Conditions: Lymphoma, Non Hodgkin
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 140
Healthy volunteers: no

Brief summary:
This open-label, single-arm, phase IIIb study will evaluate the safety of switching from intravenous (IV) to subcutaneous (SC) administration of rituximab during first-line treatment for participants with CD20+ non-Hodgkin's follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL) who have already received at least one full dose of rituximab IV. Participants with FL will be given 1400 mg rituximab SC during induction therapy (once monthly for 4-7 cycles) and maintenance therapy (once every 2 months for 6-12 cycles). 1400 mg SC of rituximab will be given to participants with DLBCL once monthly for 4-7 cycles. Treatment duration is expected to last up to 7 months for participants with DLBCL and up to 32 months for participants with FL.

Detailed description:

Arms:
arm 1: Participants with CD20+ non-Hodgkin's follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL), who had already received at least one full dose of intravenous (IV) rituximab will be treated with subcutaneous (SC) rituximab. Participants with FL will be administered 1400 mg rituximab during induction therapy (once monthly for 4-7 cycles) and maintenance therapy (once every 2 months for 6-12 cycles). Participants with DLBCL will be administered 1400 mg SC of rituximab once monthly for 4-7 cycles. Treatment duration is expected to last up to 7 months for participants with DLBCL and up to 32 months for participants with FL.

Interventions: intervention 1: Rituximab
Intervention descriptions: intervention 1: 1400 mg will be injected subcutaneously (SC).

Protocol document:
Prot_000.pdf: 
 
Official Title: 
Open Label, Single-Arm, Phase IIIb Clinical Trial to Evaluate the 
Safety of Switching From Intravenous Rituximab to 
Subcutaneous Rituximab During First Line Treatment for CD20+ 
Non-Hodgkin’s Follicular Lymphoma and Diffuse Large B-Cell 
Lymphoma. 
NCT Number: 
NCT01987505 
Document Date: 
Protocol Version 1: 30-May-2013 
 
 
 




ML28943, version 1 (30th of May 2013) 
2 
TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM ............................................................................... 7 
PROTOCOL SYNOPSIS ................................................................................................. 8 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS¡ERROR! MARCADOR NO DEFINIDO.6 
 
1. BACKGROUND ...................................................................................................... 21 
1.1 
Background on Non-Hodgkin’S Lymphoma ................................ 21 
1.1.1 
Current Management.................................................................. 21 
1.2 
Background on Rituximab .......................................................... 22 
1.2.1 
Subcutaneous (SC) Rituximab ................................................... 22 
1.3 
Study Rationale and Benefit–Risk Assessment .......................... 25 
1.3.1 
Study rationale ........................................................................... 25 
1.3.2 
Benefits of Rituximab.................................................................. 25 
1.3.3 
Mitigation of the Known Safety Risks of Rituximab ..................... 26 
2. OBJECTIVES .......................................................................................................... 27 
2.1 
Primary Objective ....................................................................... 27 
2.2 
Secondary Objectives................................................................. 27 
2.3 
Exploratory Objectives ................................................................ 28 
2.4 
Patient-Reported Outcome Objectives ....................................... 28 
3. STUDY DESIGN ..................................................................................................... 28 
3.1 
Description of Study ................................................................... 28 
3.1.1 
Overview .................................................................................... 28 
3.2 
End of Study ............................................................................... 31 
3.3 
Rationale for Study Design ......................................................... 31 
3.3.1 
Rationale for Test Product Dosage ............................................. 31 
3.3.2 
Rationale for Patient Population and Analysis Groups ................ 32 
3.4 
Outcome Measures .................................................................... 32 
3.4.1 
Safety Outcome Measures ......................................................... 32 
3.4.2 
Efficacy Outcome Measures ....................................................... 32 
3.4.3 
Exploratory Outcome Measures ................................................. 33 
3.4.4 
Patient-Reported Outcome Measures ........................................ 33 
4. MATERIALS AND METHODS ................................................................................. 33 


ML28943, version 1 (30th of May 2013) 
3 
4.1 
Patients ...................................................................................... 33 
4.1.1 
Inclusion Criteria ......................................................................... 34 
4.1.2 
Exclusion Criteria ....................................................................... 34 
4.2 
Method of Treatment Assignment and Blinding .......................... 36 
4.3 
Study Treatment ......................................................................... 36 
4.3.1 
Formulation, Packaging, and Handling ....................................... 36 
4.3.2 
Dosage, Administration and Compliance .................................... 37 
4.3.3 
Investigational Medicinal Product Accountability ......................... 37 
4.3.4 
Post-Trial Access to Rituximab ................................................... 38 
4.4 
Concomitant Therapy ................................................................. 38 
4.4.1 
Permitted Therapy ...................................................................... 38 
4.4.2 
Prohibited Therapy ..................................................................... 39 
4.4.3 
Initiation of New Anti-lymphoma Treatment ................................ 39 
4.5 
Study Assessments .................................................................... 40 
4.5.1 
Description of Study Assessments ............................................. 40 
4.5.2 
Timing of Study Assessments .................................................... 43 
4.6 
Patient, Study, and Site Discontinuation ..................................... 45 
4.6.1 
Patient Discontinuation ............................................................... 45 
4.6.2 
Study and Site Discontinuation ................................................... 45 
5. ASSESSMENT OF SAFETY ................................................................................... 46 
5.1 
Safety Plan ................................................................................. 46 
5.1.1 
Adverse Events of Special Interest ............................................. 46 
5.1.2 
Interaction with Other Medicinal Products ................................... 46 
5.1.3 
Administration-Associated 
Reactions 
and 
their 
Management .............................................................................. 47 
5.2 
Safety Parameters and Definitions ............................................. 47 
5.2.1 
Adverse Events .......................................................................... 48 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor)..................................................................................... 48 
5.2.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) ................................... 49 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ...................................................................... 49 
5.3.1 
Adverse Event Reporting Period ................................................ 49 
5.3.2 
Eliciting Adverse Event Information ............................................ 50 
5.3.3 
Assessment of Severity of Adverse Events ................................ 50 


ML28943, version 1 (30th of May 2013) 
4 
5.3.4 
Assessment of Causality of Adverse Events ............................... 51 
5.3.5 
Procedures for Recording Adverse Events ................................. 51 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ...................................................................................... 56 
5.4.1 
Emergency Medical Contacts ..................................................... 56 
5.4.2 
Reporting Requirements for Serious Adverse Events 
and Non-Serious Adverse Events of Special Interest ................. 57 
5.4.3 
Reporting Requirements for Pregnancies ................................... 57 
5.5 
Follow-Up of Patients after Adverse Events ................................ 58 
5.5.1 
Investigator Follow-Up ................................................................ 58 
5.5.2 
Sponsor Follow-Up ..................................................................... 58 
5.6 
Post-Study Adverse Events ........................................................ 58 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees .................. 59 
6. STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN .................................... 59 
6.1 
Determination of Sample Size .................................................... 59 
6.2 
Summaries of Conduct of Study ................................................. 60 
6.3 
Summaries of PATIENT pOPULATION ...................................... 60 
6.3.1 
Analysis Populations .................................................................. 61 
6.4 
Safety Analyses .......................................................................... 61 
6.5 
EFFICACY Analyses .................................................................. 62 
6.6 
Exploratory Analyses .................................................................. 63 
6.7 
Patient-Reported Outcome Analyses .......................................... 63 
6.8 
Interim Analyses ......................................................................... 63 
7. DATA COLLECTION AND MANAGEMENT ............................................................ 64 
7.1 
Data Quality Assurance .............................................................. 64 
7.2 
Electronic Case Report Forms .................................................... 64 
7.3 
Source Data Documentation....................................................... 64 
7.4 
Use of Computerized Systems ................................................... 65 
7.5 
Retention of Records .................................................................. 65 
8. ETHICAL CONSIDERATIONS ................................................................................ 65 
8.1 
Compliance with Laws and Regulations ..................................... 65 
8.2 
Informed Consent ....................................................................... 66 
8.3 
HEALTH AUTHORITY, Institutional Review Board or 
Ethics Committee ....................................................................... 66 


ML28943, version 1 (30th of May 2013) 
5 
8.4 
Confidentiality ............................................................................. 67 
8.5 
Financial Disclosure ................................................................... 67 
9. STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION .................. 67 
9.1 
Study Documentation ................................................................. 67 
9.2 
Site Inspections .......................................................................... 68 
9.3 
Administrative Structure ............................................................. 68 
9.4 
Publication of Data and Protection of Trade Secrets .................. 68 
9.5 
Protocol Amendments ................................................................ 68 
10. REFERENCES ........................................................................................................ 69 
11. APPENDICES ......................................................................................................... 76 
11.1 
Appendix 1 
 
 
Schedule 
of 
Assessments 
FOR 
PATIENTS WITH CD20+ FOLLICULAR NHL ............................. 77 
11.2 
Appendix 2 Schedule of Assessments FOR PATIENTS 
WITH CD20+ DLBCL ................................................................. 81 
11.3 
Appendix 3 Response Assessment According to the 
International Working Group Response Criteria.......................... 84 
11.4 
Appendix 4 Grading Systems and Scales ................................... 86 
11.4.1 
ECOG Performance status ......................................................... 86 
11.4.2 
Follicular Lymphoma International Prognostic Index 
(FLIPI) ........................................................................................ 87 
11.4.3 
Prognosis 
in 
Diffuse 
Large 
B-cell 
Lymphoma: 
International Prognostic Index (IPI) and Revised 
International Prognostic Index (R-IPI). ........................................ 88 
11.4.4 
GELF Criteria ............................................................................. 89 
11.5 
Appendix 5 Guidelines for Standard Rituximab SC 
Preparation and Administration .................................................. 90 
11.6 
Appendix 6 NCI Common Terminology Criteria for 
Adverse Events .......................................................................... 91 
11.7 
Appendix 7 RASQ ...................................................................... 92 
11.8 
APPENDIX 8: Guidelines for Managing Specific AE 
related to R-CHOP treatment ..................................................... 98 
 


ML28943, version 1 (30th of May 2013) 
6 
LIST OF TABLES 
Table 1: Summary of Adverse Events from Stage 1 of Study BP22333 ........................ 23 
Table 2: Adverse Event Severity Grading Scale ............................................................ 51 
LIST OF FIGURES 
Figure 1: enrollment conditions ..................................................................................... 10 
Figure 2: Study visits ..................................................................................................... 30 
  


ML28943, version 1 (30th of May 2013) 
7 
PROTOCOL ACCEPTANCE FORM 
TITLE: 
Open label, single-arm, phase IIIb clinical trial to evaluate 
the safety of switching from intravenous rituximab to 
subcutaneous rituximab during first line treatment for 
CD20+ Non-Hodgkin’s Follicular Lymphoma and  Diffuse 
Large B-cell Lymphoma.. 
PROTOCOL NUMBER: 
ML28943 
VERSION NUMBER: 
1.0 
EUDRACT NUMBER: 
2013-001118-14 
IND NUMBER: 
N/A 
TEST PRODUCT: 
Rituximab (RO 45-2294) 
MEDICAL MONITOR: 
 
 
SPONSOR: 
Roche Farma, S.A 
I agree to conduct the study in accordance with the current protocol. 
_______________________________________ 
Principal Investigator’s Name (print) 
_______________________________________ 
____________________________ 
Principal Investigator’s Signature 
 
 
 
 
 
 
Date 
 
Please return the signed original of this form as instructed by your local study monitor. 
Please retain a copy for your study files. 


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ML28943, version 1 (30th of May 2013) 
10 
Figure 1: enrollment conditions  
 
a) Patients with CD20+ Follicular NHL 
 
b) Patients with CD20+ DLBCL 
 
 
 
 
 
 
 
 
 


ML28943, version 1 (30th of May 2013) 
11 
Number of Patients 
A total of 139 patients will be recruited into this study. 
Target Population 
The target population will consist of adults with CD20+ DLBCL or CD20+ follicular NHL grade 1, 2 or 
3a, according to the World Health Organization (WHO) classification system, undergoing first line 
treatment with intravenous rituximab treatment as per local clinical practice. 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
Subject related criteria 
1. Signed, written informed consent form 
2. Age ≥ 18 and ≤ 80 years at time of enrolment 
3. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 3 (see Appendix 4). 
Disease related criteria 
4. Histologically confirmed, CD20+ DLBCL or CD20+ follicular NHL grade 1, 2 or 3a, according to 
the WHO classification system. 
5. Induction only: 
a. 
For DLBCL: An International Prognostic Index (IPI) score of 1-4 or IPI score of 0 with 
bulky disease, defined as one lesion ≥ 7.5 cm (see Appendix 4). 
b. 
For FL: Follicular Lymphoma International Prognostic Index (FLIPI) (low, intermediate 
or high risk). Patients with FL should also meet GELF criteria to initiate treatment (see 
Appendix 4) 
6. Induction only: At least one bi-dimensionally measurable lesion defined as ≥ 1.5 cm in its largest 
dimension on computed tomography (CT) scan 
NHL Treatment related criteria 
7. Currently being treated with rituximab IV as first line Induction or Maintenance therapy, 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 
8. 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) 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
Cancer-Related Criteria 
1. Transformed lymphoma or follicular lymphoma (FL) 3b 
2. Primary central nervous system lymphoma, , primary effusion lymphoma, primary mediastinal 
DLBCL, DLBCL of the testis,  primary cutaneous DLBCLor  histologic evidence of transformation 
to a Burkitt lymphoma 
3. History of other malignancy that could affect compliance with the protocol or interpretation of 
results. This includes a malignancy that has been treated but not with curative intent, unless the 
malignancy has been in remission without treatment for ≥ 5 years prior to dosing. Note: Patients 


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ML28943, version 1 (30th of May 2013) 
15 
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 select 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 this study will be exploratory and will primarily make use of descriptive statistical 
methods. In addition, exploratory statistical testing and modelling will be used to highlight interesting 
aspects of the data. All tests will be two-sided and carried out with a 5% α-error rate without correction 
for multiplicity.  
All enrolled patients who receive at least one dose of study medication will be included in the Safety 
Population, which will be the primary analysis population for safety parameters. All enrolled patients 
will be included in the Intent-to-Treat (ITT) population.  Efficacy parameters and patient reported 
outcome measures will be analysed separately using subsets of the  ITT population for patients 
undergoing Induction therapy, Induction + Maintenance therapy and Maintenance therapy. Other 
analysis populations may be defined based on more restrictive criteria, such as fulfilment of eligibility 
criteria or a minimum duration of the observation period. 
Endpoint and Analysis 
The proportion of patients experiencing at least one AAR will be estimated with 95%-Clopper-Pearson 
confidence intervals. 
 
