A Non-Interventional, Retrospective And Prospective, Multicenter, Single Arm Study Evaluating The Effectiveness And Safety Of Obinutuzumab In Patients With Previously Untreated Advanced Follicular Lymphoma
Conditions: Follicular Lymphoma
Sponsor: Hoffmann-La Roche

 
Official Title: 
A Non-Interventional, Retrospective and Prospective, Multicenter, 
Single Arm Study Evaluating the Effectiveness and Safety of 
Obinutuzumab in Patients with Previously Untreated Advanced 
Follicular Lymphoma 
NCT Number: 
NCT04034056 
Document Date: 
Protocol Amendment Version 2: 23-May-2021 
 
 
 

PROTOCOL AMENDMENT APPROVAL 
CONFIDENTIAL 
The information contained in this document, especially any unpublished data, is the property of 
F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence as a 
treating physician, or consultant, for review by you, your staff, and an applicable Ethics Committee or 
Institutional Review Board.  It is understood that this information will not be disclosed to others without 
written authorization from Roche except to the extent necessary to obtain informed consent from 
persons who will participate. 
 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
Protocol ML41215, Version 2.0 
 
1 
NIS PROTOCOL AMENDMENT 
TITLE: 
A NON-INTERVENTIONAL, RETROSPECTIVE AND 
PROSPECTIVE, MULTICENTER, SINGLE ARM 
STUDY EVALUATING THE EFFECTIVENESS AND 
SAFETY OF OBINUTUZUMAB IN PATIENTS WITH 
PREVIOUSLY UNTREATED ADVANCED 
FOLLICULAR LYMPHOMA 
Short title: Untreated FolliculaR Lymphoma treated 
with OBinituzumAb in a Non-interventional study 
(URBAN) 
PROTOCOL NUMBER: 
ML41215 
VERSION NUMBER: 
2.0 
STUDIED MEDICINAL 
PRODUCT 
Obinutuzumab 
MARKETING AUTHORIZATION 
HOLDER:  
 
Roche Registration GmbH 
Emil-Barell-Strasse 1 
D-79639 Grenzach-Wyhlen - Germany 
DATE FINAL: 
Version 1.0:  16-May-2019 
DATE AMENDED 
Version 2.0:  See electronic date stamp below 
 
 
23-May-2021 08:54:07
Title
Approver's Name
Company Signatory
Date and Time (UTC)

Obinutuzumab—F. Hoffmann-La Roche Ltd 
Protocol ML41215, Version 2.0 
2 
PROTOCOL AMENDMENT, VERSION 2.0: 
RATIONALE 
Protocol ML41215 has been amended to align the protocol to the protocol template 
Version 7.0 released on 16 Dec 2019 and to implement other changes. 
Changes to protocol to align the protocol to the protocol template Version 7.0 released 
on 16 Dec 2019 are as follows: 
 
A new section (Section 6.2.2: Recruitment Procedure) has been added to describe 
procedures for recruitment. 
 
Section 6.8.4 (Retention of Records): record retention requirements have been 
updated. 
 
Section 7.2 (Informed Consent): details about the accountability of the physician on 
the ICF administration process. 
 
Section 7.4 (Confidentiality): a description of any foreseen further use of data has 
been added. 
 
A new section (Section 8.3: Reporting of Products Complaints Without Adverse 
Events) has been added to define procedures for reporting of Roche product 
complaints without Adverse Events. 
Additional changes to the protocol are as follows: 
 
Synopsis, Section 5.2.3 and Section 6.3.4 – Other objectives and variables updated 
 
Synopsis - Study design and Appendix 2. Minimum requirements for follow-up data 
have been added. 
 
Synopsis – Data Analysis , and Section 6.7.4 an additional Interim Analysis has 
been added 
 
Synopsis – End of study. Further specifications have been added. 
 
Section 6.4.2 and Appendix 2. Details on time for administration of PRO 
questionnaires have been added. 
 
Section 6.4.3. referral to “appendix 2” has been removed because it is not 
applicable for this study. 
 
Section 6.7. The program used for statistical analysis has been changed. 
 
Section 6.7.3. Text has been removed (“no biomarker analysis is scheduled in the 
study”), and replaced with other scheduled analyses (use of Obinutuzumab in the 
real world setting, prescription profile, and impact of COVID-19).  
 
Section 6.8.5. Details of administrative procedures have been changed. 
 
Section 8.1.1.2. The list of adverse events of special interest has been changed. 
 
Section 8.1.2.2. A specification on procedures for recording of adverse events has 
been added. 

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 
Section 8.1.3.4. The paragraph about Pregnancies in Female Partners of Male 
Patients has been removed 
 
Additional minor changes have been made to improve clarity and consistency. 
Substantive new information appears in italics. This amendment represents cumulative 
changes to the original protocol. 

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Protocol ML41215, Version 2.0 
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PROTOCOL AMENDMENT, VERSION 2.0: 
SUMMARY OF CHANGES 
PROTOCOL SYNOPSIS (Other Objectives – other Variables of interest) and 
Section 5.2.3 (Other Objectives) and Section 6.3.4 (Other Variables of 
Interest) 
The following objectives have been added: 
 
To explore effectiveness of Obinutuzumab in the real world setting; 
 
To explore prescription profile 
 
To explore COVID-19 impact on therapy adherence 
 
PROTOCOL SYNOPSIS (Study design, 4th paragraph) and Appendix 2 (Data 
Collection Overview (as per Standard of Care), item b 
The following sentence has been added: 
‘Follow-up data will include at least tumor assessments, new anti-lymphoma therapy 
informations and safety data’.  
 
PROTOCOL SYNOPSIS (Data Analysis) and SECTION 6.7.4 (Interim and 
Final Analyses and Timing of Analyses) 
The following sentences have been added: 
“A second interim analysis will be performed approximately two years after the first 
patient included in the study in order to evaluate safety and primary and secondary 
effectiveness data, and the impact of COVID-19 on the patient management.  
The results of the first two interim analysis will be compared.  
The final Analysis will be performed at the end of the study.” 
 
