen on 
high-power field microscopy (Nathwani et al, 2001). Grade 3 FL is further subdivided 
into 3a and 3b, where 3b may represent a distinct biological entity more similar to 
DLBCL (Nathwani et al, 2001). Biologically, FL has been associated with the 
translocation of chromosomes 14 and 18 [t(14;18)], which results in constitutive 
activation of the bcl-2 oncogene and the subsequent inhibition of apoptosis of 
lymphoid cancer cells (Bordeleau and Berinstein, 2000). Given that FL is currently 
incurable with standard treatment options, there is a need to improve the clinical 
outcomes. 

Rituximab – Roche North Africa (Algeria, Morocco &Tunisia) 
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1.1.1 
Epidemiology 
NHLs account for almost 5% of all cancers occurring in the US, with an estimated 
70,130 new diagnoses (38,160 men and 31,970 women) in the year 2012. Based on 
cases diagnosed in 2005-2009 from 18 Surveillance, Epidemiology and End Results 
(SEER) geographic areas, the age-adjusted incidence rate for NHL was 19.6 per 
100,000 men and women per year and the age-adjusted death rate was 6.6 per 
100,000 men and women per year (Howlander et al. 2012). In Algeria and Tunisia, 
the reported age-adjusted incidence rate was <5.3 per 100,000 but in Morocco, it 
was <6.8 per 100,000 (Boffetta P Ann Oncol 2011;22:iv27-iv31).  
A recent study of incidence of NHL has been carried out in Algeria but it contains 
data from Pathology based laboratories from predominantly urban areas. The 
incidence was 3.8 per 100,000 in general with 3.2 per 100,000 in women and 4,4 per 
100,000 in men with a predominance of large B-cell lymphoma.  
In Morocco, the first report of cancer incidence done in Rabat from a population-
based cancer registry for the period 2006–2008 showed 271 malignant 
haemopathies recorded between 2006 and 2008, 11% of all cases, and their 
incidence rate is significantly higher in men than in women (ASR: 18.2 vs. 
10.5/100,000). The most frequent was NHL (43%). The NHL was nodal in 43% of 
cases, while the most frequent extranodal sites were the stomach (12%) and 
nasopharynx (6%). Nearly half of the NHL cases were large B-cell lymphoma (Tazi 
M.A. et al. ecancer 2013) 
The incidence and mortality rates for NHL were reported to have risen steadily in the 
US (with an estimated 50% increase in age-adjusted incidence of NHL from 1970 to 
1990) and in other populations over several decades. Although further reports 
suggested that the steep rise in incidence may have slowed in the late 1990s, this 
group of closely related diseases is still an important contributor to the overall cancer 
burden (Morton et al. 2006; Cartwright 1999; Eltorn et al. 2002; Clarke and Glazer 
2002). Cancer incidence and mortality patterns vary remarkably across regions 
within Africa because of the substantial regional differences in economic 
development and social, cultural, and other environmental factors, including major 
known risk factors (Globocan 2008). 
Among the NHL cases included in the SEER database, B-cell NHL accounted for 
90.4%, T-cell NHL accounted for 6.8%, and NHL of unknown cell lineage accounted 
for 2.8%.  
Based on other reports, FL accounts for 20-25% of all cases of NHL (ILSG 1997). Its 
incidence is rapidly increasing in Western countries and has nearly doubled within 
the past three decades. Like many lymphomas, it is increasing in incidence with over 
24,000 new cases diagnosed each year. It remains incurable with standard 
treatment options. 
DLBCL constitutes 25-30% of NHL cases, and its incidence increases with 
advancing age, such that the disease represents 54% of NHL cases among patients 
older than 75 years (Michallet and Coiffier, 2009; Niitsu 2010). A crude incidence of 
3-4 cases/100,000/year was reported in the European Union, increasing from 0.3 
cases/100,000/year in patients aged 35-39 years to 26.6 cases/100,000/year in 
patients aged 80-84 years (Tilly and Dreyling, 2010). In the US, the incidence of 
DLBCL is approximately 7 cases per 100,000 person years and varies by ethnicity, 
with Caucasian Americans having higher rates than African Americans, Asians, and 
American Indian or Alaska Natives, in order of decreasing incidence (Morton et al, 
2006). 

Rituximab – Roche North Africa (Algeria, Morocco &Tunisia) 
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Patients with DLBCL typically present with a rapidly enlarging symptomatic mass, 
most usually nodal enlargement in the neck or abdomen. The median age at 
presentation is approximately 65 years, and it is slightly more common in males than 
females. In appreciation of rapid lymph node enlargement, systemic "B" symptoms 
(i.e. fever, weight loss, drenching night sweats) are present in approximately 30% of 
patients. About 40% of DLBCLs occur from extranodal sites, most commonly the 
gastrointestinal canal. Among DLBCL cases, 11-27% have bone marrow infiltration, 
approximately 50% have elevated serum lactate dehydrogenase (LDH), and about 
half have advanced stage (stage III/IV) disease (Niitsu N, 2010). Bone marrow 
involvement in DLBCL can also be detected after histologic transformation from most 
other types of B-cell lymphoma. In general, patients who have undergone histologic 
transformation have a poorer response to therapy and prognosis than those with a 
de novo appearance (Swerdlow S et al, 2008; Niitsu N, 2010). 
1.1.2 
Current Management 
The CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone/prednisolone) 
regimen, administered every 21 days (and every 14 days in some countries), has 
been the standard therapy for DLBCL for over three decades (Michallet and Coiffier, 
2009; Niitsu 2010). However, the cure rate with CHOP is considered suboptimal, 
with 3-year progression-free survival (PFS) and overall survival (OS) rates of about 
40% and 50%, respectively (Fisher et al. 1993). Rituximab, a genetically engineered 
chimeric monoclonal antibody that specifically binds to CD20, is the first monoclonal 
antibody approved for the treatment of B-cell lymphoma. The addition of rituximab to 
chemotherapy has improved PFS and OS of patients with DLBCL (Niitsu 2010). 
Based on randomized controlled trials (RCTs) demonstrating that the addition of 
rituximab to CHOP (R-CHOP) improved disease-free survival (DFS), event-free 
survival (EFS) and OS, R-CHOP has become the standard of care in DLBCL. 
Rituximab administration on Day 1 of each treatment cycle is also convenient 
(Habermann 2007). 
Since approval was granted for the use of rituximab in the first-line treatment of 
patients with CD20+ DLBCL in combination with CHOP or other anthracycline-based 
chemotherapy regimens, rituximab has been recommended in relevant guidelines as 
standard therapy in the treatment of DLBCL (Tilly and Dreyling 2010; Keating 2010; 
NCCN 2011). 
The scale of therapeutic options for FL is wide and ranges from a watch-and-wait 
policy to aggressive alternatives, such as haematopoietic stem cell transplant. There 
are several reports of significant improvements in the clinical course of the disease 
over the past decades (Swenson et al 2005; Fisher et al, 2005). However, the most 
striking outcome improvement has been achieved with the introduction of anti-CD20 
monoclonal antibodies in combination with standard chemotherapy as demonstrated 
in several phase III studies (Marcus et al, 2005; Marcus et al, 2008; Hiddemann et al, 
2005; Herold et al, 2007; Salles et al, 2008) and registry data (Pulte et al, 2008). The 
combination of rituximab with chemotherapy as first-line treatment has become the 
standard Induction therapy. 
Initial treatment of NHL with chemotherapy (such as alkylating agents, 
prednisone/prednisolone, anthracyclines, vinca alkaloids, purine analogues), 
combined with interferon or monoclonal antibodies such as rituximab is associated 
with a high rate of clinical response, although typically followed by relapse. Patients 
with aggressive B-cell lymphoma are potentially curable when treated with multi-
agent chemotherapy such as CHOP (Fisher et al, 1993). In 30-70% of the FL cases, 
the disease eventually transforms to aggressive lymphoma, responding only to 

Rituximab – Roche North Africa (Algeria, Morocco &Tunisia) 
Mabrella ML28964 Daughter Protocol – V3.1 – 07 February 2016 
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combination chemotherapies usually employed for aggressive disease, such as 
anthracyclines or cytosine arabinoside-containing regimens or high-dose 
chemotherapy with autologous stem cell transplantation (Lossos 2005). The 
standard of care for patients with aggressive lymphoma has changed recently with 
the implementation of therapy with the chimeric anti-CD20 monoclonal antibody 
rituximab (Boye et al, 2003). Combination treatment with R-CHOP or similar 
regimens has resulted in superior treatment outcomes compared with multi-agent 
chemotherapy alone, making combined immunochemotherapy with rituximab the 
new standard of care for this group of patients (Feugier et al, 2005). The combination 
of cyclophosphamide, vincristine, and prednisone/prednisolone (CVP) is one of 
several standard treatment options for advanced FL. Similar to other 
chemotherapeutic regimens; this combination induces response rates of 60-80%, 
with median response duration of under 2 years (Marcus et al, 2005).  
A recently published large, prospective, longitudinal, observational study to identify 
current patterns of care of FL in the US (conducted between 2004 and 2007) found 
that amongst the 2728 patients enrolled, the most common initial therapeutic 
strategy was chemotherapy plus rituximab (51.9%), followed by observation (17.7%), 
rituximab monotherapy (13.9%), clinical trial-related interventions (6.1%), radiation 
therapy (5.6%) and chemotherapy alone (3.2%). Chemotherapy plus rituximab 
regimens were R-CHOP (55.0%), rituximab plus CVP (R-CVP, 23.1%), rituximab 
plus fludarabine based-chemotherapy (15.5%), and other (6.4%). The choice to 
initiate therapy rather than observation only was associated with age, Follicular 
Lymphoma International Prognostic Index (FLIPI), stage, and grade (p < 0.01) 
(Friedberg et al, 2009). 
Toxicity of rituximab is mild and occurs most frequently during the first infusion. 
Importantly, it does not produce treatment-related cytopenias or severe cumulative 
toxicity (Sousou and Friedberg, 2010). Compared to single-agent cytotoxic therapy, 
single-agent rituximab was better tolerated and had similar efficacy (McLaughlin et al, 
1998). Several Phase II and Phase III multicentre RCTs demonstrated that the 
addition of rituximab to various chemotherapy regimens in patients with FL 
significantly improves outcomes when compared with standard chemotherapy 
regimens, without adding significant toxicity (Sousou and Friedberg, 2010). In clinical 
trials with rituximab monotherapy given for 4 weeks, haematological abnormalities 
occurred in a minority of patients and were usually mild and reversible. Severe 
(grade 3/4) neutropenia was reported in 4.2%, anaemia in 1.1% and 
thrombocytopenia in 1.7% of the patients. During rituximab Maintenance treatment 
for up to 2 years, grade 3/4 leucopenia (5% vs. 2%, grade 3/4) and neutropenia 
(10% vs. 4%, grade 3/4) were reported at a higher incidence when compared to 
observation. In studies with rituximab in combination with chemotherapy, grade 3/4 
leucopenia, neutropenia, and pancytopenia were reported higher frequencies when 
compared to chemotherapy alone. However, the higher incidence of neutropenia in 
patients treated with rituximab and chemotherapy was not associated with a higher 
incidence of infections and infestations compared to patients treated with 
chemotherapy alone and the neutropenia was not prolonged in the rituximab group. 
There were no differences reported for the incidence of thrombocytopenia or 
anaemia (Rituximab Summary of Product Characteristics). 
Rituximab, an anti-CD20 antibody, has had a large impact on the treatment of 
indolent NHL. Its effectiveness as a single agent and in conjunction with known 
chemotherapy regimens has made it a standard of care in the treatment of NHL. 
Analysis of data obtained from NHL clinical trials, as well as data from the National 