 
 
For EQ-5D analysis, the proportion of subjects reporting problems in mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression will be calculated 
The RASQ is a 19-item questionnaire measuring the impact of the mode of treatment administration 
on five domains: Physical Impact, Psychological Impact, Impact on Activities of Daily Living, 
Convenience, and Satisfaction.  Descriptive statistics will be presented by domain and timepoint, for 
the total sample. Listings will present by patient data for individual responses and domain scores. 
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 summarised with a 95% Clopper-
Pearson confidence interval. 
Determination of Sample Size  
A total of 139 patients will be recruited into this study. 


ML28943, version 1 (30th of May 2013) 
16 
The incidence of AAR is deemed of primary interest for this study. Based on the results of a recent 
study, the most frequent AAR with SC rituximab is the injection site-erythema (10%) (Davies et al. 
2012). If this endpoint is achieved by 10% of a sample size of 139 evaluable study patients, the two 
sided 95% confidence will have a maximum imprecision of +-5%. The precision of these estimates is 
considered sufficient to address the main objective of the study. 
Interim Analyses  
Two interim analyses are planned: 
- 
The first interim analysis will be done one year after the end of recruitment (i.e. one year after 
last patient first visit). 
- 
The second interim analysis will be done at the end of study treatment (i.e. last patient end of 
treatment visit). 
Study Procedures  
See Schedule of Assessments, Appendix 1- Appendix 2.  


ML28943, version 1 (30th of May 2013) 
17 
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 
EFS
event-free survival 


ML28943, version 1 (30th of May 2013) 
18 
Abbreviation
Definition 
EGSG
East German Study Group 
EU
European Union 
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-α 
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) 
IWG
International Working Group 
LDH
lactate dehydrogenase  
LPLV
last patient, last visit 
MCP
mitoxantrone, chlorambucil, prednisone/prednisolone 
MedDRA
Medical Dictionary for Regulatory Activities 


ML28943, version 1 (30th of May 2013) 
19 
Abbreviation
Definition 
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
pharmacodynamic 
PET
positron emission tomography 
PFS
progression-free survival 
PK
pharmacokinetic 
PML
Progressive Multifocal Leukoencephalopathy 
PR
partial response 
PRO
patient-reported outcome 
PT
Prothrombin Time 
QoL
Quality of life 
 
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
rituximab plus CHVP chemotherapy 
rHuPH20
recombinant human hyaluronidase 
R-MCP
Rituximab plus MCP chemotherapy 
SAE
serious adverse event 
SAP
Statistical Analysis Plan 
SC
subcutaneous(ly) 
SD
stable disease 
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  


ML28943, version 1 (30th of May 2013) 
20 
Abbreviation
Definition 
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 


ML28943, version 1 (30th of May 2013) 
21 
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). NHL has been classified into two types: aggressive (i.e. 
fast growing) and indolent (i.e. slow growing) (Landis et al. 1999). 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.  
1.1.1 
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. 


ML28943, version 1 (30th of May 2013) 
22 
1.2 
Background on Rituximab  
Rituximab (RO 45-2294) is a chimeric murine/human monoclonal antibody that specifically 
binds to CD20, a hydrophobic trans-membrane protein present on the surface of B 
lymphocytes (Tedder and Engel, 1994).  
Rituximab has had a large impact on the treatment of indolent non-Hodgkin’s lymphoma 
(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 (Dreyling et al, 2001; 
Rodríguez-Abreu D et al, 2010; López-Guillermo A et al, 2011; OncoGuía LBDCG). The 
approved oncology indications for rituximab IV in the EU include, among others, the 
treatment of diffuse large B-cell (DLBCL) and follicular non-Hodgkin’s lymphoma (FL). 
1.2.1 
Subcutaneous (SC) Rituximab 
The available marketed formulation of rituximab is administered via intravenous (IV) 
injection. Recently a subcutaneous (SC) injection has been developed which is currently 
being studied for its clinical usage. 
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 towards an IV administration profile. rHuPH20 was approved by the US Food and 
Drug Administration (FDA) in 2005. The approved indication includes ‘hypodermoclysis’, i.e. 
SC injection/infusion of fluid in large volume. Preclinical, clinical and extensive post-
marketing experience with the rHuPH20 excipient used in the rituximab SC formulation has 
shown the component to be well-tolerated (Bookbinder et al. 2006; Frost 2007). 
The results of a recently presented IV/SC pharmacokinetic/pharmacodynamic (PK/PD) 
cynomolgus monkey B cell depletion model study suggest that the SC versus IV dosing 
routes do not influence the pre-clinical efficacy of rituximab. Cynomolgus monkeys were 
treated twice, one week apart, with the rituximab SC formulation containing rHuPH20 or with 
IV rituximab. The results indicate similar rituximab trough concentrations in serum as well as 
similar B-cell depletion efficacy in both peripheral blood and distal secondary lymphoid tissue 
after IV and SC dosing (Del Nagro et al. 2010). 
 
 
 




ML28943, version 1 (30th of May 2013) 
24 
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 are ongoing . 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 
Hematology (ASH) conference 2012. 
Lastly, 3  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, study will investigate the efficacy of the combination of subcutaneous rituximab in 
combination with chemotherapy in patients with previously untreated diffuse large B cell 
lymphoma. 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 diffuse large B cell 
lymphoma 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. 


ML28943, version 1 (30th of May 2013) 
25 
1.3 
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT 
1.3.1 
Study rationale 
For safety reasons SC Rituximab should be given after at least one dose of IV Rituximab 
has been successfully administered (IB for rituximab SC). Therefore, in all the on-going 
clinical trials, SC dose is being administered after the first IV dose of Rituximab. However, in 
the clinical practice setting, given the fact that the SC injection could significantly reduce the 
burdens associated with IV administration (time, costs, patients preferences…), it is more 
likely that the switch to SC injection will occur at any point in time after the first dose of IV 
Rituximab, rather than only in the second cycle of the induction therapy. This scenario is 
particularly expected in patients who are undergoing long-term treatment with rituximab (i.e. 
maintenance for a maximum of 2 years). In this context, the aim of this pragmatic clinical trial 
is to evaluate the safety of switching from IV to SC Rituximab at any point in time during 
standard rituximab-based regimens administered to patients with previously untreated 
DLBCL or FL.  
1.3.2 
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 1.2.1. 
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 


ML28943, version 1 (30th of May 2013) 
26 
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). 
1.3.3 
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 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). 


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ML28943, version 1 (30th of May 2013) 
29 
For those patients who finish the induction therapy and start the maintenance therapy, the 
first dose of maintenance rituximab SC will be given within 8-12 weeks after the last dose of 
induction rituximab SC. 
 
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).  


ML28943, version 1 (30th of May 2013) 
30 
Figure 2: Study visits 
Figure 2a: Patients with FL 
 


ML28943, version 1 (30th of May 2013) 
31 
 
Figure 2b: Patients with DLBCL 
 
 
3.2 
END OF STUDY 
The end of the study will occur  up to 32 months after the last study patient has been 
enrolled. 
3.3 
RATIONALE FOR STUDY DESIGN 
The objective of this clinical trial is to evaluate the safety of switching from IV to SC 
Rituximab at any point in time during standard rituximab-based regimens administered to 
patients with previously untreated DLBCL or FL. Given the expected change of the ARR 
profile after the switching to rituximab SC (Davies et al. 2012), the primary outcome of 
interest will be the incidence of AARs. 
This will be a pragmatic clinical trial, in order to reproduce as much as possible real clinical 
practice conditions. Therefore, the diagnosis, the treatment and the follow up of the disease 
will be done as per local clinical practice (Rodríguez-Abreu D et al, 2010; López-Guillermo A 
et al, 2011; OncoGuía LBDCG).  
3.3.1 
Rationale for Test Product Dosage 
Modelling and simulation of PK data from Stage 1 and initial results of Stage 2 of the 
aforementioned study BP22333 (NCT00930514) (Salar et al. 2010; Salar et al. 2012), 
indicate that the fixed dose of 1400 mg rituximab SC achieves trough levels that are non-
inferior to the rituximab IV dose of 375 mg/m2 in patients with previously treated or untreated 
FL (grade 1, 2 or 3a). Rituximab SC was well tolerated with an AE profile comparable to that 


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ML28943, version 1 (30th of May 2013) 
34 
4.1.1 
Inclusion Criteria 
 
Patients must meet the following criteria for study entry: 
Subject related criteria 
1. 
Signed, written informed consent form 
2. 
Age ≥ 18 and ≤ 80 years at time of enrolment 
3. 
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 3 (see Appendix 4) 
 
Disease related criteria 
4. 
Histologically confirmed, CD20+ DLBCL or CD20+ follicular NHL grade 1, 2 or 3a, 
according to the WHO classification system 
5. 
Induction only 
a. 
For DLBCL: An International Prognostic Index (IPI) score of 1-4 or IPI score of 
0 with bulky disease, defined as one lesion ≥ 7.5 cm (see Appendix 4). 
b. 
For FL: Follicular Lymphoma International Prognostic Index (FLIPI) (low, 
intermediate or high risk). Patients with FL should also meet GELF criteria to 
initiate treatment (see Appendix 4) 
6. 
Induction only: At least one bi-dimensionally measurable lesion defined as ≥ 1.5 cm in 
its largest dimension on CT scan 
NHL Treatment related criteria  
7. 
Currently being treated with rituximab IV as first line Induction or Maintenance therapy, 
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 
8. 
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) 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
Cancer-Related Criteria 
1. 
Transformed lymphoma or FL3b  
2. 
Primary central nervous system lymphoma, , primary effusion lymphoma, primary 
mediastinal DLBCL, DLBCL of the testis,  primary cutaneous DLBCL or histologic 
evidence of transformation to a Burkitt lymphoma  
3. 
History of other malignancy that could affect compliance with the protocol or 
interpretation of results. This includes a malignancy that has been treated but not with 
curative intent, unless the malignancy has been in remission without treatment for ≥ 5 
years prior to dosing. Note: Patients with a history of curatively treated basal or 


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ML28943, version 1 (30th of May 2013) 
36 
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 
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, since it is an open label study with only one treatment group. 
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), α,α-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 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. 
The recommended storage condition for rituximab SC is 2°C to 8°C, protected from light. 
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 and would normally not be longer than 24 hours at 2°C to 8°C. 
Batch specific details and information on shelf-life are given on the packaging label. 
Under no circumstances the investigator should allow the study drug to be used other than 
as directed by the protocol. 
For further details, see the rituximab SC IB. 


ML28943, version 1 (30th of May 2013) 
37 
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.  
During induction therapy, cycles will be repeated every 14, 21 or 28 days, depending on the 
combination chemotherapy regimen selected, according to standard local practice.  
During Maintenance therapy, rituximab SC will be administered every 2 months. 
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 5 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. 
.  
4.3.3 
Investigational Medicinal Product Accountability 
The IMP (i.e. 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. 
Storage temperature conditions in the label must be ensured at any time, including the 
shipment. 
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 IMP. All drug supplies that will be used in the study 


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ML28943, version 1 (30th of May 2013) 
40 
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 1-2). 
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, surgeries, cancer history (including 
prior cancer therapies and procedures) happened to the patient within 28 days prior to the 
Screening visit. 
 Also 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 end of treatment/early termination 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. 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.  
4.5.1.4 
Tumour and Response Evaluations 
Tumour assessments will be done according the protocol schedule of assessments 
(Appendix 1-2) based on imaging tests used as per clinical practice.  


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ML28943, version 1 (30th of May 2013) 
43 
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 
with rituximab SC, unless otherwise specified. Standard-of-care tests or examinations 
performed prior to obtaining informed consent and within 35 days prior to start of treatment 
with rituximab IV 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.  
RASQ-IV will be administered at baseline before switching to SC Rituximab (see Appendix 
7). 
 
Please see Appendix 1-2 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 1-2). 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. PRO 
assessments should be performed prior to the completion of other study assessments. 
The same imaging modalities should be used for tumour assessments throughout the study 
unless new disease sites are indicated. The frequency of tumour assessments should be as 
consistent as possible. Tumour assessments should be continued in patients who 
discontinue study treatment for reasons other than disease progression until progression is 
documented.  
Please see Appendix 1-2 for the Schedule of Assessments performed during the 
treatment period. 
During induction, patients with SD or PD at staging will be withdrawn from Study treatment 
and will only be followed for all AEs and SAEs and for survival until the end of the Study. 
Patients who do not complete the study treatment per protocol will undergo end-of-study 
assessment within 4-6 weeks after the last dose of study treatment and will be followed until 
the end of the whole study according to local practice for safety assessment [i.e. resolution 
of SAEs related to rituximab SC therapy (as applicable)] and efficacy assessment [i.e. 
tumour response / progression (if PD not yet documented), survival, or documentation of any 
new anti-lymphoma treatment, whatever happens first]. 


ML28943, version 1 (30th of May 2013) 
44 
 
EuroQoL will be administered: 
- At the end of the induction treatment (for those patient undergoing induction 
treatment). 
- At the end of the maintenance treatment (for those patient undergoing maintenance 
treatment). 
RASQ-SC will be administered: 
- At the end of induction treatment (for those patients undergoing induction treatment). 
- At the end of maintenance treatment (for those patients undergoing maintenance 
treatment). 
 