PROTOCOL SYNOPSIS (End of study) and Section 6.1.1 (Overview of Study 
design), End of Study 
The following sentence: 
‘The end of the study will be the date from which the last information of the last patient is 
recorded in the study database.’ 
has been replaced with the following:  
‘The end of the study will be the date from which the last information of the last patient 
still in the study is recorded in the study database.’ 
 
SECTION 4.1 (STUDY RATIONALE) 
The following sentence: 

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“For information on the condition under observation and on the Obinutuzumab please 
refer to the Investigator's Brochure and to the most recent version of the Summary of 
Product Characteristics (SmPC) of Gazyvaro®, i.e. the brand name of Obinutuzumab, for 
further details on nonclinical and clinical studies”. 
has been replaced with the following: 
“For information on the condition under observation and on the Obinutuzumab please 
refer to the Investigator's Brochure and to the most recent version of the Summary of 
Product Characteristics (SmPC) of Gazyvaro®, i.e. the brand name of Obinutuzumab, for 
further details on nonclinical and clinical studies”. 
 
 
SECTION 6.2.2 (Recruitment Procedure):   
This section has been added to describe procedures for recruitment, to align the 
protocol to the protocol template Version 7.0 released on 16 Dec 2019. 
6.2.2   Recruitment Procedure  
‘No specific procedures for recruitment (e.g. advertisements, published information or 
other) were used for the study. 
The Principal Investigator or a co-investigator in each investigational site will verify the 
eligibility of each patient for the participation in the study based on adherence to 
inclusion/exclusion criteria. Eligible patients who signed the ICF were then included in 
the study’. 
 
SECTION 6.4.2 (Data Collected During the Observation Period), last 
paragraph and Appendix 2 (Data Collection Overview (as per Standard of 
Care), item g:   
The following sentence: 
‘PRO questionnaires (FACT-Lym, EQ-5D) should be administered prior to any treatment 
and assessments’.  
Has been replaced with the following sentence: 
‘PRO questionnaires (FACT-Lym, EQ-5D) should be administered on Day 1 of alternate 
cycles during induction treatment period and at each cycle during manteinace treatment 
period. PRO Questionnaires should be administered on Day 1 of the cycle prior to any 
treatment and assessments, i.e. PRO questionnaires should be collected only when 
corresponding to a treatment cycle. PRO questionnaires should also be administered at 
first visit after reporting disease progression. 

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Protocol ML41215, Version 2.0 
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Please see Appendix 2 for the data collection overview (as per standard of care).’ 
 
SECTION 6.4.3 (Data Collected at Study Completion):   
As no predetermined study completion visit is not scheduled, the following text has been 
removed: 
‘Please see Appendix 2 for the data collection overview at the study completion visit’. 
 
SECTION 6.7 (STATISTICAL CONSIDERATIONS):   
The following text in the second sentence: 
‘The statistical analysis will be performed using the SAS System version 9.4 or higher’. 
Has been replaced with the following text to update the program used for statistical 
analysis: 
‘The statistical analysis will be performed using the R System. 
 
SECTION 6.7.3. (Other Analyses):   
As no biomarkers analyses are scheduled in the study, the following sentence has been 
deleted: 
‘The results of biomarker analyses will be presented using descriptive statistics only.’ 
Details of other analyses have been added with the following text: 
The following other analyses will be performed: 
Use of Obinutuzumab in the real world setting 
Descriptive statistics for the use of Obinutuzumab in real world setting will be performed. 
At least the following conditions will be considered in the analysis: 
 
Not performing obinutuzumab administration on Day 8 and Day 15 in Cycle 1 
(without safety reasons)  
 
Maintenance period: administration of obinutizumab in an interval superior to 10 days 
from the expected date (every 2 months per label). NOTE: An analysis will be 
performed to assess if this condition will have impact on efficacy parameters (PFS/ 
POD24) and to explore the delay reason (COVID-19 or others) 
 
All the chemotherapy scheme used with Obinutuzumab in the real word setting  
Prescription profile  
Obinutuzumab prescription profile and chemotherapy backbone choice by Italian region, 
age range, patient’s profile and site dimension (outlying sites/universities, etc.) 

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Impact of COVID-19 
 Safety (infections and COVID-19 related events) 
 
Choice of chemotherapy in combination with Obinutuzumab 
 Maintenance delay or interruption due to pandemic status 
 Therapy interruption due to patient’s complications caused by COVID-19  
 
SECTION 6.7.4 (Interim and Final Analyses and Timing of Analyses) 
The following sentences have been added: 
“A second interim analysis will be performed approximately two years after the first 
patient included in the study in order to evaluate safety and primary and secondary 
effectiveness data, and the impact of COVID-19 on the patient management.  
The results of the first two interim analysis will be compared.  
The final Analysis will be performed at the end of the study.” 
 
SECTION 6.8.4 (Retention of Records):   
The following sentence has been added at the beginning of the section to align the 
protocol to the protocol template Version 7.0 released on 16 Dec 2019: 
Archiving at the study site has to be for 15 years after final study report or first 
publication of study results, whichever comes later. 
SECTION 6.8.4 (Retention of Records):   
The following text: 
“Records and documents pertaining to the conduct of this study, including eCRFs and 
Informed Consent Forms, must be retained by the physician for at least 15 years after 
completion or discontinuation of the study, or for the length of the time required by 
relevant national or local health authorities, whichever is longer” 
has been changed with: 
“Records and documents pertaining to the conduct of this study, including eCRFs and 
Informed Consent Forms, must be retained by the physicianMAH for at least 125 years 
after completion or discontinuation of the study, or for the length of the time required by 
relevant national or local health authorities, whichever is longer” 
SECTION 6.8.5 (Administrative Structure):   
The following text: 

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‘Enrolment will occur through an interactive web response system (IWRS) or similar 
system to capture electronically enrolled patients.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected as applicable’. 
Has been replaced with: 
‘Enrolment will occur through an eCRF system to capture electronically enrolled patients.  
Local laboratories will be used for routine monitoring; local laboratory ranges will be 
included in eCRF as applicable’. 
 