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Rituximab – Roche North Africa (Algeria, Morocco &Tunisia) 
Mabrella ML28964 Daughter Protocol – V3.1 – 07 February 2016 
26 
Abbreviations: aaIPI: age-adjusted International Prognostic Index (score); CR: complete response; CRu: 
complete response unconfirmed; FU: follow-up; GELA: Groupe d’Etude des Lymphomes de l’Adulte; IPI: 
International Prognostic Index (score); Med: median; mo: months; MInT: MabThera International Trial; NR: not 
reported; yrs: years 
1.2.1.2 
Efficacy of Rituximab IV Plus Chemotherapy in the Treatment of 
FL 
Several multicentre RCTs have demonstrated that the addition of rituximab to first-
line therapy for FL significantly improves clinical outcomes when compared with 
standard chemotherapy regimens of varying intensities, without adding significant 
toxicity. See details in Table 2. 

Rituximab – Roche North Africa (Algeria, Morocco & Tunisia) 
Mabrella ML28964 Daughter Protocol – v3.1 – 07 February 2016  
32 
and 97% vs. 88% respectively), but the incidence of grade 2 to 4 infections was only 
slightly higher (46% in the R-CHOP arm compared to 42% in the CHOP arm). 
1.2.1.3.3 
Other toxicities 
Tumour Lysis Syndrome (TLS) has been reported to occur after the first rituximab 
infusion in patients with a high tumour burden or high numbers of circulating 
malignant lymphocytes during Induction treatment.  
Pulmonary events were also reported. They have included hypoxia, pulmonary 
infiltrates, and acute respiratory failure.  
In studies evaluating rituximab in combination with chemotherapy, the incidence of 
grade 3 and 4 cardiac arrhythmias, predominantly supraventricular arrhythmias such 
as tachycardia and atrial flutter/fibrillation, was higher in the R-CHOP group (14 
patients, 6.9%) as compared to the CHOP group (3 patients, 1.5%) (Rituximab 
Summary of Product Characteristics). 
Very rare cases of hepatitis B reactivation, including reports of fulminant hepatitis, 
have been reported in patients receiving rituximab, although these reports are 
confounded by both underlying disease and exposure to other cytotoxic 
chemotherapy. Patients with a history of hepatitis B infection should be carefully 
monitored for signs of active hepatitis B infection when rituximab is used in 
association with cytotoxic chemotherapy. 
Use of rituximab may be associated with an increased risk of Progressive Multifocal 
Leukoencephalopathy (PML). Patients must be monitored at regular intervals for any 
new or worsening neurological symptoms or signs that may be suggestive of PML. If 
PML is suspected, further dosing must be suspended until PML has been excluded. 
Some patients who were treated with rituximab and chemotherapy have developed 
gastrointestinal perforation.  
Immunization following rituximab treatment in the oncology setting has been 
evaluated in controlled studies. Impaired response to tetanus, influenza, and the 
neo-antigen keyhole limpet hemocyanin were observed. It is recommended that any 
course of immunization for patients should be completed at least 4 weeks before 
starting rituximab Maintenance therapy and patients should not receive any 
vaccinations that contain live or attenuated organisms during the study. 
Further information concerning rituximab safety can be found in the current version 
of the IB for rituximab IV, Summary of Product Characteristics and local prescribing 
information. 
1.2.2 
Subcutaneous (SC) Rituximab 
In contrast to the IV infusion, the rituximab SC injection takes only 5-6 minutes, and 
could thus significantly reduce the time a patient spends in the hospital and could 
eliminate hospital burdens associated with IV administration (e.g., nursing time for IV 
dosing, clinic space and utilities). It is therefore envisaged that an SC formulation of 
rituximab could bring significant clinically-meaningful benefits to patients and 
considerable economic reductions to healthcare providers. 
Until now, the relatively large volume of the established rituximab IV dose has 
hindered the SC administration route for rituximab. By concentrating the IV rituximab 
formulation 12-fold and by adding recombinant human hyaluronidase (rHuPH20) as 
a novel excipient and a permeation enhancer, the injectable volume is no longer 
considered to be an issue. rHuPH20 hydrolyses hyaluronic acid fibres of the 
interstitial matrix allowing the installation of volumes larger than 2-3 mL and 
increasing the dispersion of locally injected drugs across a broad range of molecular 
weights without tissue distortion. rHuPH20 improves the PK profiles of large 
biopharmaceuticals administered via the interstitial route and drives the PK profile 

Rituximab – Roche North Africa (Algeria, Morocco & Tunisia) 
Mabrella ML28964 Daughter Protocol – v3.1 – 07 February 2016  
34 
CTC: common terminology criteria; SAE: serious adverse event; SC: subcutaneous  
* One additional SAE (major depression) was subsequently downgraded to a non-serious event. 
Data available on clinical database as of September 28, 2010 
 
Four serious adverse events (SAEs) were reported in four patients (appendicitis 
[Cohort A], hospitalization for transluminal angioplasty [Cohort C], major depression 
[Cohort A], subsequently downgraded to a non-serious event, and angina pectoris 
[Cohort D]). All were considered unrelated to study treatment. There have been no 
reports of serious or severe infections. There were no AEs leading to death, 
withdrawal or treatment discontinuation. 
The most commonly documented AE was local administration-associated reactions 
(AARs; N = 30). AARs are defined as all AEs occurring within 24 hours of rituximab 
administration and considered related to study drug. AARs included IRRs, injection-
site reactions, administration site conditions and all symptoms thereof. After AARs, 
the most common events were mild infections (N = 18) and gastrointestinal disorders 
(N = 17). The majority of AARs (85%) and of AEs overall (68%) were assessed as 
mild (National Cancer Institute Common Terminology Criteria for Adverse Events 
[NCI CTCAE] grade 1), 27% of AEs as moderate (CTC grade 2) and the remaining 
5% as severe (CTC grade 3), all of which resolved. 
Safety data is now available from the comparative part of study BP22333 (Salar et 
al, 2012). Results showed that the incidence and intensity of AEs were generally 
balanced, as 79% of patients in each arm experienced AEs. Serious AEs were 
observed in 12% and 14% of patients in the SC and IV arms, respectively.  No SAE 
occurred in > 1 patient in either treatment arm. Grade 3/4 AEs occurred in 18% and 
17% of patients in the SC and IV arms, respectively.  Neutropenia (2 patients in each 
arm) and arthralgia (2 patients in the IV arm) was the only grade 3/4 AE occurring 
in > 1 patient in either treatment arm. ARRs were the most frequent AE and had a 
higher incidence in the SC arm (31% of SC vs. 4% of IV patients). ARRs consisted 
mostly or local reactions, and the most common in the SC arm were erythema (13%), 
injection site erythema (5%), and myalgia (5%). 
Ongoing Clinical Studies 
Two additional clinical studies with rituximab SC have started recently. Study 
BO22334 (NCT01200758), investigating the PK, safety and efficacy of rituximab SC 
in combination with chemotherapy followed by rituximab SC Maintenance therapy in 
530 patients with FL and study BO25431 (NCT01292603), investigating the PK and 
safety of rituximab SC in 200 patients with CLL. First interim results were presented 
at the American Society of Haematology (ASH) conference 2012. 
Lastly, three phase IIIb trials have been initiated. 
MO25455 will evaluate the efficacy in terms of PFS after randomization of rituximab 
SC in 770 patients with relapsed or refractory, indolent NHL who responded to 
induction and initial two years maintenance therapy (Maintenance I), and were 
randomized to either prolonged rituximab maintenance until progression 
(Maintenance II) or observation. First interim results are expected in Q4/2013. 
MO28107 will investigate the efficacy of the combination of subcutaneous rituximab 
in combination with chemotherapy in patients with previously untreated DLBCL. First 
interim results are expected in Q4/2013. 
MO28457 will evaluate patient preference with subcutaneous administration of 
rituximab versus intravenous rituximab in previously untreated patients with DLBCL 
or follicular lymphoma. First interim results are expected in Q1/2014. 
Refer to the current rituximab SC IB for further details on nonclinical and clinical 
studies of rituximab SC. 

Rituximab – Roche North Africa (Algeria, Morocco & Tunisia) 
Mabrella ML28964 Daughter Protocol – v3.1 – 07 February 2016  
35 
1.3 
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT 
1.3.1.1 
Benefits of Rituximab 
The efficacy and safety of rituximab IV is well established. Rituximab IV is 
administered as an infusion over 3 to 4 hours. Frequently observed IRRs may 
require prolonging the infusion time further. These long infusion times and the side 
effects related to the infusion were cited by some patients as uncomfortable 
consequences of the current therapeutic treatment. Furthermore, the required 
procedure to establish IV access is considered invasive and can be painful, 
particularly in patients with malignant diseases who are treated repeatedly. 
Rituximab for SC administration has been developed to address these limitations (i.e. 
IIRRs, long administration times, hospital facilities requirements, difficulty treating 
patients with poor venous access). SC administration of rituximab takes significantly 
less time (5-6 minutes) compared to IV infusion and this is expected to improve 
treatment convenience, patient satisfaction and compliance.  
Based on modelling and simulation of PK data from Stage 1 of the dose-finding 
study BP22333 (Salar A et al. 2010), a fixed rituximab SC dose of 1400 mg has been 
found non-inferior to the rituximab IV dose of 375 mg/m2 and selected for further 
investigation. BP22333 was the first-in-human adaptive two-stage study (Stage 1 
and Stage 2) for selecting a rituximab SC dose that achieves non-inferior trough 
concentrations compared to those of rituximab IV, and comparing exposure and 
safety for the IV and SC formulations in patients with FL. Preliminary safety data 
collected for 108 patients treated with a single SC dose and 16 patients receiving 
standard rituximab IV in Stage 1 of study BP22333 indicate that rituximab SC was 
well tolerated, with an AE profile comparable to that of the IV formulation. A total of 
65 patients experienced 157 AEs in the 4 cohorts combined, including 57 of the 108 
patients receiving rituximab SC. Observed AEs were mostly mild to moderate and 
none required discontinuation of treatment. A total of 3 SAEs were reported, none of 
which were considered related to rituximab (SC or IV). Further details about the 
BP22333 study design, as well as PK and preliminary safety findings are provided in 
Section  1.2.2. 
The safety profile and the efficacy of the rituximab SC formulation containing 
rHuPH20 are expected to be similar to those of the IV formulation. Preclinical, clinical 
and extensive post-marketing experience with the rHuPH20 excipient used in the SC 
formulation has shown the component to be well-tolerated. In addition, the SC route 
of administration may reduce the risk and intensity of IIRRs compared to IV 
administration. For other monoclonal antibodies in other clinical settings the switch 
from IV to SC administration has resulted in an improved tolerability with less IIRRs, 
increased patient-convenience and improved cost-effectiveness (Stilgenbauer et al. 
2009; Wynne et al. 2010; Moreau et al. 2011). For example, the administration of 
alemtuzumab by the IV route resulted in a significant proportion of patients 
experiencing IRRs; however these were rare or absent following SC administration 
(Stilgenbauer et al. 2009). 
1.3.1.2 
Mitigation of the Known Safety Risks of Rituximab  
The safety of rituximab IV in patients with haematologic malignancies, including 
previously untreated DLBCL or follicular NHL is well characterised.  
The contraindications for rituximab administration in NHL (known hypersensitivity to 
the active substance or to any of the excipients or to murine proteins, active, severe 
infections and severely immunocompromised state) are specified as exclusion 
criteria for the current study. The risk of hypersensitivity reaction to rituximab after 
SC injection is minimized by administering the rituximab SC formulation only to 