 
4.5.2.3 
Post-Treatment Follow-up (Observation) Period  
After the end of study treatment/early termination visit, AEs should be followed as outlined in 
Sections 5.5 and 5.6. 
Please see Appendix 1-2 for the schedule of follow-up assessments. 
All patients who complete the Study treatment will then enter the post-treatment follow-up 
phase until the end of Study. Patients with SD at staging during induction 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) during induction will be 
permanently discontinued from Study treatment and will be followed only for survival and 
AEs / 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 safety assessment [i.e. 
resolution of SAEs related to rituximab SC therapy (as applicable)] and efficacy assessment 
[i.e. tumour response / progression (if PD not yet documented), survival, or documentation of 
any new anti-lymphoma treatment, whatever happens first]. 
Follow-up of patients after last dose of SC rituximab will occur every 3 months for the first 
year and then every 6 months (± 2 weeks) for the second year, as detailed in Appendix 1-2 
(Schedule of Assessments). In sites where it is not feasible to perform a CT scan every 3 
months (± 1 week) for 2 years, it is acceptable to perform a CT scan every 6 months (± 1 
week) for 2 years instead or as per clinical practice.  
4.5.2.4 
Assessments at the End of Study Treatment/Early Termination Visit 
Patients who complete the study treatment (i.e. as described in figure 2) or discontinue from 
the study early will be asked to return to the clinic 4-6 weeks after the last dose of study drug 
for the end of treatment study visit.  
Please see Appendix 1-2 for the Schedule of Assessments performed at the study 
completion/early termination visit. 


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ML28943, version 1 (30th of May 2013) 
47 
Patients with HAMA or HACA titers may develop allergic or hypersensitivity reactions when 
treated with other diagnostic or therapeutic monoclonal antibodies. 
5.1.3 
Administration-Associated Reactions and their Management 
AEs of special interest include AARs. AARs are defined as all AEs occurring within 24 hours 
of rituximab administration and considered by the investigator to be related to study drug. 
AARs include IIRRs, injection-site reactions, administration site conditions and all symptoms 
thereof. IIRRs can present with one or more of the following symptoms: allergic reaction, 
arthralgia, bronchospasm, chills, cough, dizziness, dyspnea, headache, hypertension, 
hypotension, myalgia, nausea, pruritus, pyrexia, rash, tachycardia, urticaria, vomiting. 
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. 
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 Appendix 8.  
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording AEs, including SAEs and non-
serious adverse events of special interest; measurement of protocol-specified safety 


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ML28943, version 1 (30th of May 2013) 
50 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all patient evaluation time-points. Examples of non-directive questions include 
the following: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?”  
5.3.3 
Assessment of Severity of Adverse Events 
The NCI CTCAE (version 4.0; see Appendix 6) will be used for assessing AE severity. 
Table 2 will be used for assessing severity for AEs that are not specifically listed in the NCI 
CTCAE. 




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ML28943, version 1 (30th of May 2013) 
57 
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 (please contact local monitor 
for further information). 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 (please contact local monitor for further information). 
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. 


ML28943, version 1 (30th of May 2013) 
58 
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 


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ML28943, version 1 (30th of May 2013) 
60 
The incidence of AAR is deemed of primary interest for this study. Based on the results of a 
recent study, the most frequent AAR with SC rituximab is the injection site-erythema (10%) 
(Davies et al. 2012). If this endpoint is achieved by 10% of a sample size of 139 evaluable 
study patients, the two sided 95% confidence will have a maximum imprecision of +-5%. The 
precision of these estimates is considered sufficient to address the main objective of the 
study. 
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 139 
adult patients with CD20+ DLBCL or CD20+ follicular NHL (grades 1, 2 or 3a; NHL), who are 
currently undergoing Induction and/or Maintenance therapy with rituximab IV. Patients 
receiving Induction therapy must be eligible to receive at least 4 cycles of rituximab SC in 
addition to standard chemotherapy. Patients with follicular NHL receiving Maintenance 
therapy must be eligible 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. 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) or GELF criteria (see Appendix 4), 
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), 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). 


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61 
6.3.1 
Analysis Populations 
All enrolled patients who receive at least one dose of study medication will be included in the 
Safety Population, which will be the primary analysis population for safety parameters.  
All enrolled patients will be included in the Intent-to-Treat (ITT) population.  Efficacy 
parameters and patient reported outcome measures will be analysed separately using 
subsets of the for the ITT population for patients undergoing Induction therapy, Induction + 
Maintenance therapy and Maintenance therapy.  
Other analysis populations may be defined based on more restrictive criteria, such as 
fulfilment of eligibility criteria or a minimum duration of the observation period. 
6.4 
SAFETY ANALYSES 
Safety will be assessed by AEs, AEs of grade ≥ 3, SAEs, IIRRs / AARs, 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 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 select laboratory parameters may also be displayed graphically.  
Vital signs will be summarized over time. 
ECOG performance status will be summarized by frequency tables and percentage of 
patients in different categories will be presented by bar charts at baseline. 
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.  
Primary safety endpoint will be summarized as incidence proportion together with its 95% 
confidence interval. Since AARs could occur more than once in one patient, only the first 
event will be considered to estimate the incidence proportion of AARs (i.e. proportion of 


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62 
patients with at least 1 AAR of interest over the total number of patients included in the 
safety population).  
Secondary safety endpoints will be also summarized as incidence proportions together with 
their 95% confidence interval. 
 
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 proportion, PR, SD, PD and will be 
analysed separately for the population undergoing Induction therapy, Induction + 
Maintenance therapy and Maintenance therapy. 
Response assessments will be based on the Investigator’s assessment, completed 
according to the IWG response criteria (Cheson et al 1999, see Appendix 3) or other 
country standards.  
EFS is defined as the time from first dose of rituximab IV to first occurrence of progression or 
relapse, according to the IWG response criteria (Cheson et al 1999, see Appendix 3) 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 IV to the first occurrence of 
progression or relapse, according to the IWG response criteria (Cheson et al 1999, see 
Appendix 3) or other country standards, or death from any cause.  
OS is defined as the time from first dose of rituximab IV to until death from any cause. 
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 proportion 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. The same estimation will be done for PR, SD and PD 
proportions, after the last dose of induction treatment. 
Endpoints will be summarized with a 95% 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. 


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63 
6.6 
EXPLORATORY ANALYSES 
 
 
 
 
 
6.7 
PATIENT-REPORTED OUTCOME ANALYSES 
For EQ-5D analysis, the proportion of subjects reporting problems in mobility, self-care, 
usual activities, pain/discomfort and anxiety/depression will be calculated 
The RASQ is a 19-item questionnaire measuring the impact of the mode of treatment 
administration on five domains: Physical Impact, Psychological Impact, Impact on Activities 
of Daily Living, Convenience, and Satisfaction. The Physical Impact domain comprises of 3 
items (Pain, swelling, and redness, Pain experience, Side effects as expected), the 
Psychological Impact domain contains 5 items (Anxious about injection/IV, Worry condition 
will get worse, Anxious thinking about disease, Confidence the injection/IV treating disease, 
Feeling restricted by injection/IV), the Convenience domain contains 3 items (Is it convenient 
to get injection/IV, Length of time to get injection/IV as expected, Bothered by the amount of 
time to get injection/IV) and the Satisfaction domain includes 2 items (How satisfied or 
dissatisfied are you with the injection/IV, Would you recommend the way you received the 
treatment). All 15 RASQ items included in the above domains have five response options. 
Reverse-coded response values will be created for eight of the RASQ items (Q2, Q3, Q5, 
Q6, Q7, Q9, Q14a, and Q14b). In addition, there are 4 descriptive questions that are not part 
of the above domains and scored separately. For each domain, if the number of completed 
items is greater than or equal to the pre-specified minimum number, the domain will be 
scored using the formula: 
- 
Domain score = [(Sum of completed item responses / Number of completed items) - 1] x 
100 / (Maximum possible item response value – Minimum possible item response value) 
However, if fewer items are completed than the minimum number indicated above, then the 
domain will not be scored (i.e. a missing value is assigned). 
Since the maximum possible item response value is 5 and the minimum possible response 
value is 1 for all RASQ items, a simpler way to represent the above formula for the RASQ 
domains is: 
- 
RASQ domain score = (Mean of completed item responses – 1) x 25 
 Descriptive statistics will be presented by domain and timepoint, for the total sample. 
Listings will present by patient data for individual responses and domain scores. 
6.8 
INTERIM ANALYSES 
Two interim analyses are planned: 
- 
The first interim analysis will be done one year after the end of recruitment (i.e. one 
year after last patient first visit). 


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64 
- 
The second interim analysis will be done at the end of study treatment (i.e. last patient 
end of treatment visit). 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will supply electronic eCRF specifications for this Study. 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.  
The CRO will produce a Data Quality Plan that describes the quality checking to be 
performed on the data.  
The Sponsor will perform oversight of the data management of this study, including approval 
of the CRO’s data management plans and specifications. Data will be periodically 
transferred electronically from the CRO to the Sponsor, and the Sponsor’s standard 
procedures will be used 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 
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 


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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. 
7.4 
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 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. 
7.5 
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). 


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This study will be conducted in the European Union (EU)/European Economic Area, so it will 
comply with the EU Clinical Trial Directive (2001/20/EC), in addition to the local Spanish 
Royal Decree 223/2004, of February 6th, regulating clinical tests with medicines and 
subsequent orders SCO/256/2007 and SCO/362/2008. 
Roche Farma S.A. has taken out civil responsibility insurance with the company 
 
, branch in Spain, that is in accordance with the Spanish Royal Decree 
223/2004 of February 6th that establishes the requirements for the conduct of Clinical Trials 
with drugs and covers any damage to you that may occur as a consequence of  the Clinical 
Trial.  
 
 
8.2 
INFORMED CONSENT 
Roche’s 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. 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's 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 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 
HEALTH AUTHORITY, 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/IRB and the Agencia Española de Medicamento y 


ML28943, version 1 (30th of May 2013) 
67 
Productos Sanitarios (AEMPS), and reviewed and approved by both of them before the 
study is initiated. In addition, any patient recruitment materials must be approved by the 
IRB/EC and the AEMPS.  
Written summaries of the status of the study will be provided to the EC/IRB and the AEMPS 
annually or more frequently in accordance with the requirements, policies, and procedures 
established by the EC/IRB and AEMPS. 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). 
Investigators may receive written 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.  
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. 
Additionally, the study will be conducted in observance of the the Ley Orgánica 15/1999, 
from December 13th, for Personal Data Protection and its development through the Royal 
Decree 1720/2007.  
 
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. 
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, protocol amendments, 


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68 
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 
ADMINISTRATIVE STRUCTURE 
The Reference Ethics Committee will be the Ethics Committee of “
 
”. 
9.4 
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. 
9.5 
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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ML28943, version 1 (30th of May 2013) 
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2010;28:(suppl; abstract e13108) [Published in conjunction with the ASCO 2010 Annual 
Meeting]. 


ML28943, version 1 (30th of May 2013) 
76 
11. 
APPENDICES 
 






 
ML28943, version 1 (28th of May 2013) 
  
 
 
 
 
 
 
 
 
79 
FDG-PET scanners, an FDG-PET scan cannot be mandated. The CT scan used for eligibility assessment may be performed up to 35 days before first dose of IV rituximab. 
The end-of-treatment response assessment including radiology/imaging report must be obtained 4-6 weeks after the last dose of Induction treatment. Response should be 
determined on the basis of radiographic and clinical evidence of disease according the IWG guidelines (Cheson et al. 1999; see Appendix 3), or if not applicable, 
institutional standards should be used for tumour evaluation. Disease progression will be evaluated by the Investigator according to the IWG response criteria for NHL 
(Cheson et al. 1999; see Appendix 3) or other country standards until PD. Screening/Baseline bone marrow examinations should include biopsy and aspirate for 
morphology (flow studies are optional) for staging purposes unless it has been performed within 4 months prior to first dose of rituximab IV and was done for the purpose 
of diagnosis and staging of FL. Subsequent bone marrow assessments are required to confirm any suspected CR in patients with bone marrow involvement at baseline. 
e.2) Patients who do not complete the study treatment per protocol will undergo end-of-study assessment within 4-6 weeks after the last dose of study treatment and will 
be followed until the end of the whole study according to local practice efficacy assessment [i.e. tumour response / progression (if PD not yet documented), survival, or 
documentation of any new anti-lymphoma treatment, whatever happens first]. 
f. 
As part of physical exam, SC injection sites will be checked at every treatment visit. As part of tumour assessments, physical examinations should also include the 
evaluation of the presence and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly. Patients should be assessed for presence of active infections 
throughout the treatment periods. Vital signs assessment includes resting heart rate, body temperature and blood pressure.  
g. 
FLIPI score determined at Baseline (prior to Cycle 1). Where possible, the baseline FLIPI score should be calculated from the patient notes. Missing FLIPI scores will not 
preclude enrolment. GELF Criteria to initiate treatment. See Appendix 4. 
h. 
ECOG performance status needs to be ≤ 3 for inclusion of the patient into the study. See Appendix 4. 
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, 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. For laboratory assessments it will be allowed a time window of  
5 days. 
k. 
Patients undergoing induction therapy must be eligible to receive at least 4 cycles of rituximab SC in addition to standard chemotherapy. Patients undergoing Maintenance 
therapy must be eligible to receive at least 6 cycles of rituximab SC. For those patients who finish the induction therapy and start the maintenance therapy, the first dose of 
maintenance rituximab SC will be given within 8-12 weeks after the last dose of induction rituximab SC. 
l. 
l.1) 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. l.2) . After initiation of study drug, all AEs/SAEs, regardless of relationship to study drug, will be 
reported until study closure. 
m. During post-treatment follow-up concomitant medication will be recorded only if required for post-treatment safety assessment (i.e. SAEs related to rituximab therapy 
and/or adverse events of special interest starting up until 6 months after the last dose of study medication). 


 
ML28943, version 1 (28th of May 2013) 
  
 
 
 
 
 
 
 
 
80 
n. 
Treatment satisfaction will be assessed using the Rituximab Administration Satisfaction Questionnaire (RASQ): n1) RASQ – IV will be done after last dose of rituximab IV 
prior to switching to the SC route; n2) RASQ-SC will be done at the end of induction therapy (i.e. after last induction dose of rituximab SC, prior to chemotherapy) and at 
the end of maintenance therapy (i.e. after last maintenance dose of rituximab SC, prior to chemotherapy). . 
 