SECTION 7.2 (Informed Consent):   
To align the protocol to the protocol template Version 7.0 released on 16 Dec 2019, the 
following text: 
‘It is the accountability of the physician to obtain written informed consent from each 
patient participating in the study, after adequate explanation of the aims, methods, 
anticipated benefits, and potential hazards of the study.’ 
has been replaced with the following text: 
‘It is the accountability of the physician for ascertaining that the subject has 
comprehended the information and to obtain written informed consent from each patient 
participating in the study, after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study.’.  
Furthermore, the following sentences have been changed with the added words in italics: 
 
"The sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) 
and the privacy form will be provided to each site." 
 
"The Consent and Privacy Forms must be signed and dated by the patient or the 
patient’s legally authorized representative before start of documentation of his or her 
data in the CRF." 
 
 "A copy of each signed and dated Consent Form must be provided to the patient or the 
patient’s legally authorized representative."  
 
 
SECTION 7.4 (Confidentiality):   
The following text has been added (third paragraph) to align the protocol to the 
protocol template Version 7.0 released on 16 Dec 2019: 
‘The sponsor, including affiliates, collaborators and licensees may use study data 
labeled with the patient ID numbers. Study data may also be shared with independent 
researchers or government agencies, but only after personal information that can identify 
the patient has been removed. Patients’ study data may be combined with 
other patient’s data and/or linked to other data collected from the patients. Patients’ 
study data may be used to help better understand why people get diseases, how to best 

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9 
prevent, diagnose and treat diseases, and to develop and deliver access to new 
medicines, medical devices, and healthcare solutions to advance patient care’.   
 
SECTION 8.1.1.2 (Assessment of Serious Adverse Events (Immediately 
Reportable to the Marketing Authorization Holder), Non-serious Adverse 
Events of Special Interest (AESI) and Other Non-serious Adverse Events) 
The following list of Adverse events of special interest: 
 
Serious IRRs; 
 
Tumour lysis syndrome (irrespective of regulatory seriousness criteria); 
 
Serious neutropenia 
 
Serious infections; 
 
Hepatitis B reactivation while receiving the appropriate anti-viral therapy. 
Has been replaced with the following list of Adverse events of special interest: 
 
Tumor lysis syndrome (TLS), irrespective of causality 
 
Second malignancies 
 
Cases of potential medicine-induced liver injury that include an elevated ALT or AST 
in combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
law (see Appendix 3). 
 
Suspected transmission of an infectious agent by the study medicine, as defined 
below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection in a 
patient exposed to a medicinal product. This term only applies when a contamination 
of the study medicine is suspected. 
 
SECTION 8.1.2.2 (Procedures for Recording of Adverse Events):  
This specification has been added (8th bullet): 
‘Deaths that are clearly attributable to disease progression must not be reported as an 
AE’. 
The following sentence (13rd bullet) 
Quality Defects and Falsified Medicinal Products 
has been changed with  
‘Quality Defects, Falsified Medicinal Products and Product Complaints’ 

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SECTION 8.1.3.4 (Reporting Requirements for Pregnancies/Breastfeeding): 
The paragraph “Pregnanacies in Female Partners of Male Patients” has been removed 
because not applicable. 
 
SECTION 8.3 (Reporting of Products Complaints Without Adverse Events):   
This section has been added to define procedures for reporting of Roche product 
complaints without Adverse Events, to align the protocol to the protocol template 
Version 7.0 released on 16 Dec 2019: 
8.3   REPORTING OF PRODUCT COMPLAINTS WITHOUT ADVERSE 
EVENTS 
Report Roche product complaints without Adverse Events, where Product Complaint is 
any written or oral information received from a complainant that alleges deficiencies 
related to Identity, Quality, Safety, Strength, Purity, Reliability, Durability, Effectiveness, 
or Performance of a product after it has been released and distributed to the commercial 
market, to the sponsor. Report non-Roche-product complaints as per local regulation.  
 
APPENDIX 2 (Data collection Overview) item h 
The following words “AEs/SAEs/IRR/ADR” have been replaced with 
“AEs/SAEs/AESI/SS”. 
APPENDIX 3.3.12 (OVERDOSES, MISUSES, ABUSES, OFF-LABEL USE, 
OCCUPATIONAL EXPOSURE, OR MEDICATION ERROR)  
The following sentence: 
‘Any overdose, misuse, abuse, off-label use, occupational exposure, medication error 
(including intercepted or potential), or any other incorrect administration of medicine 
under observation should be noted in the Drug Administration section of the CRF.’   
 
has been replaced by: 
‘Any overdose, misuse, abuse, off-label use, occupational exposure, medication error 
(including intercepted or potential), or any other incorrect administration of medicine 
under observation should be noted in the Drug Administration section of the CRF as 
Special Situation (SS)’. 
 

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NIS PROTOCOL (PRIMARY DATA COLLECTION) 
TITLE: 
A NON-INTERVENTIONAL, RETROSPECTIVE AND 
PROSPECTIVE, MULTICENTER, SINGLE ARM 
STUDY EVALUATING THE EFFECTIVENESS AND 
SAFETY OF OBINUTUZUMAB IN PATIENTS WITH 
PREVIOUSLY UNTREATED ADVANCED 
FOLLICULAR LYMPHOMA 
Short title: Untreated FolliculaR Lymphoma treated 
with OBinituzumAb in a Non-interventional study 
(URBAN) 
PROTOCOL NUMBER: 
ML41215 
VERSION NUMBER: 
2.0 
STUDIED MEDICINAL 
PRODUCT 
Obinutuzumab 
AUTHOR: 
SPARC Consulting Srl  
Via Archimede 94 - 20129 Milan, Italy 
Mail: 
  
Phone number: ++ 39 02 43119667 / 87071294; 
Fax number: ++ 39 02 45476209 
DATE FINAL: 
See electronic date stamp  
MARKETING AUTHORIZATION 
HOLDER:  
 