Rituximab – Roche North Africa (Algeria, Morocco & Tunisia) 
Mabrella ML28964 Daughter Protocol – v3.1 – 07 February 2016  
36 
patients that have been previously treated with rituximab IV and who, consequently, 
are unlikely to have relevant quantities of circulating B-cells that may induce IIRRs, 
such as fever, or hypotension, upon their destruction through rituximab. In the event 
of an allergic reaction during administration of rituximab, standard treatment for 
hypersensitivity reactions (e.g. epinephrine [adrenaline], antihistamines and 
glucocorticoids), should be available for immediate use. 
Rituximab is associated with IIRRs, which may be related to release of cytokines 
and/or other chemical mediators. Severe IIRRs might be clinically indistinguishable 
from hypersensitivity reactions or cytokine release syndrome. Severe IRRs with fatal 
outcome have been reported with rituximab IV during post-marketing use. Severe 
IIRRs usually manifested within 30 minutes to 2 hours after starting the first rituximab 
IV infusion, were characterized by pulmonary events and included, in some cases, 
rapid tumour lysis and features of TLS in addition to fever, chills, rigors, hypotension, 
urticaria, angioedema and other symptoms (Rituximab IV IB). In order to reduce the 
incidence and severity of IIRRs, it is recommended that all patients receive 
premedication with paracetamol (acetaminophen) and diphenhydramine 
hydrochloride (or alternative antihistamine), administered 30-60 minutes prior to 
each rituximab administration (see Section  4.4.1.1). Recommendations for TLS 
prophylaxis are also provided (see Section  4.4.1.2). Patients who were not able to 
receive the full dose of rituximab at Cycle 1 as a result of IIRRs will not continue in 
the study. 
Use of rituximab may be associated with an increased risk of neurotoxicity, including 
PML. If PML is suspected based on any new or worsening neurological, cognitive or 
psychiatric symptoms or signs, further dosing will be suspended until PML has been 
excluded. The protocol provides guidance for management of neurotoxicity (see 
Section  5.1.3).  
Although rituximab is not myelosuppressive when given as monotherapy, decreased 
red blood cell (RBC), leucocyte and platelet counts have been reported with the R-
CHOP combination regimens. Therefore, only patients with adequate haematological 
function (defined as haemoglobin  9 g/dL, absolute neutrophil count  1.5 x 109/L 
and platelet counts of  75 x 109/L), will be enrolled in the study. The protocol also 
provides guidance for management of haematological toxicities (see Section  5.1.3). 
Angina pectoris or cardiac arrhythmia (such as atrial flutter and fibrillation), heart 
failure and myocardial infarction have occurred in patients treated with rituximab IV. 
Prospective study patients will therefore undergo an electrocardiogram (ECG) 
assessment at baseline, to rule out clinically significant abnormalities. 
The potential risk of side effects at the injection site is minimized by instructing the 
study personnel and Investigators to pay special attention to the injection site and to 
report any findings in the case report form (CRF).  
Patients treated with monoclonal antibodies may develop antibodies against these 
monoclonal antibodies potentially resulting in hypersensitivity reactions or 
attenuation of therapeutic effects. Patients with human anti-mouse antibody (HAMA) 
or human antichimeric antibody (HACA) titres may develop allergic or 
hypersensitivity reactions when treated with other diagnostic or therapeutic 
monoclonal antibodies (Kornbrot et al. 1994). The development of such antibodies is 
a rare event. In an integrated review of data from 356 patients, four patients 
developed a HACA response following treatment with rituximab IV. Two of these 
patients were retreated without problems. No correlation was seen between HACA 
response and loss of, or interference with, response to treatment.  

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Rituximab – Roche North Africa (Algeria, Morocco & Tunisia) 
Mabrella ML28964 Daughter Protocol – v3.1 – 07 February 2016  
38 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
3.1.1 
Overview 
This is an open-label, single-arm study to evaluate the safety of rituximab SC 
administered during first line treatment for FL (Induction and/or Maintenance), or DLBCL 
(treatment plus 24 months of follow-up). 
This study will include adult patients with CD20+ DLBCL or CD20+ follicular NHL 
(grade 1 to 3a; NHL), who have already received at least one full dose of IV 
rituximab during induction or maintenance. Patients receiving Induction therapy must 
be able to receive at least 4 cycles of rituximab SC in addition to standard 
chemotherapy. FL Patients receiving Maintenance therapy must be able to receive at 
least 6 cycles of rituximab SC. 
During administration of rituximab SC, patients will be assessed for safety and 
efficacy as detailed in the Schedule of Assessments (see Appendix 1). RASQ (see 
Appendix 6) will be applied to patients at the end of the study after rituximab 
administration. Healthcare Professional  (HCP) Questionnaire (see Appendix 7) will 
be applied at the end of the study to health care professionals. 
Induction Therapy: 
Patients receiving Induction therapy prior to entry into the study must be eligible to 
receive at least four further cycles of rituximab SC (i.e. 4 additional months of 
Induction treatment). Patients with follicular NHL who will continue into Maintenance 
therapy (after staging at the end of Induction) can continue to receive rituximab SC 
during Maintenance (see below). 
Maintenance Therapy (patients with follicular NHL): 
Patients receiving Maintenance therapy prior to entry into the study must be eligible 
to receive at least six further cycles of rituximab SC (i.e. 12 additional months of 
Maintenance treatment). Patients who are continuing into Maintenance therapy 
following at least four cycles of rituximab SC during Induction Therapy must also be 
eligible to receive at least six cycles of rituximab SC (i.e. 12 additional months of 
Maintenance treatment). 
 
Study Design Schemes 
 

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Rituximab – Roche Algeria (Algeria, Morocco & Tunisia) 
Mabrella ML28964 Daughter Protocol – v3.1 – 07 February 2016  
43 
contraindicated. The CT scan used for eligibility assessments may be performed up 
to 28 days prior to dosing. 
3.4.3 
Exploratory Outcome Measures 
Not applicable 
3.4.4 
Pharmacodynamic and Pharmacokinetic 
Outcome Measures 
Not applicable 
3.4.5 
Pharmacoeconomic Outcome Measures 
Not applicable 
3.4.6 
Patient-Reported Outcome (PRO) 
Measures 
Patient satisfaction with administration of treatment will be evaluated by all patients 
using the RASQ (see Appendix 6) after last Rituximab SC in induction and after last 
Rituximab SC in maintenance. The RASQ will be completed immediately after 
rituximab administration and before chemotherapy administration in case the patient 
will receive chemotherapy. Patients prematurely discontinuing treatment during the 
study should complete the questionnaire at time of discontinuation, as long as they 
had been administered at least one dose of treatment via both administration routes. 
3.4.7 
Healthcare Professional Reported 
Outcome Measures 
Healthcare Professionals’ experiences about rituximab SC administration and it’s 
convenience will be evaluated using Healthcare Professional (HCP) Questionnaire 
(see Appendix 7). Questionnaire will be completed at the end of the study by the 
healthcare Professionals such as hematologists, internists, nurses or other 
healthcare professionals who administered rituximab SC to the subjects. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
The target population will consist of adults with CD20+ DLBCL or CD20+ follicular 
NHL grade 1 to 3a, according to the WHO classification system. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
1. 
Signed, written informed consent form 
2. 
Age  18 and  80 years at time of enrolment 
3. 
Histologically confirmed, CD20+ DLBCL or CD20+ follicular NHL grade 1 to 3a, 
according to the WHO classification system 
4. 
Currently being treated with rituximab IV in the Induction or Maintenance setting, having 
received at least one full dose of rituximab IV, defined as standard full dose of rituximab 
IV 375 mg/m2 administered without interruption or early discontinuation because of 
tolerability issues 
5. 
Expectation and current ability for the patient to receive at least four additional cycles of 
treatment during the Induction phase or six additional cycles of treatment during the 
Maintenance phase (patients with follicular NHL) 
6. 
Induction only: An International Prognostic Index (IPI) score of 1-4 or IPI score of 0 with 
bulky disease, defined as one lesion  7.5 cm, or FLIPI (low, intermediate or high risk) 
(see Appendix 3) 

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Rituximab – Roche Algeria (Algeria, Morocco & Tunisia) 
Mabrella ML28964 Daughter Protocol – v3.1 – 07 February 2016  
45 
10. Other serious underlying medical conditions, which, in the Investigator’s judgment, could 
impair the ability of the patient to participate in the study (e.g., significant cardiovascular 
disease, uncontrolled diabetes mellitus, gastric ulcers, active autoimmune disease) 
11. Recent major surgery (within 4 weeks prior to dosing, other than for diagnosis 
12. Active and/or severe bacterial, viral, fungal, mycobacterial, parasitic, or other infection 
(excluding fungal infections of nail beds) or any major episode of infection requiring 
treatment with IV antibiotics or hospitalization (relating to the completion of the course of 
antibiotics except if for tumour fever) within 4 weeks prior to dosing 
13. Active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection (must be ruled 
out during Screening) 
14. History of human immunodeficiency virus (HIV) seropositive status 
General Criteria 
15. Inability to provide informed consent and comply with protocol requirements.  
16. Life expectancy of less than 6 months 
17. A positive serum pregnancy test in women of childbearing potential within 7 days prior 
to dosing or within 14 days if with a confirmatory urine pregnancy test within 7 days prior 
to dosing. Women of childbearing potential are defined as pre-menopausal women or 
women who are < 2 years after the onset of menopause and are not surgically sterile 
18. Fertile men or women of childbearing potential who do not agree to use a highly 
effective measure of contraception (such as oral contraceptives, intrauterine device or 
barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) 
throughout the study and for at least 12 months after the last dose of rituximab.  
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
Not applicable. 
4.3 
STUDY TREATMENT  
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Rituximab SC 
Rituximab for SC administration (MabThera® SC; RO 45-2294) is supplied as a 
ready-to-use liquid formulation with rituximab at a concentration of 120 mg/mL. 
Rituximab must not be diluted prior to administration. Furthermore, rituximab SC 
contains rHuPH20 as an excipient at a concentration of 2000 U/mL (manufactured in 
a Chinese Hamster Ovary [CHO] cell line) acting as a permeation enhancer, 
histidine/histidine-HCl (buffer), ,-trehalose (bulking agent), methionine (stabilizer), 
and polysorbate 80 (surfactant) in water for injection at a pH of 5.5. The drug product 
is a sterile, colourless to yellowish, clear to opalescent liquid.  
The rituximab SC dose is 1400 mg for all patients, independent of patient body 
surface area (BSA). This translates into an injection volume of 11.7 mL. 
Rituximab SC will be supplied by Roche, with a study specific package labeled 
according to local applicable regulations in each participating country and shipped to 
the pharmacist of each centre by the local Roche affiliate or contract research 
organization (CRO) designee.  Upon arrival of investigational products at the site, 
site personnel should check them for damage and verify proper identity, quantity, 
integrity of seals and temperature conditions, and report any deviations or product 
complaints to the monitor upon discovery. 
For further details, see the rituximab SC IB and Appendix 4. 