 
ML28943, version 1 (28th of May 2013) 
  
 
 
 
 
 
 
 
 
83 
radiology/imaging report must be obtained 4-6 weeks after the last dose of Induction treatment. Response should be determined on the basis of radiographic and clinical 
evidence of disease according the IWG guidelines (Cheson et al. 1999; see Appendix 3), or if not applicable, institutional standards should be used for tumour evaluation. 
Screening/Baseline bone marrow examinations should include biopsy and aspirate for morphology (flow studies are optional) for staging purposes unless it has been 
performed within 4 months prior to first dose of rituximab IV and was done for the purpose of diagnosis and staging of DLBCL. Subsequent bone marrow assessments are 
required to confirm any suspected CR in patients with bone marrow involvement at baseline. e.2) Patients who do not complete the study treatment per protocol will 
undergo end-of-study assessment within 4-6 weeks after the last dose of study treatment and will be followed until the end of the whole study according to local practice 
efficacy assessment [i.e. tumour response / progression (if PD not yet documented), survival, or documentation of any new anti-lymphoma treatment, whatever happens 
first]. 
f. 
As part of physical exam, SC injection sites will be checked at every treatment visit. As part of tumour assessments, physical examinations should also include the 
evaluation of the presence and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly. Patients should be assessed for presence of active infections 
throughout the treatment periods. Vital signs assessment includes resting heart rate, body temperature and blood pressure.  
g. 
IPI (according to Shipp et al. 1993) score determined at Baseline (prior to Cycle 1). Where possible, the baseline IPI score should be calculated from the patient notes. 
Missing IPI scores will not preclude enrolment. See Appendix 4. 
h. 
ECOG performance status needs to be ≤ 3 for inclusion of the patient into the study. See Appendix 4. 
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, 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. For laboratory assessments it will be allowed a time window of 5 
days. 
k. 
Patients undergoing induction therapy must be eligible to receive at least 4 cycles of rituximab SC in addition to standard chemotherapy.  
l. 
l.1) 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. During post-treatment follow-up, only SAEs related to rituximab therapy will be followed. Adverse 
events of special interest, regardless of relationship to study treatment or whether or not they are SAEs, will be reported if they start up until 6 months after the last dose 
of study medication. l.2). After initiation of study drug, all AEs/SAEs, regardless of relationship to study drug, will be reported until study closure 
m. 
During post-treatment follow-up concomitant medication will be recorded only if required for post-treatment safety assessment (i.e. SAEs related to rituximab therapy 
and/or adverse events of special interest starting up until 6 months after the last dose of study medication). 
n. 
Treatment satisfaction will be assessed using the Rituximab Administration Satisfaction Questionnaire. RASQ: n1) RASQ – IV will be done after last dose of rituximab IV 
prior to switching to the SC route; n2) RASQ-SC will be done at the end of induction therapy (i.e. after last induction dose of rituximab SC, prior to chemotherapy) and at 
the end of maintenance therapy (i.e. after last maintenance dose of rituximab SC, prior to chemotherapy). 


 
ML28943, version 1 (28th of May 2013) 
84 
11.3 
APPENDIX 3 
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 








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ML28943, version 1 (28th of May 2013) 
90 
 
11.5 
APPENDIX 5 
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), α,α-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. 


 
ML28943, version 1 (28th of May 2013) 
91 
 
11.6 
APPENDIX 6 
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. 


 
ML28943, version 1 (28th of May 2013) 
92 
 
11.7 
APPENDIX 7 
RASQ 
Rituximab Administration Satisfaction Questionnaire-IV (RASQ-IV): will de done after 
last dose of Rituximab IV prior to switching to rituximab SC. 
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 
Somewhat 
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? 


 
ML28943, version 1 (28th of May 2013) 
93 
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 
10.  Thinking about the Rituximab IV infusion, how convenient is it for you to get your IV 
infusion? 
Very 
convenient 
Convenient 
Neither 
convenient nor 
inconvenient 
Inconvenient 
Very 
inconvenient 
11.  Thinking about the Rituximab IV infusion, how do you feel about the amount of time it 
takes to get your IV infusion? 
 
Too short 
Just right 
Too long 
 
12.  Thinking about the Rituximab IV infusion, do you feel that the length of time to get your 
IV infusion was as you expected? 
Much 
shorter 
than expected 
Somewhat 
shorter 
than 
expected 
As expected 
Somewhat 
longer 
than 
expected 
Much 
longer 
than expected 
13. Thinking about the Rituximab IV infusion, how bothered are you by the amount of time it 
takes to get the infusion? 
Not 
at 
all 
bothered 
A little bothered 
Moderately 
bothered 
Quite bothered 
Very bothered 
14. How much does the Rituximab IV infusion: 
a) Interfere with your usual or daily activities? 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
b) Limit your daily activities? 
Never 
Rarely 
Sometimes 
Most 
of 
the 
time 
Always 
15.  Because of the length of time to apply the Rituximab IV infusion do you feel that you 
have lost or gained time for other things?   


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ML28943, version 1 (28th of May 2013) 
95 
Rituximab Administration Satisfaction Questionnaire-SC (RASQ-SC): will be done at 
the end of induction therapy (i.e. after last induction dose of rituximab SC, prior to 
chemotherapy) and, if applicable, at the end of maintenance therapy (i.e. after last 
maintenance dose of rituximab SC, prior to chemotherapy). 
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 
Somewhat 
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? 


 
ML28943, version 1 (28th of May 2013) 
96 
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 
10.  Thinking about the Rituximab SC injection, how convenient is it for you to get your SC 
injection? 
Very 
convenient 
Convenient 
Neither 
convenient nor 
inconvenient 
Inconvenient 
Very 
inconvenient 
11.  Thinking about the Rituximab SC injection, how do you feel about the amount of time it 
takes to get your SC injection? 
 
Too short 
Just right 
Too long 
 
12.  Thinking about the Rituximab SC injection, do you feel that the length of time to get your 
SC injection is as you expected? 
Much 
shorter 
than expected 
Somewhat 
shorter 
than 
expected 
As expected 
Somewhat 
longer 
than 
expected 
Much 
longer 
than expected 
13. Thinking about the Rituximab SC injection, how bothered are you by the amount of time 
it takes to get the injection? 
Not 
at 
all 
bothered 
A little bothered 
Moderately 
bothered 
Quite bothered 
Very bothered 
14. How much does the Rituximab SC injection: 
a) Interfere with your usual or daily activities? 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
b) Limit your daily activities? 
Never 
Rarely 
Sometimes 
Most 
of 
the 
time 
Always 
15.  Because of the length of time to apply the Rituximab SC injection do you feel that you 
have lost or gained time for other things?   
Lost a lot of 
time 
Lost some time 
Neither lost nor 
gained time 
Gained 
some 
time 
Gained a lot of 
time 
16.  When you receive the Rituximab treatment, are you able to talk to your nurse and/or 
doctor as much as you would like about your illness? (please only check ONE answer) 


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SAP_001.pdf: 
 
Official Title: 
Open Label, Single-Arm, Phase IIIb Clinical Trial to Evaluate the 
Safety of Switching From Intravenous Rituximab to 
Subcutaneous Rituximab During First Line Treatment for CD20+ 
Non-Hodgkin’s Follicular Lymphoma and Diffuse Large B-Cell 
Lymphoma. 
NCT Number: 
NCT01987505 
Document Date: 
Statistical Analysis Plan: 22-Jan-2016 
Statistical Analysis Plan: 11-Sep-2017 
 
 
 
 


 
 
 
 
  
 
 
 
 
 
MABRELLA Study 
 
“A Study to Evaluate the Safety of Switching From 
Intravenous 
to 
Subcutaneous 
Administration 
of 
Mabthera/Rituxan During First-Line Treatment for 
Lymphoma” 
 
 
Statistical Analysis Plan for an Interim Analysis  
(one year after end of recruitment) 
Code ML 28943 
22/Jan/2016
Sponsor:  
Roche 
Prepared by: 
 
Date:  
January 2016 


MABRELLA Study 
 
Statistical interim analysis plan: January 2016  
17 
 
TABLE OF CONTENTS 
1 
Introduction _____________________________________________________ 5 
2 
STUDY OBJECTIVES AND DESIGN __________________________________ 6 
2.1 
Aim of Statistical Analysis Plan ________________________________________ 6 
2.2 
Interim Analysis of Primary Outcome ___________________________________ 6 
2.3 
Study Design _______________________________________________________ 6 
2.4 
Study Population ____________________________________________________ 6 
2.5 
Inclusion Criteria ____________________________________________________ 6 
2.6 
Exclusion criteria ____________________________________________________ 7 
3 
STATISTICAL METHODS __________________________________________ 9 
3.1 
Close-out Database Agreement _______________________________________ 10 
4 
ANALYSIS POPULATIONS ________________________________________ 10 
5 
DESCRIPTIVE ANALYSIS: demographic and clinical characteristics _____ 11 
5.1 
Recruitment Period _________________________________________________ 11 
5.2 
Lymphoma Diagnosis _______________________________________________ 11 
5.3 
Demographic and anthropometric data ________________________________ 11 
5.4 
Medical History ____________________________________________________ 11 
5.4.1 
DLBCL Diagnosis ______________________________________________________ 11 
5.4.2 
Follicular Lymphoma Diagnosis ___________________________________________ 11 
5.5 
Physical Examination _______________________________________________ 12 
5.6 
ECOG Performance Status ___________________________________________ 12 
5.7 
IPI Score __________________________________________________________ 12 
5.8 
FLIPI Score ________________________________________________________ 12 
6 
Evaluation of Patient Outcome Questionnaire ________________________ 13 
7 
PREVIOUS TREATMENT __________________________________________ 13 
7.1 
Chemotherapy _____________________________________________________ 13 
7.2 
Previous IV Rituximab Dose: FL ______________________________________ 13 
7.3 
Previous IV Rituximab Dose: DLBCL __________________________________ 14 
8 
CURRENT TREATMENT __________________________________________ 14 
8.1 
Study Drug Administration ___________________________________________ 14 
8.2 
Study Drug Discontinuation __________________________________________ 14 
9 
FOLLOW-UP PERIOD ____________________________________________ 15 
10 DEATHS _______________________________________________________ 15 
11 SAFETY _______________________________________________________ 15 
11.1 
Adverse Events ____________________________________________________ 15 
11.2 
Serious Adverse Events _____________________________________________ 15 


MABRELLA Study 
 
Statistical interim analysis plan: January 2016  
17 
11.1 
Adverse Event of Special Interest _____________________________________ 15 
11.2 
Adverse Events related to SC Rituximab _______________________________ 16 
11.3 
Administration-Associated Reactions (AARs) for SC Rituximab ____________ 16 
11.4 
Action taken related to study treatment Rituximab _______________________ 16 
11.5 
Outcome __________________________________________________________ 17 
 


MABRELLA Study 
 
Statistical interim analysis plan: January 2016  
17 
 
GLOSARY 
AE 
Adverse Event 
SAE 
Serious Adverse Event 
CRF 
Case Report Form 
ST 
Standard deviation 
ECOG 
Eastern Cooperative Oncology Group 
SD 
Stable Disease 
PK 
Pharmacokinetics 
FNA 
Fine Needle Aspiration 
CI 
Confidence Interval 
BMI 
Body Mass Index 
IV 
Intravenous 
DLBCL 
CD20+ diffuse large B-cell lymphoma 
FL 
CD20+ non-Hodgkin’s follicular lymphoma  
Max 
Maximum 
Min 
Minimum 
N 
Sample size 
NE 
Nonevaluable 
DP 
Disease progression 
Q1 
First quartile 
Q3 
Third quartile 
AARs 
Administration-Associated Reactions 
CR 
Complete response 
CRu 
Unconfirmed complete response 
PR 
Partial response 
IRAE 
Infusion/injection-related adverse event 
SC 
Subcutaneous 
OS 
Overall survival 
DFS 
Disease-free survival 
EFS 
Event-free survival 
PFS 
Progression-free survival 
CT 
Computed tomography 


MABRELLA Study 
 
Statistical interim analysis plan: January 2016  
17 
1 INTRODUCTION 
This open-label, single-arm, phase IIIb study will evaluate the safety of switching from 
intravenous (IV) to subcutaneous (SC) administration of MabThera/Rituxan during first-line 
treatment for patients with CD20+ non-Hodgkin's follicular lymphoma (FL) or diffuse large B-
cell lymphoma (DLBCL) who have already received at least one full dose of MabThera/Rituxan 
IV.  
This trial included adult patients with CD20+ DLBCL or CD20+ FL (grades 1, 2 or 3a; LNH), 
who had already received at least one complete dose of rituximab IV during induction or 
maintenance. 
Given the expected change in the profile of AARs after switching to rituximab SC (Davies et al. 
2012), the primary objective of interest will be the incidence of AARs. 
This is a pragmatic clinical trial that seeks to reproduce as much as possible the conditions of 
clinical practice. Therefore, diagnosis, treatment and follow-up of the disease will be done 
according to local clinical practice (Rodríguez-Abreu D et al, 2010; López-Guillermo A et al, 
2011; OncoGuía LBDCG). 
Modelling and simulation of PK data from stage 1 and the initial results from stage 2 of trial 
BP22333 (NCT00930514) (Salar et al. 2010; Salar et al. 2012) indicated that the fixed dose of 
1400 mg of SC rituximab achieves noninferior trough levels to the IV dose of rituximab 375 
mg/m2 in previously treated or untreated patients with FL (grade 1, 2 or 3a). SC rituximab was 
well tolerated, with an AE profile comparable to IV rituximab. No SAE related to SC rituximab 
was reported. Therefore, the fixed dose of 1400 mg SC was chosen for all other clinical trials of 
SC rituximab, both in this trial and in the ongoing registration trials. 
The objective of this clinical trial is to evaluate the safety of switching from IV to SC 
administration of rituximab at any time during standard rituximab-regimens. Since this change 
may occur in the case of patients undergoing either induction or maintenance treatment, the 
study population included patients CD20+ FL or CD20+ diffuse large B-cell lymphoma (DLBCL) 
who had previously received at least 1 dose of IV rituximab as part of an induction or 
maintenance treatment, and who were candidates for at least 4 more cycles of SC rituximab 
(for those following an induction treatment) or 6 more admininstrations of SC rituximab (for 
those following a maintenance treatment). 