Roche Registration GmbH 
Emil-Barell-Strasse 1 
D-79639 Grenzach-Wyhlen - Germany 
SPONSOR 
Roche S.p.A. - Viale G.B. Stucchi 110 
20900 Monza (MB) – Italy 
 

Obinutuzumab—F. Hoffmann-La Roche Ltd 
Protocol ML41215, Version 1.0 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 16 
1. 
LIST OF ABBREVIATIONS ......................................................................... 17 
2. 
SYNOPSIS .................................................................................................. 20 
3. 
PROTOCOL AMENDMENTS AND UPDATES ........................................... 27 
4. 
RATIONALE AND BACKGROUND............................................................. 28 
4.1 
Study Rationale ..................................................................... 31 
5. 
RESEARCH QUESTION AND OBJECTIVES ............................................. 33 
5.1 
Research Question ................................................................ 33 
5.2 
Objectives .............................................................................. 33 
5.2.1 
Effectiveness Objectives........................................................ 33 
5.2.2 
Safety Objectives ................................................................... 34 
5.2.3 
Other Objectives .................................................................... 34 
6. 
RESEARCH METHODS ............................................................................. 34 
6.1 
Study Design ......................................................................... 34 
6.1.1 
Overview of Study Design ..................................................... 35 
6.1.2 
Rationale for Study Design .................................................... 36 
6.1.3 
Number of Patients Observed in the Study ............................ 36 
6.1.4 
Sites....................................................................................... 36 
6.2 
Population .............................................................................. 36 
6.2.1 
Rationale for Patient Population ............................................ 36 
6.2.2 
Recruitment Procedure .......................................................... 37 
6.2.3 
Dosage, Administration, and Compliance .............................. 37 
6.2.4 
Concomitant Medication and Treatment ................................ 37 
6.3 
Variables ................................................................................ 37 
6.3.1 
Primary Effectiveness Variable .............................................. 37 
6.3.2 
Secondary Effectiveness Variable ......................................... 38 
6.3.3 
Safety Variables .................................................................... 39 
6.3.4 
Other Variables of Interest ..................................................... 39 
6.4 
Data Sources ......................................................................... 40 

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6.4.1 
Collection of Data on the CRF ............................................... 40 
6.4.2 
Data Collected during the Observation Period ....................... 40 
6.4.3 
Data Collected at Study Completion ...................................... 43 
6.4.4 
Safety Data Collection ........................................................... 43 
6.5 
Patient, Study and Site Discontinuation ................................. 43 
6.5.1 
Patient Discontinuation .......................................................... 43 
6.5.2 
Discontinuation from Treatment with Studied 
Medicinal Product .................................................................................... 44 
6.5.3 
Withdrawal from Study........................................................... 44 
6.5.4 
Study and Site Discontinuation .............................................. 44 
6.6 
Data Management ................................................................. 44 
6.6.1 
Data Quality Assurance ......................................................... 44 
6.6.2 
Electronic Case Report Forms ............................................... 46 
6.6.3 
Source Data Documentation .................................................. 46 
6.7 
Statistical Considerations ...................................................... 47 
6.7.1 
Effectiveness Analyses .......................................................... 47 
6.7.2 
Safety Analyses ..................................................................... 49 
6.7.3 
Other Analyses ...................................................................... 50 
6.7.4 
Interim and Final Analyses and Timing of 
Analyses 51 
6.7.5 
Determination of Sample size ................................................ 51 
6.8 
Study Documentation, Monitoring, and 
Administration ........................................................................ 53 
6.8.1 
Study Documentation ............................................................ 53 
6.8.2 
Site Audits and Inspections ................................................... 53 
6.8.3 
Use of Site Computerized Systems ....................................... 53 
6.8.4 
Retention of Records ............................................................. 54 
6.8.5 
Administrative Structure......................................................... 54 
6.9 
Limitations of the Research Method ...................................... 54 
7. 
PROTECTION OF HUMAN SUBJECTS ..................................................... 55 
7.1 
Compliance with Laws and Regulations ................................ 55 
7.2 
Informed Consent .................................................................. 55 
7.3 
Institutional Review Board or Ethics Committee .................... 55 
7.4 
Confidentiality ........................................................................ 56 

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8. 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ 
ADVERSE REACTIONS ............................................................................. 56 
8.1 
Safety Reporting Requirements for Studied 
Medicinal Products ................................................................ 56 
8.1.1 
Safety Parameters and Definitions ........................................ 56 
8.1.1.1 Adverse Events .................................................................... 57 
8.1.1.2 Assessment of Serious Adverse Events 
(Immediately Reportable to the Marketing Authorization 
Holder), Non-serious Adverse Events of Special Interest 
(AESI) and Other Non-serious Adverse Events .................................. 57 
8.1.2 
Methods and Timing for Capturing and 
Assessing Safety Parameters .................................................................. 59 
8.1.2.1 Adverse Event Reporting Period .......................................... 59 
8.1.2.2 Procedures for Recording Adverse Events .......................... 59 
8.1.3 
Reporting Requirements from Healthcare 
Professional to Marketing Authorization Holder ....................................... 60 
8.1.3.1 Immediate Reporting Requirements from 
Healthcare Professional to Marketing Authorization 
Holder 60 
8.1.3.2 Reporting Requirements for Non-Serious 
Adverse Events .................................................................................. 61 
8.1.3.3 If EDC System is Temporarily Unavailable ........................... 61 
8.1.3.4 Reporting Requirements for 
Pregnancies/Breastfeeding ................................................................ 61 
8.1.3.5 Reporting Requirements for Adverse Events 
originating from Patient Reported Outcomes ...................................... 63 
8.1.4 
Follow-Up of Patients after Adverse Events .......................... 63 
8.1.4.1 HCP Follow-Up..................................................................... 63 
8.1.4.2 Marketing Authorization Holder Follow-Up ........................... 63 
8.2 
Safety REPORTING Requirements for non-
Studied products .................................................................... 63 
8.3 
Reporting of product complaints without adverse 
events .................................................................................... 64 
9. 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS ................................................................................................... 64 
10. REFERENCES ........................................................................................... 65 
 