Rituximab – Roche Algeria (Algeria, Morocco & Tunisia) 
Mabrella ML28964 Daughter Protocol – v3.1 – 07 February 2016  
46 
4.3.1.2 
Background Treatment 
Commercially available chemotherapy will be used in combination with rituximab SC, 
as per standard local practice. For further details, see the local prescribing 
information for CHOP, CVP or FC. 
4.3.2 
Dosage, Administration and Compliance 
Patients entering the study will already be receiving rituximab IV in the Induction or 
Maintenance setting.  Where possible, rituximab SC should start in alignment with the 
next planned cycle start date. 
Rituximab is always administered prior to chemotherapy (with the exception of the 
corticosteroid component). The day of rituximab administration in all cycles will be 
considered as ‘Day 1’. 
4.3.2.1 
Rituximab SC 
Each cycle will consist of a single SC injection of rituximab administered at a fixed 
dose of 1400 mg.  
For each injection, 11.7 mL of the solution should be withdrawn from the vial. The 27 
gauge injection needle will be inserted using sterile technique in the SC tissue of the 
abdomen. The needle should be fully inserted, being careful that the tip of the needle 
is deeper than the dermis but not as deep as the underlying muscle. The goal of the 
placement angle and needle depth is to achieve uniform placement into every 
patient’s SC tissue. Study drug should not be injected into moles, scars, or bruises. 
The skin should be pinched and needle inserted before the skin is released and the 
pressure on the syringe can be applied. 
The injection should be manually pushed at a flow rate of approximately 2 mL/min, 
therefore an administration volume of 11.7 mL should take approximately 5-6 
minutes. If there is a request by the patient to interrupt the injection, the pressure on 
the syringe should initially be eased to alleviate the pain. If the pain is not alleviated 
the injection should be stopped and the patient should be asked when they are 
comfortable to resume the injection. 
Refer to Appendix 4 for additional details. 
Rituximab SC must be administered in outpatient setting in this study. There is no 
specific recommendation regarding the observation period after rituximab SC 
injections; medical judgment should be utilized.  
No dose modification should be made for rituximab SC. If chemotherapy is delayed, 
rituximab administration must also be delayed. Fourteen days will be considered an 
acceptable delay of a cycle. In a patient experiences more than 14 days of delay, the 
Medical Monitor must be consulted before the patient can resume treatment. 
4.3.2.2 
Background Treatment 
Commercially available chemotherapy will be used in combination with rituximab SC, 
as per standard local practice. 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1. All Background therapy (e.g., CHOP for patients with DLBCL, 
or CHOP, CVP, or FC for patients with follicular NHL) should be recorded on the 
eCRF. 
Before starting a new treatment cycle, toxicity related to the previous cycle must 
have resolved. 
4.3.2.3 
Additional Required Medication 
For premedications, prophylactic treatments and any additional required medications 
see Section 4.4. 

Rituximab – Roche Algeria (Algeria, Morocco & Tunisia) 
Mabrella ML28964 Daughter Protocol – v3.1 – 07 February 2016  
47 
4.3.3 
Investigational Medicinal Product 
Accountability 
Rituximab SC will be supplied by Roche and shipped to the pharmacist of each 
centre by the local Roche affiliate or contract research organization (CRO) designee.  
In accordance with the requirements of national regulatory agencies and of local 
health authorities, the Investigator or the responsible local pharmacist will be held 
accountable for proper storage and dispensing of the IMPs. All drug supplies that will 
be used in the study must be maintained securely. All study drugs shall be 
dispensed in accordance with the Investigator's prescription. The site pharmacy must 
not release rituximab if the patient’s enrolment number is not on the prescription 
received. Under no circumstances will the Investigator supply study drug to a third 
party, or allow the study drug to be used, destroyed or disposed in other ways than 
as directed by this protocol. Adequate records for the disposition of the study drug 
(e.g. Drug Dispensing Log) must be maintained. Accountability will be assessed by 
monitoring drug dispensing and return records and the IMP stored on-site. All 
records and drug supplies must be available for inspection by the Monitor at every 
monitoring visit.  
All supplies, including partially used or empty containers and copies of the 
dispensing and inventory logs, must be returned to the Monitor at the end of the 
study, unless alternate destruction has been authorized by Roche, or is required by 
local or institutional regulations. 
The electronic case report form (eCRF) and clinic records will be checked for 
consistency with site-administered chemotherapy agents used during Induction 
treatment. 
4.3.4 
Post-Trial Access to Rituximab SC 
Currently, Roche does not have any plans to provide rituximab SC to patients after 
conclusion of the study or any earlier patient withdrawal. Roche will evaluate the 
appropriateness of continuing to provide rituximab SC to study patients after 
evaluating the primary efficacy outcome measure and safety data gathered in the 
study. These analyses may be conducted prior to completion of the study. If these 
data are medically significant, Roche may amend the protocol to continue to provide 
rituximab SC in an open-label extension study to patients who have shown a 
demonstrable benefit from rituximab SC treatment during this study as measured by 
primary and secondary endpoints. This open-label extension study will continue until 
rituximab SC is commercially available to the participating patients in their countries 
or until Roche ceases producing or studying rituximab SC. 
4.4 
CONCOMITANT THERAPY 
Concomitant therapy includes any medication (e.g. prescription drugs, over the 
counter drugs, herbal/homeopathic remedies, nutritional supplements) used by a 
patient from 7 days prior to Screening to the study completion/early termination visit. 
All concomitant medications should be reported to the Investigator and recorded on 
the Concomitant Medications eCRF.  
Background therapy (e.g., CHOP for patients with DLBCL, or CHOP, CVP, or FC for 
patients with follicular NHL) should also be recorded on the eCRF. 
4.4.1 
Permitted Therapy  
Patients should receive full supportive care, such as granulocyte colony-stimulating 
factor (G-CSF) support, transfusions of blood and blood products, prophylactic 
antiviral medication, antibiotics, anti-emetics, or local application of radiotherapy for 
consolidation after induction, as applicable and according to institutional standards. 

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Rituximab – Roche Algeria (Algeria, Morocco & Tunisia) 
Mabrella ML28964 Daughter Protocol – v3.1 – 07 February 2016  
49 
4.4.3 
Prohibited Food 
There’s no limitation of food unless it’s deemed necessary by the investigator due to 
any background treatment. 
4.4.4 
Initiation of New Anti-lymphoma 
Treatment  
New anti-lymphoma treatment is defined as start of any radiation therapy (even focal 
radiation), chemotherapy or immunotherapy, alone or in any combination of them, 
which is instituted for lymphoma treatment and is not planned in the protocol. 
New anti-lymphoma treatment should be started at any time of documented disease 
progression if this progression is symptomatic and/or if the Investigator considers 
that a new treatment is necessary for the patient’s benefit. Disease progression 
should be documented. If the new anti-lymphoma treatment was initiated during the 
rituximab-based Induction treatment, the patient will undergo end-of-study assessment and 
subsequently only be followed for survival until the end of the study. 
Data on treatment at progression will be recorded in the eCRF. If a new anti-
lymphoma treatment has been started, the therapy used and the response to therapy 
should be documented in the eCRF. 
4.5 
STUDY ASSESSMENTS  
4.5.1 
Description of Study Assessments 
Study-mandated assessments are summarised in the Schedule of Assessments 
(see Appendix 1). 
For details on the timing of each assessment listed in this section, refer to Section 
4.5.2.  
4.5.1.1 
Medical History and Demographic Data 
Medical history includes clinically significant diseases within the last 5 years, surgeries, 
cancer history (including prior cancer therapies and procedures), smoking history, use 
of alcohol and drugs of abuse, and all medications (e.g. prescription drugs, over-the-
counter drugs, herbal/homeopathic remedies, nutritional supplements) used by the 
patient within 30 days prior to the Screening visit. 
Demographic data will include age, sex and ethnicity. 
4.5.1.2 
Vital Signs 
Vital signs measurements will include resting (sitting) heart rate, systolic and 
diastolic blood pressure, and body temperature and will be performed at every study 
visit. 
4.5.1.3 
Physical Examinations 
A complete Screening/Baseline physical examination should include an evaluation of 
the head, eye, ear, nose, and throat, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological 
systems. In addition, as part of tumour assessments, physical examinations should also 
include the evaluation of the presence and degree of enlarged lymph nodes, hepatomegaly, 
and splenomegaly. Any abnormality identified at Screening/Baseline should be 
recorded on the General Medical History and Baseline Conditions eCRF. At 
subsequent study visits, limited, symptom-directed physical examinations should be 
performed. Changes from baseline abnormalities should be recorded in patient notes. 
New or worsened abnormalities should be recorded as AEs on the Adverse Event 
eCRF. As part of physical exams, SC injection sites will also be checked at every 
applicable treatment visit. 
Patients should be assessed at every visit for presence of active infections 
throughout the treatment period.  