MABRELLA Study 
 
Statistical interim analysis plan: January 2016  
17 
2 STUDY OBJECTIVES AND DESIGN 
2.1 
Aim of Statistical Analysis Plan 
This document presents the proposed analysis plan for performing the interim statistical 
analysis of the MABRELLA study. 
The analysis plan proposed below describes the aspects that should be known about the study 
and the methods of statistical analysis that will be applied to the data collected in order to 
answer the objective of the interim analysis. 
2.2 
Interim Analysis of Primary Outcome 
The aim of this interim analysis is to evaluate patient safety up to one year after the end of 
recruitment. 
2.3 
Study Design 
Clinical trial, phase III, open-label, non-randomized, single group assignment.  
2.4 
Study Population 
The target population will consist of adults with CD20+ DLBCL or CD20+ FL grade 1, 2 or 3a 
according to the World Health Organization (WHO) classification system. 
It is planned that 139 patients will participate in the study. 
2.5 
Inclusion Criteria 
Study participants must meet ALL of the following criteria in order to be included in the study: 
Criteria related to the subject 
1. Written informed consent 
2. Age >/= 18 and </= 80 years at time of enrolment. 
3. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 3  
Criteria related to disease 
4. Histologically confirmed CD20+ DLBCL or CD20+ follicular NHL (FL) grade 1, 2 or 3a 
according to the WHO classification system. 
5. Induction only: 
a. LBDCG related criteria: An International Prognostic Index (IPI) score of 1-4 or IPI score 
of 0 with bulky disease, defined as one lesion >/= 7.5 cm (Appendix 4 of protocol).  


MABRELLA Study 
 
Statistical interim analysis plan: January 2016  
17 
b. FL treatment-related criteria: Follicular Lymphoma International Prognostic Index 
(FLIPI) (low, intermediate, high risk). Patients with FL should meet Groupe D'Etude des 
Lymphomes Folliculaires (GELF) criteria to initiate treatment. (Appendix 4 of protocol). 
 
6. Induction only: At least tumor >/= 1.5 cm as measured by computed tomography (CT) scan  
Treatment-related criteria 
7. Currently being treated with MabThera/Rituxan IV during first-line therapy and has received 
at least one full dose of MabThera/Rituxan IV (defined as standard full dose of MabThera/Rituxan 
IV 375 mg/m2 administered without interruption or early discontinuation (i.e. tolerability issues) 
 8. 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) 
2.6 
 Exclusion criteria 
Participants who meet any of these criteria will not be included in the study: 
Criteria related to medical history 
1. Transformed lymphoma or follicular lymphoma (FL) IIIB 
2. Primary central nervous system lymphoma, primary effusion lymphoma, primary mediastinal 
DLBCL, DLBCL of the testis, primary cutaneous DLBCL or histologic evidence of 
transformation to a Burkitt lymphoma. 
3. History of other malignancy that could affect compliance with the protocol or interpretation of the 
results; this includes a malignancy that has been treated but not with curative intent, unless the 
malignancy has been in remission for >/= 5 years prior to treatment administration; Note: patients 
with a history of curatively treated basal or squamous cell carcinoma or melanoma of the skin or in 
situ carcinoma of the cervix are eligible. 
Previous and concomitant treatment 
4. Ongoing corticosteroid use > 30 mg/day of prednisone or equivalent. Note: patients receiving 
corticosteroid treatment with ≤ 30 mg/day of prednisone or equivalent must be on a stable regimen 
for at least 4 weeks prior to start of dosing. 
Analytical evaluation during screening 
5. Impaired renal function defined as creatinine > 1.5 x Upper Limit of Normal, ULN (unless 
creatinine clearance [CrCl] normal), or calculated CrCl < 40 mL/min (as determined by the 
Cockcroft–Gault formula) 


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Statistical interim analysis plan: January 2016  
17 
6. 
Inadequate 
hematologic 
function, 
defined 
as 
follows: 
 - Hemoglobin < 9 g/dL 
- Absolute neutrophil count < 1.5 x 109/L 
- Platelet count < 75 x 109/L (Note: abnormalities outside the above listed are allowed if related 
to involvement of bone marrow by the underlying disease). 
7. Inadequate hepatic function, defined as any of the following abnormal laboratory values: 
• Alanine aminotransferase (AST) or aspartate aminotransferase (ALT) > 2.5 x the ULN 
• Total bilirubin ≥ 1.5 x the ULN. (Patients with documented Gilbert disease may be 
enrolled if total bilirubin is ≤ 3.0 x the ULN.) 
Other prior or current medical conditions and treatments 
8. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal 
antibodies or known sensitivity or allergy to murine products. 
9. For patients with DLBCL: Contraindication to any of the individual components of CHOP 
(cyclophosphamide, vincristine, doxorubicin and prednisone), including prior anthracycline 
treatment. For patients with FL: contraindication to standard chemotherapy. 
10. Other serious underlying medical conditions (i.e., severe 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 infections (excluding nail fungal infections) or any infection requiring 
treatment with IV antibiotics or hospitalization within 4 weeks prior to dosing. 
13. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Note: Patients testing 
positive for hepatitis B or C virus antibodies but with an undetectable viral load may be included 
(i.e., HBV or HCV RNA-negative by PCR).  
14. History of human immunodeficiency virus (HIV) positive status. 
General criteria 
15. Any coexisting medical or psychological condition that would preclude participation in the 
required study procedures 
16. Life expectancy < 6 months 
 
17. A positive pregnancy test for women of childbearing potential within 7 days prior to first 
rituximab administration or within 14 days if with a confirmatory urine pregnancy test within 7 
days prior to the first administration. Women of childbearing potential are defined as pre-


MABRELLA Study 
 
Statistical interim analysis plan: January 2016  
17 
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 subcutaneous rituximab. 
 
3 
STATISTICAL METHODS 
The methods of analysis to be used to achieve both the objectives of the interim analysis of the 
study and for description of the study variables are detailed below. 
All analyses described will be performed by type of lymphoma (DLBCL / FL) and overall. 
Selection criteria will not be checked unless it is expressly requested. 
 UNIVARIATE ANALYSIS 
Quantitative variables will be described with measures of central tendency and dispersion: 
mean, median, SD (standard deviation), Q1 (first quartile) and Q3 (third quartile), minimum and 
maximum). 
Qualitative variables will be described using absolute and relative frequencies. Two columns 
of percentages will be presented: Total percentage (%) and Percentage valid (% valid). 
 
Total percentage (%): Percentage over the sum of valid responses plus missing values, 
that is, over the total study sample. 
 
Percentage valid (% valid): Percentage over total valid responses, that is, with data in 
the variable. 
Ninety-five percent Clopper-Pearson confidence intervals (CI) were calculated, when 
necessary, for outcome variables associated with objectives. 
In the case of questions with more than one response option, multiple response tables will be 
shown. Two columns of percentages will be shown in these tables: 
 
Total percentage (%): Percentage over the sum of valid responses plus missing values, 
that is, over the total study sample. As it is multiple response, the sum of the 
percentages does not necessarily equal 100 (this percentage may be exceeded). 


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Statistical interim analysis plan: January 2016  
17 
 
Percentage valid (% valid): Percentage over the number of patients with at least one 
response given from among those possible. As it is multiple response, the sum of the 
percentages does not necessarily equal 100 (this percentage may be exceeded). 
 BIVARIATE ANALYSIS 
In the comparative analysis, parametric tests will be used for those variables that meet the 
conditions for application (e.g. t-test) and nonparametric tests (e.g. chi-squared, Mann-Whitney 
U, Wilcoxon, etc.) for ordinal, categorical or other variables that do not meet parametric criteria. 
All hypothesis tests will be two-sided and with a significance level of 0.05. 
Data will be analyzed using SPSS v22.0. 
3.1 
Close-out Database Agreement 
Following database close-out to perform the analyses, if any anomalous and/or inconsistent 
values are found in any table of results, the database will not reopened to modify the values, 
but instead the anomalous data value will be highlighted and it will be indicated how it was 
handled (e.g., assigning to missing values or eliminating the case depending on the statistical 
method to be used in the analysis in question). Missing data will not be imputed and will be left 
as lost. 
Any modification to this table will be recorded in writing in the report as well as the procedure 
followed (e.g. assignment to missing values, interpolation, elimination of the case, etc.).  
 
4 ANALYSIS POPULATIONS 
The population that will be included in the analysis is defined below: 
 
The safety population will consist of all patients who have received at least one dose 
of the study medication. 
This analysis is planned per protocol one year after the last visit of the last patient enrolled, that 
is, one year after the end of patient recruitment.  
Both descriptive analyses and safety analyses will be based on the safety population. 


MABRELLA Study 
 
Statistical interim analysis plan: January 2016  
17 
 
5 DESCRIPTIVE ANALYSIS: DEMOGRAPHIC AND CLINICAL CHARACTERISTICS 
5.1 
Recruitment Period 
The dates of inclusion the first and last patient will be provided. 
5.2 
Lymphoma Diagnosis 
 
Type of Lymphoma: Diffuse Large B-cell / DLBCL / FL 
5.3 
Demographic and anthropometric data 
Descriptive statistics (mean, SD, median, Q1, Q3, minimum, maximum) will be shown for the 
following variables: 
 
Age (years), based on (Date of Visit – Date of Birth). 
 
Weight  
 
Height  
 
BMI 
Categorical variables to be described:  
 
Sex: Male / Female 
 
Race: Caucasian / Black/ Asian / Other 
 
5.4 
Medical History 
5.4.1 DLBCL Diagnosis 
Descriptive statistics (mean, SD, median, Q1, Q3, minimum, maximum) will be presented for the 
following continuous variables: 
 
Time from diagnosis, defined as the time in months from the date of diagnosis (date of 
histological diagnosis) to the date of the baseline visit. 
Categorical variables to be described:  
 
Histological diagnosis: FNA / Core needle biopsy /Excisional or Incisional biopsy of 
peripheral lymph node. 
5.4.2 Follicular Lymphoma Diagnosis 
Descriptive statistics (mean, SD, median, Q1, Q3, minimum, maximum) will be presented for the 
following variables: 
 
Time from diagnosis, defined as the time in months from the date of diagnosis (date of 
histological diagnosis) to the date of the baseline visit. 
Categorical variables to be described:  


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Statistical interim analysis plan: January 2016  
17 
 
Histological diagnosis: FNA / Core needle biopsy /Excisional or Incisional biopsy of 
peripheral lymph node. 
 
Grade of FL: 1 / 2 / 3a 
5.5 
Physical Examination 
Related to baseline visit, the following will be described: 
 
Was the physical examination performed?: Yes / No 
For patients with a physical examination performed, a multiple response table will be shown for 
those affected systems with the result: Abnormal, clinically significant: 
 
Head, ears, eyes, nose, throat 
 
Cardiovascular system 
 
Dermatological 
 
Musculoskeletal system 
 
Respiratory system 
 
Gastrointestinal system 
 
Genitourinary system Nervous system 
 
Other 
5.6 
ECOG Performance Status 
Categorical variable to be described: 
 
ECOG: 0/ 1 / 2 / 3 / 4 / 5  
The ECOG score will be described for each of the visits performed, i.e., at screening and 
induction and/or maintenance. 
5.7 
IPI Score 
For DLBCL patients: Related to baseline visit, the following will be described: Low risk / Low 
intermediate risk / High intermediate risk / High risk. 
5.8 
FLIPI Score 
For FL patients: Related to baseline visit, FLIPI score will be described: Low risk / intermediate 
risk / High risk. 


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Statistical interim analysis plan: January 2016  
17 
 
6 
EVALUATION OF PATIENT OUTCOME QUESTIONNAIRE 
 The Rituximab IV Administration Satisfaction Questionnaire (RASQ-IV) will be analyzed on the 
baseline visit before switching to SC rituximab treatment and the Rituximab IV Administration 
Satisfaction Questionnaire” (RASQ-SC) at the end of induction or maintenance treatment 
(when applicable).  
The descriptive analysis (N,%) will be shown for each of the items included in the 
questionnaire. 
The protocol does not include a validation or version of these questionnaires, nor is there an 
algorithm on a possible overall score or by dimensions. If this is provided by the sponsor, the 
corresponding descriptive analysis can be performed.  It will also be taken into account if there 
are sufficient data to perform the analysis.  
7 
PREVIOUS TREATMENT 
7.1 
Chemotherapy 
The variable ‘type of chemotherapy regimen’ that the patient is receiving will be described: 
CHOP-14 x 6 / CHOP-14 x 8 / CHOP-21 x 6/ CHOP-21 x 8 / CVP-21 x 8 / Other. 
7.2 
Previous IV Rituximab Dose: FL 
Descriptive statistics (mean, SD, median, Q1, Q3, minimum, maximum) will be presented for the 
following continuous variables: 
 
 
Time from diagnosis (months), calculated from the date of histological diagnosis to the 
date of first dose of IV rituximab). 
 