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LIST OF TABLES 
LIST OF TABLES 
Synopsis Table 1 - Follicular lymphoma: Obinutuzumab dose to be 
administered during induction and maintenance treatments 
(according to SmPc) ................................................................... 19 
Synopsis Table 2 - POD24 rate and corresponding 95% Confidence 
Intervals ...................................................................................... 23 
Synopsis Table 3 - PFS rate at 3 yrs. and corresponding 95% Confidence 
Intervals ...................................................................................... 23 
Table 1 - POD24 rate and corresponding 95% Confidence Intervals ................. 49 
Table 2 - PFS rate at 3 yrs. and corresponding 95% Confidence Intervals ........ 50 
 
LIST OF FIGURES 
Figure 1 
Study Scheme ............................................................................. 35 
 
APPENDICES……………………………………………………………………………..... 68

 
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PROTOCOL AMENDMENT ACCEPTANCE FORM  
TITLE: 
A NON-INTERVENTIONAL, RETROSPECTIVE AND 
PROSPECTIVE, MULTICENTER, SINGLE ARM 
STUDY EVALUATING THE EFFECTIVENESS AND 
SAFETY OF OBINUTUZUMAB IN PATIENTS WITH 
PREVIOUSLY UNTREATED ADVANCED 
FOLLICULAR LYMPHOMA 
Short title: Untreated FolliculaR Lymphoma treated 
with OBinituzumAb in a Non-interventional study 
(URBAN) 
PROTOCOL NUMBER: 
ML41215 
VERSION NUMBER: 
2.0 
STUDIED MEDICINAL 
PRODUCT  
Obinutuzumab 
SPONSOR  
Roche S.p.A. 
Viale G.B. Stucchi 110 
20900 Monza (MB) – Italy 
 
I agree to conduct the non-interventional study in accordance with the current protocol. 
 
 
 
Treating Physician’s Name (print) 
 
 
 
 
 
Treating Physician’s Signature 
 
Date 
 
Please return a copy of this form to the CRA of this trial. Please retain the signed original 
for your study files. 
 
 

 
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1. 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADCC 
Antibody Dependent Cellular Cytotoxicity 
ADCP 
Antibody Dependent Cellular Phagocytosis 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AIFA 
Agenzia Italiana del Farmaco 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutical Classification  
BM 
Bone Marrow 
CDC 
Complement Dependent Cytotoxicity 
CHOP 
Cyclophosphamide, Doxorubicin, Vincristine, Prednisone 
CI 
Confidence Interval 
CLL 
Chronic Lymphocytic Leukemia 
CR 
Complete Response 
CR30 
Complete Response at 30 months 
CRO 
Contract Research Organization 
CRu 
Complete Response unconfirmed 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVP 
Cyclophosphamide, Vincristine, Prednisone 
DoR 
Duration of Response 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Oncology Cooperative Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EMA 
European Medicine Agency 
ePRO 
Electronic Patient-reported Outcome 
EQ-5D-5L 
EuroQol 5-Dimension Questionnaire, 5-level version 
EU 
European Union 
FACT-G 
Functional Assessment of Cancer Therapy - General 
FACT-Lym 
Functional Assessment of Chronic illness Therapy-
Lymphoma 
FDG 
18F-fluorodeoxyglucose 
FL 
Follicular Lymphoma 
FLIPI 
Follicular Lymphoma International Prognostic Index 

 
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Abbreviation 
Definition 
GPP 
Good Pharmacoepidemiological Practices 
HCP 
Healthcare Professional 
HIV 
Human Immunodeficiency Virus 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
IRR 
Infusion-related Reaction 
ISPE 
International Society of Pharmacoepidemiology 
IWRS 
Interactive Web Response System 
LDH 
Lactate Dehydrogenase 
MAH 
Marketing Authorization Holder 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
NHL 
Non-Hodgkin Lymphoma 
NK 
Natural Killer 
ORR 
Overall response Rate 
OS 
Overall Survival 
PET 
Positron Emission Tomography 
PFS 
Progression-free Survival 
PR 
Partial Response 
POD24 
Progression of disease at 2 years 
PRO 
Patient-reported Outcome 
PS 
Performance Status 
PT 
Preferred Term 
QoL 
Quality of Life 
RBC 
Red Blood Cells 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
The Statistical Analysis System software 
SD 
Stable Disease 
SDV 
Source Data Verification 
SmPC 
Summary of Product Characteristics 
SOC 
System Organ Class 
STD 
Standard Deviation 
TEAE 
Treatment-Emergent Adverse Event 
TTLCB 
Time from first dose to Loss of Clinical Benefit 
TTNT 
Time-To-Next Treatment 

 
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Abbreviation 
Definition 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cells 
WHO-DRL 
World Health Organization-Drug Reference List 
 
 
 
 

 
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2. 
SYNOPSIS 
TITLE: 
A NON-INTERVENTIONAL, RETROSPECTIVE AND 
PROSPECTIVE, MULTICENTER, SINGLE ARM STUDY 
EVALUATING THE EFFECTIVENESS AND SAFETY OF 
OBINUTUZUMAB IN PATIENTS WITH PREVIOUSLY 
UNTREATED ADVANCED FOLLICULAR LYMPHOMA 
Short title: Untreated FolliculaR Lymphoma treated with 
PROTOCOL NUMBER: 
ML41215 
VERSION NUMBER: 
1 
DATE OF SYNOPSIS: 
29 Oct 2020 
STUDIED MEDICINAL 
PRODUCT  
Obinutuzumab 
 
MAIN AUTHOR: 
SPARC Consulting Srl  
Via Archimede 94 
20129 Milan, Italy 
INDICATION: 
Untreated advanced follicular lymphoma  
SPONSOR 
Roche S.p.A 
Viale G.B. Stucchi 110 
20900 Monza (MB) – Italy 
 