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Rituximab – Roche Algeria (Algeria, Morocco & Tunisia) 
Mabrella ML28964 Daughter Protocol – v3.1 – 07 February 2016  
52 
satisfaction with the rituximab (SC or IV) treatment, rating of injection site-related and 
administration-related side effects, anxiety about the treatment and disease, 
confidence in the treatment, treatment convenience, time required and time lost for 
the treatment administrations, how much the treatment interferes or limits daily 
activities, impact of treatment on the ability to talk to the nurse and/or doctor, (no) 
preference for IV or SC administration of rituximab and whether the patient would 
recommend rituximab (SC or IV) treatment to others. 
4.5.1.9 
Healthcare Professional Reported Outcomes 
Healthcare Professionals’ experiences about rituximab SC administration and it’s 
convenience will be evaluated using Healthcare Professional (HCP) Questionnaire 
(see Appendix 7). Questionnaire will be completed at the end of the study treatment 
by the healthcare Professionals such as hematologists, internists, nurses or other 
HCP who administered rituximab SC to the subjects. The HCP Questionnaire 
contains 14 questions evaluating how much time does the rituximab SC 
administration take, administration related complications/reactions and convenience 
of administering the treatment. 
4.5.1.10 
Mandatory Samples 
Not applicable 
4.5.2 
Timing of Study Assessments 
4.5.2.1 
Screening and Pre-treatment Assessments 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations. Informed Consent 
Forms (ICFs) for enrolled patients and for patients who were screened but not 
subsequently enrolled will be maintained at the study site.  
Screening tests and evaluations will be performed within 28 days prior to start of 
treatment. Standard-of-care tests or examinations performed prior to obtaining 
informed consent and within 28 days prior to start of treatment do not need to be 
repeated for Screening. All sites of known disease should be documented at 
Screening/Baseline in order to provide an accurate basis for future assessments. All 
screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before study enrolment. Patients who are suspected of 
progressing between their Screening/Baseline tumour assessments and first dose 
should be re-screened and re-assessed for their suitability for the trial. The 
Investigator will maintain a screening log in accordance with local study file 
documentation requirements to record details of all patients screened and to confirm 
eligibility or record reasons for screening failures. 
Please see Appendix 1 for the schedule of Screening and pre-treatment 
assessments. 
4.5.2.2 
Assessments during Treatment Visits  
All assessments must be performed on the day of the specified visit, unless a time 
window is specified in the Schedule of Assessments (see Appendix 1). 
Assessments scheduled on the day of study treatment administration should be 
performed prior to administration of study treatment, unless otherwise noted in the 
Schedule of Assessments. 
Please see Appendix 1 for the Schedule of Assessments performed during the 
treatment period. 
The RASQ (see Appendix 6) will be applied at the end of the study. Patients will be 
asked to assess their satisfaction with the study treatment using RASQ immediately 
after rituximab administration and before chemotherapy administration in case the 
patient will receive chemotherapy. 

Rituximab – Roche Algeria (Algeria, Morocco & Tunisia) 
Mabrella ML28964 Daughter Protocol – v3.1 – 07 February 2016  
53 
Patients with SD or PD at staging after induction therapy for FL or first-line therapy 
for DLBCL will be withdrawn from study treatment and will only be followed for 
resolution of SAEs related to rituximab therapy (as applicable) and for survival until 
the end of the study. 
Patients who do not complete the Induction treatment per protocol will undergo end-
of-treatment assessment within 4 weeks after the last dose of Induction treatment 
and will be followed until the end of the whole study according to local practice for 
resolution of SAEs related to rituximab SC therapy (as applicable), tumour response 
/ progression (if PD not yet documented), survival, and documentation of any new 
anti-lymphoma treatment. 
4.5.2.3 
Post-Treatment Follow-up (Observation) Period  
After the study completion/early termination visit, AEs should be followed as outlined 
in Sections 5.5 and 5.6. 
Please see Appendix 1 for the schedule of follow-up assessments. 
All patients who complete Induction treatment will then enter the post-treatment 
follow-up phase until the end of study. Patients with SD at staging will be 
permanently discontinued from study treatment and will enter the post-treatment 
follow-up phase. Patients with PD at staging (or at any time during treatment) will be 
permanently discontinued from study treatment and will be followed only for survival 
and related SAES until the end of study. Patients who receive at least one dose of 
study drug but do not complete the study as per protocol will undergo the early 
treatment termination assessments within 4 weeks after the last dose of (Induction or 
Maintenance) treatment and will enter the post-treatment follow-up phase until the 
end of study for resolution of SAEs related to rituximab therapy, tumour response / 
progression (if PD not yet documented), new treatments for lymphoma, and survival. 
Follow-up of patients after Induction treatment will occur every 3 months for the first 
year and then every 6 months (± 2 weeks) until the end of the study, as detailed in 
Appendix 1 (Schedule of Assessments). In countries where it is not feasible to 
perform a CT scan every 3 months (± 2 weeks) for 1 year, it is acceptable to perform 
a CT scan every 6 months (± 2 weeks) for 2 years instead.  
4.5.2.4 
Assessments at Study Completion/Early Termination Visit 
Patients who complete the study or discontinue from the study early will be asked to 
return to the clinic (after 28 days or at least 5 half-lives of any non-rituximab IMPs, 
whichever longer) after the last dose of study drug for a follow-up visit. 
Please see Appendix 1 for the Schedule of Assessments performed at the study 
completion/early termination visit. 
Patient satisfaction with administration of treatment will be evaluated by all patients 
using the RASQ (see Appendix 6) after last Rituximab SC in induction and after last 
Rituximab SC in maintenance. The RASQ will be completed immediately after 
rituximab administration and before chemotherapy administration. Patients 
prematurely discontinuing treatment during the study should complete the 
questionnaire at time of discontinuation, as long as they had been administered at 
least one dose of treatment via both administration routes. 
Healthcare professionals such as haematologist, internists, nurses or other 
healthcare professionals who administered rituximab SC will complete Healthcare 
Professional (HCP) questionnaire (see Appendix 7) at the end of the study. 
4.5.2.5 
Unplanned Visits 
Assessments other than those specified in Appendix 1, Schedule of Assessments, 
may be performed as clinically indicated. These assessments should be adequately 
documented. 

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Rituximab – Roche Algeria (Algeria, Morocco & Tunisia) 
Mabrella ML28964 Daughter Protocol – v3.1 – 07 February 2016  
56 
All AARs must be recorded on the Adverse Event eCRF. Cutaneous and soft-tissue 
AARs will be classified in the eCRF as either localized at the injection site, or non-
localized reactions (including generalized reactions). In order to capture potential 
differences in terms of clinical relevance of these events, it is important to report and 
assess the intensity of all individual symptoms of the AARs. 
Signs and symptoms suggestive of an IIRR were reported in more than 50% of 
patients who received rituximab IV in clinical trials, and were predominantly seen 
during the first infusion. Severe IIRRs occurred in up to 12% of all patients at the 
time of the first treatment cycle with rituximab in combination with chemotherapy. 
These included cases of cytokine release syndrome accompanied by hypotension 
and bronchospasm. The incidence of infusion-related symptoms decreased 
substantially with subsequent infusions and is <1% of patients by the eighth cycle. 
Infusion reaction symptoms are usually reversible with interruption of the infusion. 
Treatment of infusion-related symptoms with an anti-pyretic (e.g. acetaminophen), 
an antihistaminic (such as diphenhydramine) is recommended. Additional treatment 
with bronchodilators, oxygen or IV saline may be indicated. In most cases, the 
infusion can be resumed at a 50% reduction in rate (e.g. from 100 mg/hour to 50 
mg/hour) when symptoms have completely resolved. 
Patients who develop severe cytokine release syndrome or severe pulmonary events 
should have their infusion interrupted immediately and should receive aggressive 
symptomatic treatment. Since initial improvement of clinical symptoms may be 
followed by deterioration, these patients should be closely monitored until TLS and 
pulmonary infiltration have been resolved or ruled out. 
Hypersensitivity reactions typically occur within minutes after starting rituximab 
infusion. Medicinal products for the treatment of hypersensitivity reactions (e.g. 
epinephrine (adrenaline), antihistamines and glucocorticoids), should be available for 
immediate use in the event of an allergic reaction during administration of rituximab. 
If PML is suspected based on any new or worsening neurological, cognitive or 
psychiatric symptoms or signs, further dosing must be suspended until PML has 
been excluded. The Investigator should evaluate the patient to determine if the 
symptoms are indicative of neurological dysfunction, and if so, whether these 
symptoms are possibly suggestive of PML. 
Guidelines for managing of specific haematologic and non-haematologic AEs 
associated with R-CHOP treatment are summarized in Table 5 below.  

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Rituximab – Roche Algeria (Algeria, Morocco & Tunisia) 
Mabrella ML28964 Daughter Protocol – v3.1 – 07 February 2016  
66 
5.4.2 
Reporting Requirements for Serious 
Adverse Events and Non-Serious 
Adverse Events of Special Interest 
For reports of SAEs and non-serious AEs of special interest, Investigators should 
record all case details that can be gathered within 24 hours on the Adverse Event 
eCRF and submit the report via the electronic data capture (EDC) system. A report 
will be generated and sent to Roche Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, a paper Serious Adverse 
Event/Non-Serious Adverse Event of Special Interest CRF and Fax Coversheet 
should be completed and faxed to Roche Safety Risk Management or its designee 
within 24 hours after learning of the event, using the fax numbers provided to 
Investigators (see Protocol Administrative and Contact Information & List of 
Investigators). Once the EDC system is available, all information will need to be 
entered and submitted via the EDC system.  
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
Investigator if they become pregnant during the study or within 12 months after the 
last dose of study drug. A Pregnancy Report eCRF should be completed by the 
Investigator within 24 hours after learning of the pregnancy and submitted via the 
EDC system. Details of the course and outcome of any pregnancy will be collected 
and reported.  A pregnancy report will automatically be generated and sent to Roche 
Safety Risk Management. Pregnancy should not be recorded on the Adverse Event 
eCRF. The Investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the foetus. 
Monitoring of the patient should continue until conclusion of the pregnancy. 
In the event that the EDC system is unavailable, a Pregnancy Report worksheet and 
Pregnancy Fax Coversheet should be completed and faxed to Roche Safety Risk 
Management or its designee within 24 hours after learning of the pregnancy, using 
the fax numbers provided to Investigators (see Protocol Administrative and Contact 
Information & List of Investigators). 
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the ICF to immediately inform the 
Investigator if their partner becomes pregnant during the study or within 90 days after 
the last dose of study drug. A Pregnancy Report eCRF should be completed by the 
Investigator within 24 hours after learning of the pregnancy and submitted via the 
EDC system. Attempts should be made to collect and report details of the course 
and outcome of any pregnancy in the partner of a male patient exposed to study 
drug. The pregnant partner will need to sign an Authorization for Use and Disclosure 
of Pregnancy Health Information to allow for follow-up on her pregnancy. Once the 
authorization has been signed, the Investigator will update the Pregnancy Report 
eCRF with additional information on the course and outcome of the pregnancy. An 
Investigator who is contacted by the male patient or his pregnant partner may 
provide information on the risks of the pregnancy and the possible effects on the 
foetus, to support an informed decision in cooperation with the treating physician 
and/or obstetrician. 
In the event that the EDC system is unavailable, the reporting instructions provided 
in Section 5.4.3.1 should be followed. 