Dose of most recent IV rituximab cycle 
Categorical variables to be described: 
 
Phase of IV rituximab (most recent IV cycle): Induction Phase / Maintenance Phase 
 
Cycles of IV rituximab that the subject had received previously: 1/ 2 / 3 / 4 / 5 / 6 / 7 / 8  
 
Treatment phase in which the patient switched from IV rituximab to the SC formulation: 
Induction Phase / Maintenance Phase 
 
First SC treatment cycle on study: Cycle 1 / Cycle 2 / Cycle 3 / Cycle 4 / Cycle 5 / Cycle 
6 / Cycle 7 


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Statistical interim analysis plan: January 2016  
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7.3 
Previous IV Rituximab Dose: DLBCL 
Descriptive statistics (mean, SD, median, Q1, Q3, minimum, maximum) will be presented for the 
following continuous variables: 
 
Time from diagnosis (months), calculated from the date of histological diagnosis to the 
date of first dose of IV rituximab). 
Categorical variables to be described: 
 
Cycles of IV rituximab that the subject had received previously: 1/ 2 / 3 / 4  
 
Dose of most recent IV rituximab cycle 
 
First SC treatment cycle on study: Cycle 2 / Cycle 3 / Cycle 4 / Cycle 5  
 
8 
CURRENT TREATMENT 
8.1 
Study Drug Administration 
Descriptive statistics (mean, SD, median, Q1, Q3, minimum, maximum) will be presented for the 
following continuous variables: 
 
For FL patients: Number of induction and/or maintenance cycle administered per 
patient. 
 
For DLBCL patients: Number of treatment cycle administered per patient. 
Categorical variables to be described: 
 
Full dose: Yes / No If No: 
o Reason: Adverse event / Technical problems / Other  
 
(If other: specify).  
 
If the reason is an AE, specify if it is a grade 3 or 4 IRAE: Yes / No 
8.2 
Study Drug Discontinuation 
Categorical variables to describe are: 
 
Number of patients who discontinued study treatment. 
 
Primary reason for patient discontinued treatment: Progression of Disease / Adverse 
Event / Pregnancy / Patient request - Withdraw consent / Investigator decision / Lack of 
compliance / Lost to Follow-up / Death / Other 
 


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Statistical interim analysis plan: January 2016  
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9 FOLLOW-UP PERIOD 
The variable ‘time in study’, defined as the time in months from inclusion to the last available 
date, will be provided. Descriptive statistics (mean, SD, median, Q1, Q3, minimum, maximum) 
will be presented. 
10 DEATHS 
Categorical variables to be described: 
 
The number of patients who died during the study. 
 
Primary cause of death: Progression of disease / Adverse Event / Unknown / Other. 
 
11 SAFETY 
All analyses described will be performed by type of lymphoma (DLBCL / FL) and overall. 
11.1 Adverse Events 
This analysis will include all adverse events occurring to patients during the study. To obtain 
the number of adverse events per patient, the maximum of most extreme intensity (maximum 
intensity grade for each toxicity) will be calculated for each of the adverse events recorded 
during the treatment of each patient and the following will be described: 
 
Number of patients with at least one adverse event (95% CI). 
 
Number of patients with different adverse events reported by grade (GI, GII, GIII, GIV, 
GV). A list of the different AEs experienced by patients according to the maximum 
grade, N and % will be presented. 
 
Number of patients with at least one adverse event of grade 3 or higher (95% CI). 
11.2 Serious Adverse Events 
The number of patients with at least one Serious Adverse Event ( 95% CI) will be described, 
as well as a list of the different events experienced by patients and the main characteristics of 
the events: causal relationship with chemotherapy or rituximab, duration (start and end date), 
action taken, treatment required (yes/no), outcome. 
11.1 
Adverse Event of Special Interest  
The number of patients with at least one  Adverse Event of Special Interest ( 95% CI) will be 
described, as well as a list of the different events experienced by patients and the main 
characteristics of the events: causal relationship with chemotherapy or rituximab, duration (start 
and end date), action taken, treatment required (yes/no), outcome. 


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Statistical interim analysis plan: January 2016  
17 
11.2 Adverse Events related to SC Rituximab  
In this section, the AEs indicating a relationship to the study treatment (SC rituximab) will be 
considered. 
This analysis will include all adverse events occurring to patients during the study. To obtain 
the number of adverse events per patient, the maximum of most extreme intensity will be 
calculated for each of the adverse events recorded during the treatment of each patient and the 
following will be described: 
 
Number of patients with at least one AE. The proportion of patients experiencing at 
least one AE will be provided, and the Clopper-Pearson 95% confidence interval. 
 
Number of patients with different AEs reported by grade (GI, GII, GIII, GIV, GV). List of 
the different AEs experienced by patients according to grade, N and %. 
 
Number of patients with at least one AE ≥ grade 3 (95% CI). 
 
Number of patients (%) with one fatal AE (leading to death): N, % (CI 95%).  
 
11.3 Administration-Associated Reactions (AARs) for SC Rituximab 
AAR: All events where the answer to "If this is an AAR related to the Rituximab SC injection, 
please specify location" is not "Not applicable" 
 
Number (%) of patients with at least one AAR (include injection site reactions, 
administration site conditions and symptoms of these conditions). 
 
Number of patients with different AARs reported by grade (GI, GII, GIII, GIV, GV). List 
of the different AARs experienced by patients according to , N and %. 
 
Number (%) of patients with at least one AAR ≥ grade 3 
 
Number (%) of patients with at least one serious AARs  
 
Number (%) of patients with at least one AAR localized at the injection site reaction and 
generalized and/or remote from the injection site. 
 
AAR localized at the injection site and generalized and/or remote. 
11.4 Action taken related to study treatment Rituximab 
The action taken related to the study treatment with rituximab will be described (for all AEs): 
None / Drug interrupted / Drug delayed / Drug permanently discontinued / Not Applicable. 
The number (%) of patients with AEs leading to treatment interruption, dose delay and 
discontinuation will be described:  
 
AEs leading to treatment interruption 


MABRELLA Study 
 
Statistical interim analysis plan: January 2016  
17 
 
AEs leading to dose delay 
 
AEs leading to discontinuation 
11.5 Outcome 
The outcome (for every AE) will be described: Fatal / Resolved / Resolved – with sequelae / 
Unresolved - Improving / Unresolved – Persisting / Unresolved – Worsening / Unknown. 
The number (%) of AEs leading to patient death will be described:  
 
AEs leading to death 




MABRELLA Study 
 
1 
 
 
TABLE OF CONTENTS 
1 
Introduction ______________________________________________________ 4 
2 
STUDY OBJECTIVES AND DESIGN ___________________________________ 5 
2.1 
Aim of Statistical Analysis Plan ________________________________________ 5 
2.2 
Objectives _________________________________________________________ 5 
2.3 
Study Design _______________________________________________________ 6 
2.4 
Study Population ____________________________________________________ 6 
2.5 
Inclusion Criteria ____________________________________________________ 7 
2.6 
Exclusion criteria ____________________________________________________ 7 
3 
STATISTICAL METHODS __________________________________________ 10 
3.1 
Close-out Database Agreement _______________________________________ 11 
4 
ANALYSIS POPULATIONS _________________________________________ 12 
5 
DESCRIPTIVE ANALYSIS: demographic and clinical characteristics ______ 13 
5.1 
Recruitment Period _________________________________________________ 13 
5.2 
Lymphoma Diagnosis _______________________________________________ 13 
5.3 
Demographic and anthropometric data ________________________________ 13 
5.4 
Medical History ____________________________________________________ 13 
5.4.1 
Relevant medical history ________________________________________________ 13 
5.4.2 
Surgery and Procedures history ___________________________________________ 13 
5.4.3 
DLBCL Diagnosis ______________________________________________________ 14 
5.4.4 
Follicular Lymphoma Diagnosis ___________________________________________ 14 
5.5 
Physical Examination _______________________________________________ 14 
5.6 
ECOG Performance Status ___________________________________________ 15 
5.7 
IPI Score __________________________________________________________ 15 
5.8 
FLIPI Score ________________________________________________________ 15 
6 
EVALUATION OF PATIENT OUTCOME QUESTIONNAIRE _______________ 16 
7 
PREVIOUS TREATMENT __________________________________________ 17 
7.1 
Chemotherapy _____________________________________________________ 17 
7.2 
Previous IV Rituximab Dose: FL ______________________________________ 17 
7.3 
Previous IV Rituximab Dose: DLBCL __________________________________ 18 
8 
CURRENT TREATMENT ___________________________________________ 18 
8.1 
Study Drug Administration ___________________________________________ 18 
8.2 
Study Drug Discontinuation __________________________________________ 18 
9 
RESPONSE _____________________________________________________ 19 
10  DEATHS ________________________________________________________ 19 
11  SURVIVAL ______________________________________________________ 20 


MABRELLA Study 
 
2 
 
11.1 
Event free survival (EFS) ____________________________________________ 20 
11.2 
Progression free survival (PFS) _______________________________________ 20 
11.3 
Overall survival (OS) ________________________________________________ 20 
11.4 
Disease free survival (DFS) __________________________________________ 20 
12  QUALITY OF LIFE ________________________________________________ 21 
13  SAFETY ________________________________________________________ 23 
13.1 
Adverse Events ____________________________________________________ 23 
13.2 
Serious Adverse Events _____________________________________________ 23 
13.1 
Adverse Event of Special Interest _____________________________________ 23 
13.2 
Adverse Events related to SC Rituximab _______________________________ 24 
13.3 
Administration-Associated Reactions (AARs) for SC Rituximab ____________ 24 
13.4 
Action taken related to study treatment Rituximab _______________________ 24 
13.5 
Outcome __________________________________________________________ 25 
14  ANALYSIS OF OBJECTIVES _______________________________________ 26 
14.1 
Primary Objective __________________________________________________ 26 
14.2 
Secondary Objectives _______________________________________________ 26 
14.3 
Exploratory Objectives ______________________________________________ 27 
14.4 
Patient reported outcomes ___________________________________________ 28 
 


MABRELLA Study 
 
3 
 
 
GLOSSARY 
AARs 
Administration-Associated Reactions 
AE 
Adverse Event 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CR 
Complete response 
CRF 
Case Report Form 
CRu 
Unconfirmed complete response 
CT 
Computed tomography 
DFS 
Disease-free survival 
DLBCL 
CD20+ diffuse large B-cell lymphoma 
DP 
Disease progression 
ECOG 
Eastern Cooperative Oncology Group 
EFS 
Event-free survival 
FL 
CD20+ non-Hodgkin’s follicular lymphoma  
FNA 
Fine Needle Aspiration 
IRAE 
Infusion/injection-related adverse event 
IV 
Intravenous 
Max 
Maximum 
Min 
Minimum 
N 
Sample size 
NE 
Nonevaluable 
OS 
Overall survival 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PR 
Partial response 
Q1 
First quartile 
Q3 
Third quartile 
SAE 
Serious Adverse Event 
SC 
Subcutaneous 
SD 
Stable Disease 
ST 
Standard deviation 


MABRELLA Study 
 
4 
 
1 
INTRODUCTION 
This open-label, single-arm, phase IIIb study will evaluate the safety of switching from 
intravenous (IV) to subcutaneous (SC) administration of MabThera/Rituxan during first-line 
treatment for patients with CD20+ non-Hodgkin's follicular lymphoma (FL) or diffuse large B-
cell lymphoma (DLBCL) who have already received at least one full dose of MabThera/Rituxan 
IV.  
This trial included adult patients with CD20+ DLBCL or CD20+ FL (grades 1, 2 or 3a; LNH), 
who had already received at least one complete dose of rituximab IV during induction or 
maintenance. 
Given the expected change in the profile of AARs after switching to rituximab SC (Davies et al. 
2012), the primary objective of interest will be the incidence of AARs. 
This is a pragmatic clinical trial that seeks to reproduce as much as possible the conditions of 
clinical practice. Therefore, diagnosis, treatment and follow-up of the disease will be done 
according to local clinical practice (Rodríguez-Abreu D et al, 2010; López-Guillermo A et al, 
2011; OncoGuía LBDCG). 
Modelling and simulation of PK data from stage 1 and the initial results from stage 2 of trial 
BP22333 (NCT00930514) (Salar et al. 2010; Salar et al. 2012) indicated that the fixed dose of 
1400 mg of SC rituximab achieves noninferior trough levels to the IV dose of rituximab 375 
mg/m2 in previously treated or untreated patients with FL (grade 1, 2 or 3a). SC rituximab was 
well tolerated, with an AE profile comparable to IV rituximab. No SAE related to SC rituximab 
was reported. Therefore, the fixed dose of 1400 mg SC was chosen for all other clinical trials of 
SC rituximab, both in this trial and in the ongoing registration trials. 
The objective of this clinical trial is to evaluate the safety of switching from IV to SC 
administration of rituximab at any time during standard rituximab-regimens. Since this change 
may occur in the case of patients undergoing either induction or maintenance treatment, the 
study population included patients CD20+ FL or CD20+ diffuse large B-cell lymphoma (DLBCL) 
who had previously received at least 1 dose of IV rituximab as part of an induction or 
maintenance treatment, and who were candidates for at least 4 more cycles of SC rituximab 
(for those following an induction treatment) or 6 more admininstrations of SC rituximab (for 
those following a maintenance treatment). 


MABRELLA Study 
 
5 
 
2 
STUDY OBJECTIVES AND DESIGN 
2.1 
Aim of Statistical Analysis Plan 
This document presents the proposed analysis plan for performing the final statistical analysis 
of the MABRELLA study. 
The analysis plan proposed below describes the aspects that should be known about the study 
and the methods of statistical analysis that will be applied to the data collected in order to 
answer the objective of the interim analysis. 
2.2 
Objectives 
Primary Objective 
 
To evaluate the incidence of 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) who have previously received at least one dose of intravenous (IV) 
rituximab.  
 
Secondary Objectives  
 
 
To further evaluate the safety of rituximab SC in terms of:   
o Grade ≥ 3 AEs  
o Grade ≥ 3 IIRRs  
o Serious adverse events (SAEs)  
 
To evaluate the efficacy of rituximab SC in terms of:  
o  event-free survival (EFS)  
o  progression-free survival (PFS)  
o  overall survival (OS)  
o  disease-free survival (DFS)  
 
Treatment response rate 4-6 weeks after the last dose of Induction classified as follows: 
complete response (CR) (including complete response unconfirmed (CRu), partial 
response (PR), stable disease (SD) and progression disease (PD).  


MABRELLA Study 
 
6 
 
Exploratory Objectives 
 
 
  
 
Patient reported outcomes  
 
 
To evaluate and compare the methods of rituximab administration (SC vs IV) in terms of 
patients´ satisfaction using the “Rituximab Administration Satisfaction Questionnaire” 
(RASQ).  
 