Research Question and Objectives 
This study will evaluate the effectiveness and safety of Obinutuzumab in patients with 
previously untreated advanced follicular lymphoma (FL) treated with Obinutuzumab in 
routine clinical care as measured by the proportion of patients relapsed within 24 
months from start of therapy (POD24). 
Effectiveness Objectives 
The primary effectiveness objective for this study is as follows: 
 
To evaluate the effectiveness of Obinutuzumab in combination with chemotherapy 
in previously untreated advanced follicular lymphoma (FL) patients, in the real world 
setting as measured by the proportion of patients relapsed within 24 months from 
start of therapy (POD24);     
The secondary effectiveness objectives for this study are as follows: 
 To evaluate the progression free survival (PFS) at 2 and 3 years; 
 To evaluate the overall and complete response rates at mid and end of induction, 
and during and after maintenance therapy (including the complete response rate at 
30 months [CR30]), as per clinical practice, with and without 18F-
fluorodeoxyglucose−positron emission tomography (FDG-PET); 
 To describe patient/disease characteristics and the second line regimens prescribed 
for patients who progressed after first line therapy during the overall study duration 
and within 24 months from start of therapy (POD24); 

 
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 To explore the effectiveness of Obinutuzumab in different patient subgroups, 
stratified by follicular lymphoma International Prognostic Index (FLIPI) – intermediate 
and high, ECOG performance status (PS), age at study entry, chemotherapy 
backbone choice, hepatitis infection (history of past/resolved infection or latent HBV 
after prophylaxis as per standard treatment guidelines), presence of autoimmune 
disease, history of renal failure and liver failure. 
Safety Objective 
The safety objective for this study is as follows: 
 To evaluate the safety of Obinutuzumab in a real-world setting.  
Other Objectives 
 To describe the treatment pattern in first and second line of treatment; 
 To evaluate methods applied to tumor and response evaluations according to used 
guidelines and clinical practice;  
 To evaluate the FDG-PET response at end of induction and end of maintenance, as 
per clinical practice;  
 To evaluate the Quality of life;  
 To evaluate the presence of B symptoms;  
 To explore effectiveness of Obinutuzumab in real world setting 
 To explore prescription profile 
 To explore COVID-19 impact on therapy adherence 
Study Design 
This is a retrospective and prospective primary data collection and secondary data use, 
non-interventional, multi-centre study designed to assess real-world effectiveness and 
safety of Obinutuzumab in previously untreated advanced FL patients, prescribed in 
first line with Obinutuzumab and chemotherapy, according to existing label.  
The study will be conducted in approximately 50 Italian centres distributed all across 
the country and will collect data during treatment with Obinutuzumab and up to 3.5 
years following the start of the treatment. Enrolment will be competitive across sites. 
Since the study is observational, the treating physician will make all treatment decisions 
according to his/her regular practice independent of this study. No treatment regimen is 
mandated by this protocol. Patients should be included after the start of treatment, 
including newly diagnosed FL patients. Patients included should have performed at 
least 2 cycles of induction treatment with Obinutuzumab and chemotherapy within 1 
year from beginning of treatment.  
During the treatment with Obinutuzumab, patient data will be collected at the clinical 
visits planned by the treating physician, including retrospective data of cycles 
performed before enrolment, baseline data and medical history. The collection of 
retrospective data will be those generated from the start of treatment with 
Obinutuzumab to study entry. 
After cessation of Obinutuzumab treatment, patient data will be collected approximately 
every 3-6 months, as part of routine clinical practice visits, or remote contact, until lost 
to follow-up, withdrawal of consent or death, for up to 3.5 years following start of 
Obinutuzumab treatment. Follow-up data will include at least tumor assessments, new 
anti-lymphoma therapy informations, and safety data.  
For each patient, the study will consist of a period of 42 months which can include: an 
induction treatment period (approximately 6 months) followed by a maintenance 
treatment period (approximately 24 months) and a follow-up period of one year, after 
the last Obinutuzumab administration. Patients will be followed for 3.5 years after the 
first treatment administration regardless of early discontinuation of treatment for any 
reason in any time point. Patients who discontinue treatment for reasons other than 
disease progression (e.g., toxicity, AE) will continue to have their data collected for 
tumor assessments performed as per clinical practice, until disease progression, 

 
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withdrawal of consent, study termination by the Sponsor, or death, whichever occurs 
first, regardless of whether patients start a new anti-cancer therapy. 
 
 
Start Date of Study:  
The study start date will be the date of the first data collection: the date from which 
information on the first study patient is recorded in the study database. The planned 
start date is July 2019. 
End of Study  
The end of the study will be the date from which the last information of the last patient 
still in the study is recorded in the study database. The planned end date is December 
2024. 
Length of Study  
This study will last approximately 5 years. 
Target Population 
Patients must meet the following criteria for study entry: 
1. Signed Informed consent according to local regulations, after performing at least 2 
cycles of induction treatment with Obinutuzumab and chemotherapy, within 1 year 
from beginning of treatment; 
2. Age ≥ 18 years.  
Patients who meet any of the following criteria will be excluded from study entry: 
1. Any contraindications to Obinutuzumab therapy according to local label for specific 
indication;  
2. Concomitant participation in an interventional clinical study; 
3. Patients not receiving treatment for untreated follicular lymphoma with 
Obinutuzumab according to standard of care and in line with the current summary of 
product characteristics (SmPC)/local labeling. 
Studied Medicinal Product  
The studied medicinal product is Obinutuzumab, an anti CD20, type II, monoclonal 
antibody that will be administered via intravenous (IV) infusion according to the SmPC 
(see Synopsis Table 1), in association with a chemotherapy regimen, during induction, 
and alone during maintenance treatment:  
Synopsis Table 1. Follicular lymphoma: Obinutuzumab dose to be administered 
during induction and maintenance treatments (according to SmPc)  
Cycle 
Treatment day 
Dose of Obinutuzumab 
Cycle 1 
 
Day 1 
1000 mg 
Day 8 
1000 mg 
Day 15 
1000 mg 
Cycles 2–6 or 2-8 
Day 1 
1000 mg 
Maintenance 
Every 2 months for 2 years or 
until disease progression (what 
occurs earlier) 
1000 mg 

 
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Obinutuzumab will not be provided by the Marketing Authorization Holder 
(MAH)/sponsor for the study as this could influence the intended real-world use, and 
should instead follow local prescribing regulations and sourcing.  
 