Rituximab – Roche Algeria (Algeria, Morocco & Tunisia) 
Mabrella ML28964 Daughter Protocol – v3.1 – 07 February 2016  
67 
5.4.3.3 
Abortions 
Any spontaneous abortion should be classified as an SAE (as the Sponsor considers 
spontaneous abortions to be medically significant events), recorded on the Adverse 
Event eCRF, and reported to the Sponsor within 24 hours after learning of the event 
(see Section 5.4.2).  
5.4.3.4 
Congenital Anomalies / Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient or female 
partner of a male patient exposed to study drug should be classified as an SAE, 
recorded on the Adverse Event eCRF, and reported to the Sponsor within 24 hours 
after learning of the event (see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The Investigator should follow each AE until the event has resolved to baseline 
grade or better, the event is assessed as stable by the Investigator, the patient is lost 
to follow up, or the patient withdraws consent. Every effort should be made to follow 
all SAEs until a final outcome can be reported. 
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF.  
In the event of medically significant unexplained abnormal laboratory test values, the 
tests should be repeated and followed up until they have returned to the normal 
range or baseline state and/or an adequate explanation of the abnormality is found. 
If a clear explanation is established it should be recorded on the eCRF. 
All pregnancies reported during the study should be followed until pregnancy 
outcome. If the EDC system is not available at the time of pregnancy outcome, follow 
reporting instructions provided in Section 5.4.3.1. 
5.5.2 
Sponsor Follow-Up 
For SAEs, non-serious AEs of special interest, and pregnancies, the Sponsor or a 
designee may follow up by telephone, fax, electronic mail, and/or a monitoring visit to 
obtain additional case details and outcome information (e.g. from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
5.6 
POST-STUDY ADVERSE EVENTS 
At the End of Study / Early Treatment Termination visit, the Investigator should instruct each 
patient to report to the Investigator any subsequent adverse events. After the study has 
ended the Sponsor should be notified if the investigator becomes aware of any death, 
serious adverse event, or other non-serious adverse event of special interest which are 
considered to be related to the study drug, occurring at any time after a patient has 
discontinued study participation. The Investigator is not required to actively monitor patients 
after the study has ended. 
The Sponsor should also be notified if the Investigator becomes aware of the development 
of cancer or a congenital anomaly/birth defect in a subsequently conceived offspring of a 
patient that participated in this study. 
The Investigator should report these events to Roche Safety Risk Management on 
the Adverse Event eCRF.  If the Adverse Event eCRF is no longer available, the 

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6.2 
SUMMARIES OF CONDUCT OF STUDY 
This is a prospective, open-label, single-arm study to evaluate the safety of rituximab 
SC administered as Induction and/or Maintenance therapy. The study will include at 
least 100 adult patients with CD20+ DLBCL or CD20+ follicular NHL (grade 1 to 3a; 
NHL), who are currently undergoing Induction and/or Maintenance therapy with 
rituximab IV. Patients receiving Induction therapy must be able to receive at least 4 
cycles of rituximab SC in addition to standard chemotherapy. Patients with follicular 
NHL receiving Maintenance therapy must be able to receive at least 6 cycles of 
rituximab SC. 
Induction Therapy: 
Patients receiving Induction therapy prior to entry into the study must be eligible to 
receive at least four further cycles of rituximab SC (i.e. 4 additional months of 
Induction treatment). Patients with follicular NHL who will continue into Maintenance 
therapy (after staging at the end of Induction) can continue to receive rituximab SC 
during Maintenance (see below). 
Maintenance Therapy (patients with follicular NHL): 
Patients receiving Maintenance therapy prior to entry into the study must be eligible 
to receive at least six further cycles of rituximab SC (i.e. 12 additional months of 
Maintenance treatment). Patients who are continuing into Maintenance therapy 
following at least four cycles of rituximab SC during Induction Therapy must also be 
eligible to receive at least six cycles of rituximab SC (i.e. 12 additional months of 
Maintenance treatment).  
6.3 
SUMMARIES OF PATIENT POPULATION 
Baseline characteristics will be summarized, as well as the demographic profile, 
medical history, IPI score (according to Shipp et al. 1993) and/or FLIPI score (see 
Appendix 3), concomitant medication use and serum pregnancy test at 
Screening/Baseline using appropriate descriptive statistics: mean, standard deviation, 
median and range (minimum and maximum) for the continuous variables, and 
number/percentage of patients for the categorical variables. 
Exposure to study treatment (rituximab) and chemotherapy, including the number of 
cycles administered, duration of treatment exposure (calculated from date of first 
treatment date to the last treatment date) and dosing information (e.g. dose 
interruptions, modifications and delays) will be summarized.  
The number of patients who prematurely discontinue study treatment and the 
number of patients who withdrew from the study will be summarized and reasons for 
withdrawal will be displayed. 
Further details about the planned analyses will be presented in the Statistical 
Analysis Plan (SAP). 
6.3.1 
Analysis Populations 
The Intent-To-Treat (ITT) population will include all patients enrolled into the study. 
The Safety population will include all patients who have received at least one dose of 
rituximab. The Safety data will be summarized based on the safety set.  Efficacy 
endpoints will be summarized based on the ITT population. 
6.4 
SAFETY ANALYSES 
Safety will be assessed by AEs, AEs of grade  3, SAEs, AARs including IIRRs, AEs 
within the MedDRA SMQ ‘Anaphylactic reactions’ (wide), safety laboratory 
parameters, vital signs, concomitant medications, premature withdrawal from the 
study and from study medication due to AEs and ECOG performance status. All 

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clinical AEs and SAEs as well as laboratory abnormalities will be recorded and 
graded according to the NCI-CTCAE version 4.0. 
The analysis of AEs will focus on treatment-emergent adverse events, i.e. AEs 
occurring on the day of or after the first administration of study drug and up to 28 
days after the last dose. Non-treatment emergent AEs (i.e. those occurring before 
commencement of study medication) will only be listed. Adverse events will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
The incidence of AARs, AEs, AEs leading to premature discontinuation or 
interruption of study treatment, SAEs, grade  3 AEs will be computed with 95% 
Confidence Interval. The incidence of each AE will be summarized according to the 
primary system-organ class and by preferred term. The incidence of cutaneous and 
soft tissue AARs will additionally be summarised for those that are defined as 
localized and those that are defined as non-localized. The incidence of deaths and 
cause of deaths will be listed and summarized.  
Safety laboratory parameters (haematology, biochemistry, coagulation tests, as 
defined in Section  4.5.1.6), will be presented in shift tables of NCI CTCAE grade at 
baseline against worst grade recorded during the treatment period. Laboratory 
parameters will be summarized and selected laboratory parameters may also be 
displayed graphically.  
Vital signs will be summarized over time. 
ECOG performance status will be summarized by frequency tables over time and 
percentage of patients in different categories will be presented by bar charts at 
different time points. 
Concomitant medication will be coded according to the WHO DRUG dictionary and 
tabulated in summary tables. New anti-lymphoma treatment (chemotherapy, 
radiotherapy, immunotherapy), initiated after the Baseline visit will be presented in 
summary tables. 
All safety analyses will be based on the Safety population.  
Further details about the planned safety analyses will be presented in the SAP. 
6.5 
EFFICACY ANALYSES 
The analyses will include all enrolled patients. 
Efficacy endpoints include EFS, PFS, OS, DFS, CR/CRu rate and will be analysed for 
the ITT population. 
Response assessments will be based on the Investigator’s assessment, completed 
according to the IWG response criteria (Cheson et al 1999, see Appendix 2) or 
other country standards.  The endpoints of EFS, PFS and OS will be defined and 
analysed twice using two different starting points for the time-to-event calculations.  
The first starting point will be first dose of rituximab IV and the second will be first 
dose of rituximab SC. 
EFS is defined as the time from first dose of rituximab (analysed using both first dose 
of IV and first dose of SC) to first occurrence of progression or relapse, according to 
the IWG response criteria (Cheson et al 1999, see Appendix 2) or other country 
standards, or initiation of a non–protocol-specified anti-lymphoma therapy or death, 
whichever occurs first.  
PFS is defined as the time from first dose of rituximab (analysed using both first dose 
of IV and first dose of SC) to the first occurrence of progression or relapse, according 
to the IWG response criteria (Cheson et al 1999, see Appendix 2) or other country 
standards, or death from any cause.  
OS is defined as the time from first dose of rituximab (analysed using both first dose 
of IV and first dose of SC) until death from any cause. 

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DFS will be assessed in patients achieving CR/CRu and is defined as the period 
from the date of the initial CR/CRu until the date of relapse or death from any cause.  
CR/CRu rate at 4-6 weeks after the last dose of Induction treatment will be 
summarized and presented with the corresponding 95% two-sided Pearson-Clopper 
CI by treatment group and overall. 
Endpoints resulting in a incidence rate (e.g. CR/CRu) will be summarised with a 95% 
Clopper-Pearson confidence interval. 
The analysis of endpoints measured as a time to event (e.g. EFS, PFS, OS and DFS) 
is based on the survivor function, which is the probability of remaining event free 
beyond a certain point in time. The survivor function will be estimated using Kaplan-
Meier methodology and summarized using the range, the 25th and 75th percentiles 
and median survival along with a 95% confidence interval for median survival. 
Patients who have experienced none of these events at the time of analysis (clinical-
cut off) and patients who are lost to follow up will be censored at their last clinical 
assessment date.  Patients without post-baseline tumour assessments will be 
censored at the time of their baseline visit except if death occurs prior to their first 
scheduled tumour assessment. 
6.6 
EXPLORATORY ANALYSES 
Not applicable 
6.7 
PHARMACODYNAMIC AND PHARMACOKINETIC ANALYSES 
Not applicable 
6.8 
PHARMACOECONOMIC ANALYSES 
Not applicable 
6.9 
PATIENT-REPORTED OUTCOME ANALYSES 
Descriptive statistics will be computed for the questions assessing patient responses 
regarding convenience, satisfaction and preference for rituximab SC as compared to 
rituximab IV. Specifically, frequencies and percentages will be presented, for the 
total sample and by country.  
Further details about RASQ analyses will be presented in the SAP. 
6.10 
HEALTHCARE PROFESSIONAL REPORTED OUTCOME 
ANALYSES 
Healthcare Professional (HCP) Questionnaire will be evaluated with descriptive 
statistics. Frequencies and percentages will be presented for the total sample and by 
country. Further details will be presented in the SAP. 
6.11 
INTERIM ANALYSES 
Not applicable 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
A CRO will be responsible for the data management of this study, including quality 
checking of the data. Data entered manually will be collected via EDC using eCRFs. 
Sites will be responsible for data entry into the EDC system. In the event of 
discrepant data, the CRO will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.  
Roche will supervise the data management of this study. Roche will produce an EDC 
Study Specification document that describes the quality checking to be performed on 
the data. Laboratory data and/or other electronic data will be sent directly to the CRO, 