To assess patients’ quality of life and utilities by EUROQoL 5D instrument.  
 
2.3 
Study Design 
Clinical trial, phase IIIb, open-label, non-randomized, single group assignment.  
2.4 
Study Population 
The target population will consist of adults with CD20+ DLBCL or CD20+ FL grade 1, 2 or 3a 
according to the World Health Organization (WHO) classification system. 
It is planned that 140 patients will participate in the study. 


MABRELLA Study 
 
7 
 
 
2.5 
Inclusion Criteria 
Study participants must meet ALL of the following criteria in order to be included in the study: 
Criteria related to the subject 
1. Written informed consent 
2. Age >/= 18 and </= 80 years at time of enrolment. 
3. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 3  
Criteria related to disease 
4. Histologically confirmed CD20+ DLBCL or CD20+ follicular NHL (FL) grade 1, 2 or 3a 
according to the WHO classification system. 
5. Induction only: 
a. DLBCL related criteria: An International Prognostic Index (IPI) score of 1-4 or IPI score 
of 0 with bulky disease, defined as one lesion >/= 7.5 cm (Appendix 4 of protocol).  
b. FL treatment-related criteria: Follicular Lymphoma International Prognostic Index 
(FLIPI) (low, intermediate, high risk). Patients with FL should meet Groupe D'Etude des 
Lymphomes Folliculaires (GELF) criteria to initiate treatment. (Appendix 4 of protocol). 
 
6. Induction only: At least tumor >/= 1.5 cm as measured by computed tomography (CT) scan  
Treatment-related criteria 
7. Currently being treated with MabThera/Rituxan IV during first-line therapy and has received 
at least one full dose of MabThera/Rituxan IV (defined as standard full dose of MabThera/Rituxan 
IV 375 mg/m2 administered without interruption or early discontinuation (i.e. tolerability issues) 
 8. 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) 
2.6 
 Exclusion criteria 
Participants who meet any of these criteria will not be included in the study: 
Criteria related to medical history 
1. Transformed lymphoma or follicular lymphoma (FL) IIIB 


MABRELLA Study 
 
8 
 
2. Primary central nervous system lymphoma, primary effusion lymphoma, primary mediastinal 
DLBCL, DLBCL of the testis, primary cutaneous DLBCL or histologic evidence of 
transformation to a Burkitt lymphoma. 
3. History of other malignancy that could affect compliance with the protocol or interpretation of the 
results; this includes a malignancy that has been treated but not with curative intent, unless the 
malignancy has been in remission for >/= 5 years prior to treatment administration; Note: patients 
with a history of curatively treated basal or squamous cell carcinoma or melanoma of the skin or in 
situ carcinoma of the cervix are eligible. 
Previous and concomitant treatment 
4. Ongoing corticosteroid use > 30 mg/day of prednisone or equivalent. Note: patients receiving 
corticosteroid treatment with ≤ 30 mg/day of prednisone or equivalent must be on a stable regimen 
for at least 4 weeks prior to start of dosing. 
Analytical evaluation during screening 
5. Impaired renal function defined as creatinine > 1.5 x Upper Limit of Normal, ULN (unless 
creatinine clearance [CrCl] normal), or calculated CrCl < 40 mL/min (as determined by the 
Cockcroft–Gault formula) 
6. Inadequate hematologic function, defined as follows: 
 - Hemoglobin < 9 g/dL 
- Absolute neutrophil count < 1.5 x 109/L 
- Platelet count < 75 x 109/L (Note: abnormalities outside the above listed are allowed if related 
to involvement of bone marrow by the underlying disease). 
7. Inadequate hepatic function, defined as any of the following abnormal laboratory values: 
• Alanine aminotransferase (AST) or aspartate aminotransferase (ALT) > 2.5 x the ULN 
• Total bilirubin ≥ 1.5 x the ULN. (Patients with documented Gilbert disease may be 
enrolled if total bilirubin is ≤ 3.0 x the ULN.) 
Other prior or current medical conditions and treatments 
8. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal 
antibodies or known sensitivity or allergy to murine products. 
9. For patients with DLBCL: Contraindication to any of the individual components of CHOP 
(cyclophosphamide, vincristine, doxorubicin and prednisone), including prior anthracycline 
treatment. For patients with FL: contraindication to standard chemotherapy. 


MABRELLA Study 
 
9 
 
10. Other serious underlying medical conditions (i.e., severe 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 infections (excluding nail fungal infections) or any infection requiring 
treatment with IV antibiotics or hospitalization within 4 weeks prior to dosing. 
13. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Note: Patients testing 
positive for hepatitis B or C virus antibodies but with an undetectable viral load may be included 
(i.e., HBV or HCV RNA-negative by PCR).  
14. History of human immunodeficiency virus (HIV) positive status. 
General criteria 
15. Any coexisting medical or psychological condition that would preclude participation in the 
required study procedures 
16. Life expectancy < 6 months 
 
17. A positive pregnancy test for women of childbearing potential within 7 days prior to first 
rituximab administration or within 14 days if with a confirmatory urine pregnancy test within 7 
days prior to the first administration. 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 subcutaneous rituximab. 


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3 STATISTICAL METHODS 
The methods of analysis to be used to achieve both the objectives of the final analysis of the 
study and for description of the study variables are detailed below. 
All analyses described will be performed by type of lymphoma (DLBCL / FL) and overall.  
Analyses of current treatment will be performed by type of treatment (induction therapy / 
maintenance therapy). 
Selection criteria will not be checked unless it is expressly requested. 
 UNIVARIATE ANALYSIS 
Quantitative variables will be described with measures of central tendency and dispersion: 
mean, median, SD (standard deviation), Q1 (first quartile) and Q3 (third quartile), minimum and 
maximum). 
Qualitative variables will be described using absolute and relative frequencies. Two columns 
of percentages will be presented: Total percentage (%) and Percentage valid (% valid). 
 
Total percentage (%): Percentage over the sum of valid responses plus missing values, 
that is, over the total study sample. 
 
Percentage valid (% valid): Percentage over total valid responses, that is, with data in 
the variable. 
Ninety-five percent Clopper-Pearson confidence intervals (CI) will be calculated, when 
necessary, for outcome variables associated with objectives. 
In the case of questions with more than one response option, multiple response tables will be 
shown. Two columns of percentages will be shown in these tables: 
 
Total percentage (%): Percentage over the sum of valid responses plus missing values, 
that is, over the total study sample. As it is multiple response, the sum of the 
percentages does not necessarily equal 100 (this percentage may be exceeded). 
 
Percentage valid (% valid): Percentage over the number of patients with at least one 
response given from among those possible. As it is multiple response, the sum of the 
percentages does not necessarily equal 100 (this percentage may be exceeded). 


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 BIVARIATE ANALYSIS 
In the comparative analysis, parametric tests will be used for those variables that meet the 
conditions for application (e.g. t-test) and nonparametric tests (e.g. chi-squared, Mann-Whitney 
U, Wilcoxon, etc.) for ordinal, categorical or other variables that do not meet parametric criteria. 
All hypothesis tests will be two-sided and with a significance level of 0.05. 
The "time to event" variables (i.e. progression-free survival, overall survival, etc.) will be 
analyzed using the Kaplan-Meier method.   
Data will be analyzed using SPSS v22.0. 
3.1 
Close-out Database Agreement 
Following database close-out to perform the analyses, if any anomalous and/or inconsistent 
values are found in any table of results, the database will not reopened to modify the values, 
but instead the anomalous data value will be highlighted and it will be indicated how it was 
handled (e.g., assigning to missing values or eliminating the case depending on the statistical 
method to be used in the analysis in question). Missing data will not be imputed and will be left 
as lost. 
Any modification to this section will be recorded in writing in the report as well as the 
procedure followed (e.g. assignment to missing values, interpolation, elimination of the 
case, etc.).  


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4 
ANALYSIS POPULATIONS 
The populations that will be included in the analysis are defined below: 
All enrolled patients who receive at least one dose of study medication will be included in the 
Safety Population, which will be the primary analysis population for safety parameters.  
All enrolled patients will be included in the Intent-to-Treat (ITT) population.  
Efficacy parameters and patient reported outcome measures will be analyzed using the ITT 
population. 
 
All analyses described will be performed by type of lymphoma (DLBCL / FL) and overall. 


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5 
DESCRIPTIVE ANALYSIS: DEMOGRAPHIC AND CLINICAL CHARACTERISTICS 
5.1 
Recruitment Period 
The dates of inclusion the first and last patient will be provided. 
5.2 
Lymphoma Diagnosis 
 
Type of Lymphoma: Diffuse Large B-cell / DLBCL / FL. 
5.3 
Demographic and anthropometric data 
Descriptive statistics (mean, SD, median, Q1, Q3, minimum, maximum) will be shown for the 
following variables: 
 
Age (years), based on (Date of Visit – Date of Birth). 
 
Weight. 
 
Height.  
 
BMI. 
Categorical variables to be described:  
 
Sex: Male / Female. 
 
If female, is patient of childbearing potential: Yes / No. 
 
Race: Caucasian / Black/ Asian / Other. 
 
Ethnicity: Hispanic / Not Hispanic / Not applicable as local regulations / Others. 
 
5.4 
Medical History 
5.4.1 Relevant medical history 
Categorical variables to be described:  
 
Does the patient have any clinical significant relevant medical history other than DLBCL 
or FL?: Yes / No. 
For patients with any clinical significant relevant medical history, a multiple response table will 
be shown (the table will be shown by System Organ Class and Preferred Term). 
5.4.2 Surgery and Procedures history 
Categorical variables to be described:  
 
Has the patient had any cancer or non-cancer surgeries to report?: Yes / No 
For patients with any cancer or non-cancer surgeries, a multiple response table will be shown 
for type of surgery or procedure. 


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5.4.3 DLBCL Diagnosis 
Descriptive statistics (mean, SD, median, Q1, Q3, minimum, maximum) will be presented for the 
following continuous variables: 
 
Time from diagnosis, defined as the time in months from the date of diagnosis (date of 
histological diagnosis) to the date of the baseline visit. 
Categorical variables to be described:  
 
Histological diagnosis: FNA / Core needle biopsy /Excisional or Incisional biopsy of 
peripheral lymph node. 
5.4.4 Follicular Lymphoma Diagnosis 
Descriptive statistics (mean, SD, median, Q1, Q3, minimum, maximum) will be presented for the 
following variables: 
 
Time from diagnosis, defined as the time in months from the date of diagnosis (date of 
histological diagnosis) to the date of the baseline visit. 
Categorical variables to be described:  
 
Histological diagnosis: FNA / Core needle biopsy /Excisional or Incisional biopsy of 
peripheral lymph node. 
 
Grade of FL: 1 / 2 / 3 / 3a. 
5.5 
Physical Examination 
Related to baseline visit, the following will be described: 
 
Was the physical examination performed?: Yes / No 
For patients with a physical examination performed, a multiple response table will be shown for 
those affected systems with the result: Abnormal, clinically significant: 
 
Head, ears, eyes, nose, throat. 
 
Cardiovascular system. 
 
Dermatological. 
 
Musculoskeletal system. 
 
Respiratory system. 
 
Gastrointestinal system. 
 
Genitourinary system. 
 
Nervous system. 
 
Other. 
The physical examination will be described for each of the visits performed. 
 


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5.6 
ECOG Performance Status 
Categorical variable to be described: 
 
ECOG: 0/ 1 / 2 / 3 / 4 / 5. 
The ECOG score will be described for each of the visits performed, i.e., at screening and 
induction and/or maintenance. 
5.7 
IPI Score 
For DLBCL patients: Related to baseline visit, the following will be described: Low risk / Low 
intermediate risk / High intermediate risk / High risk. 
5.8 
FLIPI Score 
For FL patients: Related to baseline visit, FLIPI score will be described: Low risk / intermediate 
risk / High risk. 


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6 EVALUATION OF PATIENT OUTCOME QUESTIONNAIRE 
All analyses described will be performed by type of lymphoma (DLBCL / FL) and overall. 
 
The Rituximab IV Administration Satisfaction Questionnaire (RASQ-IV) will be analyzed on the 
baseline visit before switching to SC rituximab treatment and the Rituximab IV Administration 
Satisfaction Questionnaire” (RASQ-SC) at the “end of induction” and/or “maintenance 
treatment” (when applicable).  
 
The RASQ is a 20-item questionnaire measuring the impact of the mode of treatment 
administration on five domains: Physical Impact, Psychological Impact, Impact on Activities of 
Daily Living, Convenience, and Satisfaction. The Physical Impact domain comprises of three 
items 
(Pain, 
swelling, and 
redness, 
Pain 
experience, 
Side 
effects 
as 
expected), 
the Psychological Impact domain contains five items (Anxious about injection/IV, Worry 
condition will get worse, Anxious thinking about disease, Confidence the injection/IV treating 
disease, Feeling restricted by injection/IV), the Impact on Activities of Daily Living domain 
contains three items (Interference with usual/daily activities, Limit daily activities, Lost/gained 
time), the Convenience domain contains three items (Is it convenient to get injection/IV, Length 
of time to get injection/IV as expected, Bothered by the amount of time to get injection/IV) and 
the Satisfaction domain includes two items (How satisfied or dissatisfied are you with the 
injection/IV, Would you recommend the way you received the treatment). All 16 RASQ items 
included in the above domains have five response options. Reverse-coded response values 
will be created for eight of the RASQ items (Q2, Q3, Q5, Q6, Q7, Q9, Q14a, and Q14b). 
In addition, there are four descriptive questions that are not part of the above domains and 
scored separately. Descriptive statistics (mean, SD, median, Q1, Q3, minimum, maximum) will 
be presented for this domains. 
For each domain, if there are no missing responses, the domain will be scored using the 
formula: 
Domain score = [(Sum of completed item responses / Number of completed items) - 1] x 100 / 
(Maximum possible item response value – Minimum possible item response value) 
However, if there are any missing responses within a domain then the domain will not be 
scored (i.e. a missing value is assigned to the domain). 
Since the maximum possible item response value is 5 and the minimum possible response 
value is 1 for all RASQ items, a simpler way to represent the above formula for the RASQ 
domains is: 
RASQ domain score = (Mean of completed item responses – 1) x 25. 