Variables 
Only variables, obtained according to routine clinical practice and follow objectives can 
and should be documented in this study. 
Primary Effectiveness Variable 
 Progression of disease at 2 years (POD24), defined as the time from the date of 
treatment initiation with Obinutuzumab until the first documented progression of 
disease or death due to disease progression, whichever occurs first, within 24 months 
from the start of treatment with Obinutuzumab. Patients who have no disease 
progression and have not died due to disease progression or who are lost to follow-up 
at the time of analysis will be censored at the date of last tumor assessment where no 
progression was documented or the last date of follow-up for disease, whichever is 
last. Patients without post-baseline tumor assessments will be censored at the time of 
their baseline visit unless death due to disease progression occurs prior to their first 
scheduled tumor assessment. Patients who die for reasons not related to the disease 
progression within 24 months from the treatment start with Obinutuzumab will be 
excluded from the statistical analysis of the endpoint. 
Moreover, the POD24 will be also analyzed as binary variable. Number and 
percentage of patients with its 95% confidence interval for POD24 will be calculated. 
Secondary Effectiveness Variables  
 Progression free survival (PFS) at 2 and 3 years, defined as the time from the date 
of treatment initiation until the first documented progression of disease measured by 
routine clinical care or death from any cause, whichever occurs first. Patients who 
have no disease progression and have not died or who are lost to follow-up at the 
time of analysis will be censored at the date of last tumor assessment where no 
progression was documented or the last date of follow-up for disease, whichever is 
last. Patients without post-baseline tumor assessments will be censored at the time 
of their baseline visit unless death occurs prior to their first scheduled tumor 
assessment; 
 Time to next treatment (TTNT), defined as the Time to initiation of subsequent 
systemic anti-cancer therapy following initiation of Obinutuzumab containing therapy. 
Patients not starting a subsequent systemic anti-cancer therapy will be censored at 
the date of the last study visit;  
 Overall survival (OS), defined as the time from initiation of study treatment to death 
from any cause. Patients who still alive at the time of analysis and patients who are 
lost to follow-up will be censored at their last time known to be alive;  
 Correlation between POD24 and OS; 
 TTLCB, defined as the time from first dose to loss of clinical benefit as assessed by 
the treating physician (single or multiple reasons possible: e.g. disease progression, 
deterioration in ECOG PS, death, other). Patients who do not loss clinical benefit will 
be censored at the date of the last study visit. Patients without post-baseline tumor 
assessments will be censored at the time of their baseline visit unless death occurs 
prior to their first scheduled tumor assessment; 
 Overall response rate (ORR); 
 Complete response (CR); 
 Complete response at 30 months (CR30); 

 
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 Duration of response (DoR) measured per clinical practice, defined as the time from 
first documentation of CR or partial response (PR) (whichever occurs first) until 
disease progression, as evaluated by the physician according to routine clinical 
practice or death. Patients who have no disease progression and have not died or 
who are lost to follow-up at the time of analysis will be censored at the date of last 
tumor assessment where no progression was documented or the last date of follow-
up for disease, whichever is last; 
 Time to response, defined as the time from first dose of Obinutuzumab to first 
documented response as assessed in clinical routine. Patients without response at 
the time of analysis and patients who are lost to follow-up will be censored at the 
date of their last tumour assessment. Patients without post-baseline tumor 
assessments will be censored at the time of their baseline visit unless death occurs 
prior to their first scheduled tumor assessment;  
 Rate of patients with stable disease (SD); 
 Effectiveness of Obinutuzumab in different patient subgroups, stratified by FLIPI 
(intermediate/high), ECOG-PS, age at study entry, hepatitis infection (history of 
past/resolved infection or latent HBV after prophylaxis as per standard treatment 
guidelines), chemotherapy backbone, presence of autoimmune disease, history of 
renal failure and liver failure; 
 FDG-PET response at end of induction and end of maintenance, as per clinical 
practice. When PET is not performed, the alternative routine tumor assessment 
method will be collected.  
Safety Variables 
 Incidence, nature, seriousness, severity and relatedness of all adverse events (AEs) 
and serious adverse events (SAEs); 
 Infusion related reactions (IRRs) management at each center as per clinical practice; 
 Clinical laboratory abnormalities;  
 Adverse events of special interest (AESI); 
 Vital signs. 
Other Variables of Interest  
 Patient/disease characteristics: age, sex, ECOG PS, Ann Arbor staging, FLIPI 
(intermediate/high), medical history and history of FL, comorbidities, physical 
examination and vital signs; 
 Treatment pattern: 
- Time from diagnosis to start of treatment with Obinutuzumab; 
- Duration of treatment with Obinutuzumab;  
- Dose modifications;  
- Treatment discontinuation; 
- Prophylaxis medications; 
- Type of chemotherapy chosen in association with Obinutuzumab; 
- Second line regimens prescribed for patients who progressed within two years 
after starting  first line therapy; 
- Time to initiation of subsequent systemic anti-lymphoma therapy following 
initiation of Obinutuzumab containing therapy; 
- Adherence to treatments. 
 Quality of life: EuroQol 5-Dimension Questionnaire, 5-level version (EQ-5D-5L); 
Functional Assessment of Chronic illness Therapy-Lymphoma (FACT-Lym); 
 Presence of B symptoms; 