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using the CRO’s standard procedures to handle and process the electronic transfer of 
these data. 
Electronic CRFs and correction documentation will be maintained in the EDC 
system’s audit trail. System backups for data stored at Roche and records retention 
for the study data will be consistent with Roche’s standard procedures. 
Data from paper PRO questionnaires will be entered into the EDC system by site 
staff. 
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed using a Sponsor-designated EDC system. Sites will 
receive training and a have access to a manual for appropriate eCRF completion. 
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff. eCRFs should be 
reviewed and electronically signed and dated by the Investigator or a designee. 
At the end of the study, the Investigator will receive patient data for his or her site in 
a readable format on a compact disc that must be kept with the study records. 
Acknowledgement of receipt of the compact disc is required. 
7.3 
ELECTRONIC PATIENT-REPORTED OUTCOME DATA 
Not applicable 
7.4 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel 
are accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time. They include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, PROs, evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies of transcriptions that are certified after verification as being accurate and 
complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will 
be clearly defined in the Trial Monitoring Plan. This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) 
and considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained 
per the policy for retention of records described in Section 7.6. 
To facilitate source data verification, the Investigators and institutions must provide 
the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and EC review. The investigational site must 
also allow inspection by applicable health authorities. 
7.5 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated 
in accordance with health authority requirements pertaining to computerized systems 
used in clinical research. An acceptable computerized data collection system allows 
preservation of the original entry of data. If original data are modified, the system 

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should maintain a viewable audit trail that shows the original data as well as the 
reason for the change, name of the person making the change, and date of the 
change. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data (if applicable), ICFs, laboratory test results, and 
medication inventory records, must be retained by the Principal Investigator for at 
least 15 years after completion or discontinuation of the study, or for the length of 
time required by relevant national or local health authorities, whichever is longer. 
After that period of time, the documents may be destroyed, subject to local 
regulations.  
No records may be disposed of without the written approval of the Sponsor. Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of 
the ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards 
for Expedited Reporting) and the EU Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
Roche sample ICF (and any applicable ancillary sample ICFs such as a Child’s 
Assent or Caregiver's ICF, if applicable) will be provided to each site. If applicable, it 
will be provided in a certified translation of the local language. Roche or its designee 
must review and approve any proposed deviations from Roche sample ICFs or any 
alternate consent forms proposed by the site (collectively, the “Consent Forms”) 
before EC submission. The final EC-approved Consent Forms must be provided to 
Roche for health authority submission purposes according to local requirements. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorised representative before his or her participation in the study. The case 
history or clinical records for each patient shall document the informed consent 
process and that written informed consent was obtained prior to participation in the 
study. 
The Consent Forms should be revised whenever there are changes to study 
procedures or when new information becomes available that may affect the 
willingness of the patient to participate. The final revised EC-approved Consent 
Forms must be provided to Roche for health authority submission purposes. 
Patients must be re-consented to the most current EC-approved version of the 
Consent Forms (or to a significant new information/findings addendum in accordance 
with applicable laws and EC policy) during their participation in the study. For any 
updated or revised Consent Forms, the case history or clinical records for each 
patient shall document the informed consent process and that written informed 
consent was obtained using the updated/revised Consent Forms for continued 
participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorised representative. All signed and dated Consent Forms must remain 

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in each patient’s study file or in the site file and must be available for verification by 
study monitors at any time. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the ICFs, any information to be given to the patient, and relevant 
supporting information must be submitted to the EC by the Principal Investigator or, 
as applicable, the Country Study Manager and reviewed and approved by the EC 
before the study is initiated. In addition, any patient recruitment materials must be 
approved by the EC.  
The Principal Investigator or, as applicable, the Country Study Manager is 
responsible for providing written summaries of the status of the study to the EC 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the EC. Investigators or, as applicable, the Country Study 
Manager are/is also responsible for promptly informing the EC of any protocol 
amendments (see Section 9.5). 
In addition to the requirements for reporting all AEs to the Sponsor, Investigators 
must comply with requirements for reporting SAEs to the local health authority and 
EC. Investigators may receive written IND safety reports or other safety-related 
communications from Roche. Investigators are responsible for ensuring that such 
reports are reviewed and processed in accordance with health authority 
requirements and the policies and procedures established by their EC, and archived 
in the site’s study file.  
8.4 
CONFIDENTIALITY 
Roche maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number. This means that 
patient names are not included in data sets that are transmitted to any Roche 
location. 
Patient medical information obtained by this study is confidential and may only be 
disclosed to third parties as permitted by the ICF (or separate authorisation for use 
and disclosure of personal health information) signed by the patient, unless 
permitted or required by law. 
Medical information may be given to a patient’s personal physician or other 
appropriate medical personnel responsible for the patient’s welfare, for treatment 
purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the US FDA and other national and local health authorities, Roche 
monitors, representatives, and collaborators, and the EC for each study site, as 
appropriate. 
8.5 
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 health 
authorities. Investigators are responsible for providing information on financial 
interests during the course of the study and for 1 year after completion of the study 
(i.e. LPLV). 
9. 
STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The Investigator must maintain adequate and accurate records to enable the 
conduct of the study to be fully documented, including but not limited to the protocol, 

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protocol amendments, ICFs, and documentation of EC and governmental approval. 
In addition, at the end of the study, the Investigator will receive the patient data, 
which includes an audit trail containing a complete record of all changes to data. 
9.2 
SITE INSPECTIONS 
Site visits will be conducted by Roche or an authorised representative for inspection 
of study data, patients’ medical records, and eCRFs. The Investigator will permit 
national and local health authorities, Roche monitors, representatives, and 
collaborators, and the ECs to inspect facilities and records relevant to this study. 
9.3 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 
The results of this study may be published or presented at scientific meetings. If this 
is foreseen, the Investigator agrees to submit all manuscripts or abstracts to the 
Sponsor prior to submission. This allows the Sponsor to protect proprietary 
information and to provide comments based on information from other studies that 
may not yet be available to the Investigator. 
The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicentre trials only in their entirety and not as individual 
centre data. In this case, a coordinating Investigator will be designated by mutual 
agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. Any formal 
publication of the study in which contribution of Sponsor personnel exceeded that of 
conventional monitoring will be considered as a joint publication by the Investigator 
and the appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating 
from the use of data from this study will become and remain the exclusive and 
unburdened property of the Sponsor, except where agreed otherwise. 
9.4 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor. Protocol amendments 
will be submitted to the EC and to regulatory authorities in accordance with local 
regulatory requirements.  
Approval must be obtained from the EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g. change in Medical Monitor or contact information). 

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10. 
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11. 
APPENDICES 
 

 
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i. 
Women of childbearing potential (defined as pre-menopausal women or women who are < 2 years after the onset of menopause and not surgically sterile) must undergo 
serum pregnancy test within 7 days prior to first dose or within 14 days if with a confirmatory urine pregnancy test within 7 days prior to dosing.  
j. 
Haematology parameters will include haemoglobin, RBC, WBC count and differential, and platelet count. Biochemistry parameters at Screening will include sodium, 
potassium, ALT/SGPT, AST/SGOT, total bilirubin, serum creatinine, alkaline phosphatase, albumin, BUN, C-reactive protein and LDH. Biochemistry parameters at any 
further timepoint during the study will include sodium, potassium, ALT/SGPT, AST/SGOT, total bilirubin, and serum creatinine. Coagulation tests will include: INR, PT, and 
aPTT. The results from the safety laboratory assessments must be available on treatment days, prior to the rituximab administrations. 
k. 
After informed consent has been obtained but prior to dosing, only SAEs caused by a protocol-mandated intervention should be reported (e.g. SAEs related to invasive 
procedures such as biopsies). All clinical and laboratory AEs reported during the study will be documented and graded using the NCI CTCAE criteria, version 4.0. Special 
attention should be given to any acute infusion-related toxicities. After initiation of study drug, all AEs/SAEs, regardless of relationship to study drug, will be reported until 
study closure.  
l. 
Patient reported outcomes: All patients will be required to complete the Rituximab Administration Questionnaire (RASQ, see Appendix 6) at the end of the study. Patients 
prematurely discontinuing study treatment should complete the questionnaire at time of discontinuation, as long as they had taken at least one dose via each treatment 
route (IV and SC) post-randomization. RASQ will be completed immediately after rituximab administration and before chemotherapy administration. 
m. Healthcare Professional (HCP) Questionnaire (see Appendix 7) will be completed at the end of the study by healthcare professionals such as haematologists, internists, 
nurses or other healthcareprofessionals who administered rituximab SC during the study. 
 

 
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further timepoint during the study will include sodium, potassium, ALT/SGPT, AST/SGOT, total bilirubin, and serum creatinine. Coagulation tests will include: INR, PT, and 
aPTT. The results from the safety laboratory assessments must be available on treatment days, prior to the rituximab administrations. 
k. 
After informed consent has been obtained but prior to dosing, only SAEs caused by a protocol-mandated intervention should be reported (e.g. SAEs related to invasive 
procedures such as biopsies). All clinical and laboratory AEs reported during the study will be documented and graded using the NCI CTCAE criteria, version 4.0. Special 
attention should be given to any acute infusion-related toxicities. After initiation of study drug, all AEs/SAEs, regardless of relationship to study drug, will be reported until 
study closure. 
l. 
Patient reported outcomes: All patients will be required to complete the Rituximab Administration Questionnaire (see Appendix 6) at the end of the study. Patients 
prematurely discontinuing study treatment should complete the questionnaire at time of discontinuation, as long as they had taken at least one dose via each treatment 
route (IV and SC) post-randomization. RASQ will be comleted immediately after rituximab administration and before chemotherapy administration. 
m. Healthcare Professional (HCP) Questionnaire (see Appendix 7) will be completed at the end of the study by healthcare professionals such as haematologists, internists, 
nurses or other healthcareprofessionals who administered rituximab SC during the study. 
 
 
.  