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17 
 
Descriptive statistics (mean, SD, median, Q1, Q3, minimum, maximum) will be presented for 
each domain. 
 
7 PREVIOUS TREATMENT 
7.1 
Chemotherapy 
The variable ‘type of chemotherapy regimen’ that the patient is receiving will be described: 
CHOP-14 x 6 / CHOP-14 x 8 / CHOP-21 x 6/ CHOP-21 x 8 / CVP-21 x 8 / Other. 
7.2 
Previous IV Rituximab Dose: FL 
Descriptive statistics (mean, SD, median, Q1, Q3, minimum, maximum) will be presented for the 
following continuous variables: 
 
Time from diagnosis (months), calculated from the date of histological diagnosis to the 
date of first dose of IV rituximab). 
 
Dose of most recent IV rituximab cycle. 
Categorical variables to be described: 
 
Phase of IV rituximab (most recent IV cycle): Induction Phase / Maintenance Phase 
 
Cycles of IV rituximab that the subject had received previously: 1/ 2 / 3 / 4 / 5 / 6 / 7 / 8.  
 
Treatment phase in which the patient switched from IV rituximab to the SC formulation: 
Induction Phase / Maintenance Phase. 
 
First SC treatment cycle on study: Cycle 1 / Cycle 2 / Cycle 3 / Cycle 4 / Cycle 5 / Cycle 
6 / Cycle 7. 


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7.3 
Previous IV Rituximab Dose: DLBCL 
Descriptive statistics (mean, SD, median, Q1, Q3, minimum, maximum) will be presented for the 
following continuous variables: 
 
Time from diagnosis (months), calculated from the date of histological diagnosis to the 
date of first dose of IV rituximab). 
Categorical variables to be described: 
 
Cycles of IV rituximab that the subject had received previously: 1/ 2 / 3 / 4.  
 
Dose of most recent IV rituximab cycle. 
 
First SC treatment cycle on study: Cycle 2 / Cycle 3 / Cycle 4 / Cycle 5.  
 
8 
CURRENT TREATMENT 
8.1 
Study Drug Administration 
Descriptive statistics (mean, SD, median, Q1, Q3, minimum, maximum) will be presented for the 
following continuous variables: 
 
For FL patients: Number of induction and/or maintenance cycle administered per 
patient. 
 
For DLBCL patients: Number of treatment cycle administered per patient. 
Categorical variables to be described (this analysis will be presented by cycle): 
 
Full dose: Yes / No If No: 
o Reason: Adverse event / Technical problems / Other  
 
(If other: specify).  
 
If the reason is an AE, specify if it is a grade 3 or 4 IRAE: Yes / No. 
8.2 
Study Drug Discontinuation 
Categorical variables to describe are: 
 
Number of patients who discontinued study treatment. 
 
Primary reason for patient discontinued treatment: Progression of Disease / Adverse 
Event / Pregnancy / Patient request - Withdraw consent / Investigator decision / Lack of 
compliance / Lost to Follow-up / Death / Other. 


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9 
RESPONSE 
All analyses described will be performed by type of lymphoma (DLBCL/FL) and overall. 
The response attained by patients on the End of Treatment visit (4-6 weeks after the last dose 
of Rituximab SC) will be described, including: Complete Response, Unconfirmed Complete 
Response, Partial Response, Stable Disease, Disease Progression, as well as the 95% 
confidence interval.  
Depending on the response, the complete response rate (Complete Response + Unconfirmed 
Complete Response) will be calculated and described, as well as the 95% confidence interval.  
All analyses described will be performed by type of lymphoma (DLBCL/FL) and overall. 
 
The response attained by patients on the Final Staging visit will be described, including: 
Complete Response, Unconfirmed Complete Response, Partial Response, Stable Disease, 
Disease Progression, as well as the 95% confidence interval.  
Depending on the response, the complete response rate (Complete Response + Unconfirmed 
Complete Response) will be calculated and described, as well as the 95% confidence interval.  
All analyses described will be performed by type of lymphoma (DLBCL/FL) and overall. 
The variable ‘time in study’, defined as the time in months from inclusion to the last available 
date, will be provided. Descriptive statistics (mean, SD, median, Q1, Q3, minimum, maximum) 
will be presented. 
 
10 DEATHS 
All analyses described will be performed by type of lymphoma (DLBCL/FL) and overall. 
Categorical variables to be described: 
 
The number of patients who died during the study. 
 
Primary cause of death: Progression of disease / Adverse Event / Unknown / Other. 


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11 SURVIVAL 
All analyses described will be performed by type of lymphoma (DLBCL/FL) and overall. 
11.1 Event free survival (EFS) 
Is defined as the time from first dose of rituximab IV to first occurrence of progression or 
relapse, according to the IWG response criteria (Cheson et al. 1999, see Appendix 3 in 
protocol of this study) or initiation of a non–protocol-specified anti-lymphoma therapy or death, 
whichever occurs first.   
The median EFS will be described by total and by type of lymphoma (DLBCL/FL), as well as 
the number of events and censored cases (Kaplan-Meier Analysis). 
11.2 Progression free survival (PFS) 
It is defined as the time from first dose of rituximab IV to the first occurrence of progression or 
relapse, according to the IWG response criteria (Cheson et al. 1999, see Appendix 3 in 
protocol of this study) or death from any cause.   
The median PFS will be described by total and by type of lymphoma (DLBCL/FL), as well as 
the number of events and censored cases (Kaplan-Meier Analysis). 
11.3  Overall survival (OS) 
It is defined as the time from first dose of rituximab IV to until death from any cause.  
The median OS will be described by total and by type of lymphoma (DLBCL/FL), as well as the 
number of events and censored cases (Kaplan-Meier Analysis). 
11.4 Disease free survival (DFS) 
It 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.   
The median DFS will be described by total and by type of lymphoma (DLBCL/FL), as well as 
the number of events and censored cases (Kaplan-Meier Analysis) 


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12 QUALITY OF LIFE 
All analyses described will be performed by type of lymphoma (DLBCL/FL) and overall. 
Quality of life will be analyzed at any many times as there are recorded in the CRF (at the “end 
of induction” and/or “maintenance treatment” (when applicable)).  
 
Quality of life will be assessed using the EuroQoL‐5D-5L Health Questionnaire. It consists of 
two parts:  
 
The first part evaluates 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. For each dimension, 5 health states are 
described. The patient then chooses the one that best describes his/her health state.   
 
The second part consists of a visual analog scale graded from 0 (worst imaginable 
health state) to 100 (best imaginable health state). The patient has to mark on this scale 
the point that best describes his/her overall health state on the day of the interview.  
In the EQ-5D questionnaire, the individual first self-rates his/her health state on severity levels 
by dimensions (descriptive system) and then makes a more general assessment of health 
status on a visual analog scale (VAS). A third element of the EQ-5D is the index of social 
values (or preferences), which is obtained for each health state generated by the instrument 
(tariffs). 
The descriptive system contains 5 health dimensions (mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression) and each of these dimensions has 5 severity levels 
(no problems, slight problems, moderate problems, severe problems, cannot perform the 
activity). The combination of the values of all the dimensions generates 5-digit numbers, with a 
total of 3125 possible combinations or health states. The second part is a visual analog scale 
ranging from 0 (worst imaginable health state) to 100 (best imaginable health state).  
Studies are currently being conducted to obtain index values to facilitate the calculation of the 
quality-adjusted life years (QALYs) that are necessary in economic evaluations. As the results 
of these index values values are yet not available, there are cross-tables to calculate the index 
value of a specific score obtained with the 5D-5L scale, based on the index values of the EQ-
5D-3L scale. The index of preference values ranges from a value of 1 (best health state) to 0 
(death), though there are negative values for the index, corresponding to those health states 
that are assessed as worse than death. 
- 
The descriptive analysis (N, %) will be shown by severity levels in each 
dimension and additionally  
- 
The descriptive analysis of the VAS will be provided (measures of central 
tendency and dispersion).  


MABRELLA Study 
 
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- 
The descriptive analysis of the index values or tariffs will be provided (measures 
of central tendency and dispersion).  
The index values will be taken from the webpage: 
http://www.euroqol.org/about-eq-5d/valuation-of-eq-5d/eq-5d-5l-value-sets.html 
 
 


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13 SAFETY 
All analyses described will be performed by type of lymphoma (DLBCL/FL) and overall. 
13.1 Adverse Events 
This analysis will include all adverse events occurring to patients during the study. To obtain 
the number of adverse events per patient, the maximum of most extreme intensity (maximum 
intensity grade for each toxicity) will be calculated for each of the adverse events recorded 
during the treatment of each patient and the following will be described: 
 
Number of patients with at least one adverse event (95% CI). 
 
Number of patients with different adverse events reported by grade (GI, GII, GIII, GIV, 
GV). A list of the different AEs experienced by patients according to the maximum 
grade, N and % will be presented. (Events will be run by System Organ Class and 
Preferred Term). 
 
Number of patients with at least one adverse event of grade 3 or higher (95% CI). 
13.2 Serious Adverse Events 
The number of patients with at least one Serious Adverse Event (95% CI) will be described, 
as well as a list of the different events experienced by patients and the main characteristics of 
the events: system organ class, preferred term, causal relationship with chemotherapy or 
rituximab, duration (start and end date), action taken, treatment required (yes/no), outcome. 
13.1 
Adverse Event of Special Interest  
The number of patients with at least one Adverse Event of Special Interest (95% CI) will be 
described, as well as a list of the different events experienced by patients and the main 
characteristics of the events: system organ class, preferred term, causal relationship with 
chemotherapy or rituximab, duration (start and end date), action taken, treatment required 
(yes/no), outcome. 


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24 
 
 
13.2 Adverse Events related to SC Rituximab  
In this section, the AEs indicating a relationship to the study treatment (SC rituximab) will be 
considered. 
This analysis will include all adverse events occurring to patients during the study. To obtain 
the number of adverse events per patient, the maximum of most extreme intensity will be 
calculated for each of the adverse events recorded during the treatment of each patient and the 
following will be described: 
 
Number of patients with at least one AE. The proportion of patients experiencing at 
least one AE will be provided, and the Clopper-Pearson 95% confidence interval. 
 
Number of patients with different AEs reported by grade (GI, GII, GIII, GIV, GV). List of 
the different AEs experienced by patients according to grade, N and %. (Events will be 
run by System Organ Class and Preferred Term). 
 
Number of patients with at least one AE ≥ grade 3 (95% CI). 
 
Number of patients (%) with one fatal AE (leading to death): N, % (CI 95%).  
13.3 Administration-Associated Reactions (AARs) for SC Rituximab 
AAR: All events where the answer to "If this is an AAR related to the Rituximab SC injection, 
please specify location" is "Localised at the injection site” or “Generalised and/or remote from 
the injection site" 
 
Number (%) of patients with at least one AAR  
 
Number of patients with different AARs reported by grade (GI, GII, GIII, GIV, GV). List 
of the different AARs experienced by patients according to, N and %. (Events will be run 
by System Organ Class and Preferred Term). 
 
Number (%) of patients with at least one AAR ≥ grade 3. 
 
Number (%) of patients with at least one serious AARs.  
 
Number (%) of patients with at least one AAR localized at the injection site reaction and 
generalized and/or remote from the injection site. 
 
AAR localized at the injection site and generalized and/or remote. 
13.4 Action taken related to study treatment Rituximab 
The action taken related to the study treatment with rituximab will be described (for all AEs): 
None / Drug interrupted / Drug delayed / Drug permanently discontinued / Dose modification / 
Not Applicable. 
The number (%) of patients with at least AEs leading to treatment interruption, dose delay, 
discontinuation and modification will be described:  


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25 
 
 
AEs leading to treatment interruption. 
 
AEs leading to dose delay. 
 
AEs leading to discontinuation. 
 
AEs leading to modification. 
13.5 Outcome 
The outcome (for every AE) will be described: Fatal / Resolved / Resolved – with sequelae / 
Unresolved - Improving / Unresolved – Persisting / Unresolved – Worsening / Unknown. 
The number (%) of patients with at least AEs leading to patient death will be described:  
 
AEs leading to death=Fatal. 


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14 ANALYSIS OF OBJECTIVES 
14.1 Primary Objective 
To evaluate the incidence of 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) who have previously received at least one dose 
of intravenous (IV) rituximab.  
This objective is answered with the descriptive analysis, as detailed in section 13.3 of this 
document. 
14.2 Secondary Objectives 
 
To further evaluate the safety of rituximab SC in terms of:   
o Grade ≥ 3 AEs  
o Grade ≥ 3 IIRRs  
o Serious adverse events (SAEs)  
 
This objective is answered with the descriptive analysis, as detailed in sections 13.1, 13.2 y 
13.3 of this document. 
 
 
To evaluate the efficacy of rituximab SC in terms of:  
o  event-free survival (EFS)  
o  progression-free survival (PFS)  
o  overall survival (OS)  
o  disease-free survival (DFS)  
This objective is answered with the descriptive analysis, as detailed in section 11 of this 
document. 
 
 
Treatment response rate 4-6 weeks after the last dose of Induction classified as 
follows: complete response (CR) (including complete response unconfirmed 
(CRu), partial response (PR), stable disease (SD) and progression disease (PD).  
This objective is answered with the descriptive analysis, as detailed in section 9 of this 
document. 


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14.3 Exploratory Objectives 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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14.4 Patient reported outcomes 
To evaluate and compare the methods of rituximab administration (SC vs IV) in terms of 
patients´ satisfaction using the “Rituximab Administration Satisfaction Questionnaire” 
(RASQ).  
This objective is answered with the descriptive analysis, as detailed in section 6 of this 
document. 
 
To assess patients’ quality of life and utilities by EUROQoL 5D instrument.  
This objective is answered with the descriptive analysis, as detailed in section 12 of this 
document.