 
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11.2 
APPENDIX 2 RESPONSE ASSESSMENT ACCORDING TO THE 
INTERNATIONAL WORKING GROUP RESPONSE CRITERIA 
Complete response (CR) requires the following: 
1. 
Complete disappearance of all detectable clinical and radiographic evidence of disease and 
disappearance of all disease-related symptoms if present before therapy, and normalization of 
those biochemical abnormalities (e.g., LDH) definitely assignable to NHL. 
2. 
All lymph nodes and nodal masses must have regressed to normal size ( 1.5 cm in their 
greatest transverse diameter for nodes > 1.5 cm before therapy). Previously involved nodes 
that were 1.1 to 1.5 cm in their greatest transverse diameter before treatment must have 
decreased to  1 cm in their greatest transverse diameter after treatment, or by more than 
75% in the sum of the products of the greatest diameters (SPD). 
3. 
The spleen, if considered to be enlarged before therapy on the basis of a CT scan, must have 
regressed in size and must not be palpable on physical examination. However, no normal size 
can be specified because of the difficulties in accurately evaluating splenic and hepatic size. 
For instance, spleens thought to be of normal size may contain lymphoma, whereas an 
enlarged spleen may not necessarily reflect the presence of lymphoma but variations in 
anatomy, blood volume, the use of hematopoietic growth factors, or other causes. The 
determination of splenic volume or splenic index by CT scan is cumbersome and not widely 
used. Any macroscopic nodules in any organs detectable on imaging techniques should no 
longer be present. Similarly, other organs considered to be enlarged before therapy due to 
involvement by lymphoma, such as liver and kidneys, must have decreased in size. 
4. 
If the bone marrow was involved by lymphoma before treatment, the infiltrate must be cleared 
on repeat bone marrow aspirate and biopsy of the same site. The sample on which this 
determination is made must be adequate ( 20 mm biopsy core). Flow cytometric, molecular, 
or cytogenetic studies are not considered part of routine assessment to document persistent 
disease at the present time. These studies should only be incorporated into trials examining 
important research questions. 
CR/unconfirmed (CRu) includes those patients who fulfil criteria 1 and 3 above, but with 
one or more of the following features: 
1. 
A residual lymph node mass greater than 1.5 cm in greatest transverse diameter that has 
regressed by more than 75% in the SPD. Individual nodes that were previously confluent must 
have regressed by more than 75% in their SPD compared with the size of the original mass. 
2. 
Indeterminate bone marrow (increased number or size of aggregates without cytologic or 
architectural atypia). 
Partial response (PR) requires the following: 
1. 
 50% decrease in SPD of the six largest dominant nodes or nodal masses. These nodes or 
masses should be selected according to the following features: (a) they should be clearly 
measurable in at least two perpendicular dimensions, (b) they should be from as disparate 
regions of the body as possible, and (c) they should include mediastinal and retroperitoneal 
areas of disease whenever these sites are involved. 
2. 
No increase in the size of the other nodes, liver, or spleen. 
3. 
Splenic and hepatic nodules must regress by at least 50% in the SPD. 

 
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11.3.2 
International Prognostic Index (IPI) 
Five adverse prognostic factors were selected: 
1. 
Age (> 60) 
2. 
ECOG/Zubrod performans status (2-4) 
3. 
Stage (III-IV) 
4. 
Serum LDH level (> normal) 
5. 
Extranodal site (>1) 
Four risk groups were defined: 
1. 
LOW RISK (0-1 adverse factor) 
2. 
LOW INTERMEDIATE RISK (2 adverse factors) 
3. 
HIGH INTERMEDIATE RISK (3 adverse factors) 
4. 
HIGH RISK ( 3 adverse factors) 
Source: Shipp MA, Harrington DP, Anderson JR et al. A predictive model for aggressive 
NHL: The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J 
Med 329:987, 1993 
 

 
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11.3.3 
Follicular Lymphoma International Prognostic 
Index (FLIPI)  
 
Five adverse prognostic factors were selected: 
1. 
Age (> 60 vs.  60) 
2. 
Ann Arbor Stage (III-IV vs. I-II) 
3. 
Haemoglobin level (< 12 g/dl vs.  12 d/dl) 
4. 
Number of nodal areas (> 4 vs.  4) 
5. 
Serum LDH level (> normal vs.  normal) 
Three risk groups were defined: 
6. 
LOW RISK (0-1 adverse factor) 
7. 
INTERMEDIATE RISK (2 adverse factors) 
8. 
POOR RISK ( 3 adverse factors) 
Source: Solal-Celigny P, Roy P, Colombat P et al. Follicular lymphoma international 
prognostic index. Blood 2004;104(5):1258-65. 

 
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11.4 
APPENDIX 4 GUIDELINES FOR STANDARD RITUXIMAB SC 
PREPARATION AND ADMINISTRATION 
HOW SUPPLIED 
Rituximab SC for the subcutaneous administration (MabThera SC; Ro 045-2294) is 
supplied as a ready to use liquid formulation with a nominal content of 120 mg/mL 
rituximab in an 11.7 mL vial and must not be diluted prior to administration. The drug 
product contains 2,000 U/mL rHuPH20 (manufactured in a CHO cell line) acting as a 
permeation enhancer, histidine/histidine-HCl (buffer), ,-trehalose (bulking agent), 
methionine (stabilizer), and polysorbate 80 (surfactant) in water for injection (WFI) at a pH 
of 5.5. The drug product is a sterile, colourless to yellowish, clear to opalescent liquid in 
colourless 11.7 mL vials. 
STABILITY AND STORAGE 
The recommended storage condition for rituximab SC is 2°C to 8°C, protected from light. 
Once transferred from the vial to the syringe, the solution of Mabthera SC formulation is 
physically and chemically stable for 48 hours at 2°C to 8°C, and subsequently 8 hours at 
30°C in diffuse daylight. The hypodermic injection needle must only be attached to the 
syringe immediately prior to administration to avoid any potential needle clogging. From a 
microbiological point of view the product should be used immediately after first opening. If 
not used immediately, in-use storage times and conditions prior to use are the 
responsibility of the user. The product should be handled gently and foaming avoided. It 
should not be shaken. Batch specific details and information on shelf-life are given on the 
packaging label. 
PREPARATION OF RITUXIMAB FOR SC ADMINISTRATION 
Patients receiving SC rituximab will be administered at a dose of 1400 mg. 
1. 
Withdraw 11.7 mL of solution from the vial. 
2. 
Insert the injection needle (25 or 27 gauge) using sterile technique in the subcutaneous tissue 
of the abdomen.  
Note: The needle should be fully inserted, being careful that the tip of the needle is deeper 
than the dermis but not as deep as the underlying muscle. The goal of the placement 
angle and needle depth is to achieve uniform placement into every patient’s subcutaneous 
tissue. Study drug should not be injected into moles, scars, or bruises. The skin should be 
pinched and needle inserted before the skin is released and the pressure on the syringe 
can be applied. 
3. 
Push the injection manually at a flow rate of approximately 2 mL/min; administration of the 
11.7 mL volume should take approximately 5 to 6 minutes.  
4. 
If there is a request by the patient to interrupt the injection, initially ease the pressure on the 
syringe to alleviate the pain. If the pain is not alleviated, stop the injection and ask the patient 
when he/she is comfortable to resume the injection. The remaining content of the syringe 
should be administered at the same injection site. 

 
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11.5 
APPENDIX 5 NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS 
In the present study, toxicities will be recorded according to the NCI CTCAE, version 4.0. 
At the time this protocol was issued, the full CTC document was available on the NCI site, 
at the following address: http://ctep.cancer.gov  
Investigators who do not have access to Internet can contact the Data Centre to receive a 
hard copy of this document by mail. 
 
 

 
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11.6 
APPENDIX 6 RITUXIMAB ADMINISTRATION QUESTIONNAIRE (RASQ-
IV AND RASQ-SC) 
RASQ-IV 
Instructions: Please complete the following questions based on your Rituximab treatment. Your 
Rituximab was given through a thin plastic tube and a needle that was put directly into a vein in 
your arm, called an intravenous or IV infusion. Your Rituximab treatment was given BEFORE your 
chemotherapy medicine. Please answer the questions based on your most recent Rituximab IV 
infusion. 
1. Thinking about the Rituximab IV infusion, how satisfied or dissatisfied are you with the IV 
infusion? 
Very satisfied 
Satisfied 
Neither  satisfied 
nor dissatisfied 
Dissatisfied 
Very dissatisfied 
2. Thinking about the Rituximab IV infusion, how do you rate the pain, swelling, or redness you 
experienced at the site of the drug injection? 
None
Mild
Moderate
Severe
Very Severe
3. Thinking about the Rituximab IV infusion, how do you rate the pain you experience with the IV 
infusion process? 
None
Mild
Moderate
Severe
Very Severe
4. Thinking about the Rituximab IV infusion, are the side effects of the IV infusion as you 
expected? 
Much better than 
expected 
Somewhat better 
than expected 
Met my 
expectations 
Some what 
worse than my 
expectations 
Much worse than 
my expectations 
5. Before you receive the Rituximab IV infusion do you feel anxious about having the infusion? 
Not at all
A little bit
Somewhat
Quite a bit
Very much
6. When you receive the Rituximab IV infusion do you worry that your condition would get worse?
Not at all
A little bit
Somewhat
Quite a bit
Very much
7. When you receive the Rituximab IV infusion do you feel anxious thinking about your disease? 
Not at all
A little bit
Somewhat
Quite a bit
Very much
8. Thinking about the Rituximab IV infusion, how confident are you that the Rituximab IV infusion 
is treating your disease? 
Not at all
A little bit
Somewhat
Quite a bit
Very much
9. When you receive the Rituximab treatment do you feel restricted by the IV infusion? 
Not at all
A little bit
Somewhat
Quite a bit
Very much

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Rituximab – Roche North Africa (Algeria, Morocco & Tunisia) 
Mabrella ML28964 Daughter Protocol – V3.1 – 07 February 2016   
98 
 
RASQ-SC 
Instructions: Please complete the following questions based on your Rituximab treatment. Your 
Rituximab was given through a needle injected into your abdomen (or belly) area, called a 
subcutaneous or SC injection. Your Rituximab treatment was given BEFORE your chemotherapy 
medicine. Please answer the questions based on your most recent Rituximab SC injection. 
 
1. Thinking about the Rituximab SC injection, how satisfied or dissatisfied are you with the SC 
injection? 
Very satisfied 
Satisfied 
Neither  satisfied 
nor dissatisfied 
Dissatisfied 
Very dissatisfied 
2. Thinking about the Rituximab SC injection, how do you rate the pain, swelling, or redness 
you experienced at the site of the drug injection? 
None
Mild
Moderate
Severe
Very Severe
3. Thinking about the Rituximab SC injection, how do you rate the pain you experience with the 
SC injection process?  
None
Mild
Moderate
Severe
Very Severe
4. Thinking about the Rituximab SC injection, are the side effects of the SC injection as you 
expected? 
Much better than 
expected 
Somewhat better 
than expected 
Met my 
expectations 
Some what 
worse than my 
expectations 
Much worse than 
my expectations 
5. Before you receive the SC injection do you feel anxious about having the injection? 
Not at all
A little bit
Somewhat
Quite a bit
Very much
6. When you receive the SC injection do you worry that your condition would get worse? 
Not at all
A little bit
Somewhat
Quite a bit
Very much
7. When you receive the SC injection do you feel anxious thinking about your disease? 
Not at all
A little bit
Somewhat
Quite a bit
Very much
8. Thinking about the Rituximab SC injection, how confident are you that Rituximab SC injection 
is treating your disease? 
Not at all
A little bit
Somewhat
Quite a bit
Very much
9. When you receive the Rituximab treatment do you feel restricted by the SC injection? 
Not at all
A little bit
Somewhat
Quite a bit
Very much
 

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Rituximab – Roche North Africa (Algeria, Morocco & Tunisia) 
Mabrella ML28964 Daughter Protocol – V3.1 – 07 February 2016   
103 
 
Thank you very much for your time