 
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 Concomitant medication prescribed or in current use from the start of therapy with 
Obinutuzumab until discontinuation of the treatment. 
 effectiveness of Obinutuzumab in real world setting; 
 prescription profile 
 COVID-19 impact on therapy adherence 
Data Sources 
Patients’ data will be recorded on eCRFs. The degree of detail and completeness of 
data collected is dependent on local clinical practice. Data from patient notes should be 
entered on the eCRF as soon as they become available. Data entered in the eCRF will 
not act as source documents.  
Data will be collected from patient’s records as kept by their attending physicians during 
daily clinical practice. 
As when entering in the  initial treatment/pre-treatment data are collected 
retrospectively, missing data might occur in the retrospective period as well the 
distribution of missing data might be different across the participating investigational 
sites. 
Data Analysis 
A detailed description of the statistical methods that will be used for the primary and 
secondary analyses will be provided in the Statistical Analysis Plan (SAP).  
Effectiveness analysis population includes all patients who are enrolled and have 
received at least two cycles of Obinutuzumab. Safety analysis population includes all 
patients who are enrolled. 
Data will be summarized using appropriate descriptive statistics. Categorical data will 
be presented as frequencies and percentages. For continuous data, arithmetic mean, 
standard deviation (STD), median, minimum, and maximum will be presented. 
Time-to-event outcomes (POD24, PFS at 2 and 3 years, TTNT, OS, TTLCB, duration of 
response, and time to response) will be analyzed according to the survival analysis 
methods. The quartiles with their 95% confidence interval (CI) (estimated using Kaplan-
Meier methods and Greenwood’s formula) will be presented. Kaplan-Meier plots with a 
95% CI will be prepared. Estimates for the survivor functions for all time to event 
endpoints will be obtained by the Kaplan-Meier approach. 
POD24 will be also analyzed as binary variable. Therefore, number and percentage of 
patients with its 95% confidence interval for POD24 will be calculated. 
Response rates (ORR, CR, CR30 and rate of patients with stable disease) will be 
presented with the number and proportions of responders and non-responders together 
with two-sided, 95% Clopper-Pearson CIs. 
Adverse events are those with start date beyond or equal to the date of first 
administration of Obinutuzumab and until 185 days after the last Obinutuzumab dose 
intake or until starting a new anti-cancer therapy (whichever occurs first). After this 
period AEs that are believed to be related to prior study drug treatment will be collected. 
The incidence of AEs and SAEs will be summarized according to the primary system-
organ class (SOC) and within each SOC, by the Medical Dictionary for Regulatory 
Activities (MedDRA) Preferred Term. 
Summary statistical tables including frequency counts and percentages and the number 
of adverse events will be produced. The 95% confidence interval of the observed 
proportions (calculated using either the Clopper-Pearson methodology, or the Poisson 
distribution, for frequencies below 10%) will be provided. 
An interim analysis will be performed approximately one year after the first patient is 
included in the study in order to evaluate safety data, demographic data, FLIPI and 
treatment choices. 

 
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A second interim analysis will be performed approximately two years after the first 
patient included in the study in order to evaluate safety and primary and secondary 
effectiveness data, and the impact of COVID-19 on the patient management.  
The results of the first two interim analysis will be compared.  
The final Analysis will be performed at the end of the study. 
 
Study Size/Determination of Sample Size 
Sample size of this clinical study is selected based on feasibility. 
Sample size is justified for the primary effectiveness endpoint POD24 treated as binary 
variable. 
A sample size of 300 evaluable patients will allow estimation of the two-sided 95% 
confidence interval with a width equal to 7.9% (precision 3.95%) of the POD24 when 
the expected percentage is equal to 13%. 
The Clopper-Pearson’s formula has been used for the computation. 
Synopsys Table 2 provides the actual width and the precision of the 95% CI, and the 
95% confidence limits for different percentages of POD24 when the sample size is 
equal to 300 evaluable patients. 
Synopsis Table 2 - POD24 rate and corresponding 95% Confidence Intervals 
 
POD24 
(%) 
Actual Width  
(%) 
Precision  
(%) 
95% Clopper-Pearson 
Exact CI (%) 
11% 
7.4 
3.70 
From 7.7 to 15.1 
13% 
7.9 
3.95 
From 9.4 to 17.3  
15% 
8.4 
4.20 
From 11.2 to 19.6 
17% 
8.8 
4.40 
From 12.9 to 21.7 
 
Moreover, a sample size of 300 evaluable patients will allow estimation of the two-sided 
95% confidence interval with a width equal to 9.4% (precision 4.70%) of the PFS rate at 
3 years (treated as binary variable) when the expected percentage is equal to 80%. 
Synopsis Table 3 provides the actual width and the precision of the 95% CI and the 
95% confidence limits for different percentages of PFS at 3 years when the sample size 
is equal to 300 of evaluable patients. 
 
Synopsis Table 3 - PFS rate at 3 yrs. and corresponding 95% Confidence Intervals  
 
PFS 
(%) 
Actual Width  
(%) 
Precision  
(%) 
95% Clopper-Pearson 
Exact CI (%) 
70% 
10.7 
5.35 
From 64.5 to 75.1 
75% 
10.1 
5.05 
From 69.7 to 79.8 
80% 
9.4 
4.70 
From 75.0 to 84.4 
85% 
8.4 
4.20 
From 80.4 to 88.8 
90% 
7.1 
3.55 
From 86.0 to 93.2 
Notes:  
From Gallium trial, PFS at 2 years has been estimated equal to 90% while PFS rate at 3 years to 80%. 
 
 
 

 
 
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3. 
PROTOCOL AMENDMENTS AND UPDATES 
Any protocol amendments will be prepared by the Marketing Authorization Holder or 
designee.   
Protocol amendments will be submitted to the Institutional Review Board (IRB)/Ethics 
Committee (EC) and to regulatory authorities in accordance with local regulatory 
requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes that involve 
logistical or administrative aspects only (e.g., change in Site Operations Representative 
or contact information). 
Substantial protocol amendments/updates so far: Tracked in the section “Summary of 
changes” of the Protocol none. 

 
 
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4. 
RATIONALE AND BACKGROUND 
Background on Follicular Lymphoma 
Non-Hodgkin’s lymphomas (NHL) are a heterogeneous group of lymphoproliferative 
tumours with varying behaviour and treatment-response patterns (Armitage 1993).  
NHL is the most common hematologic malignancy in adults. In 2008, over 66,000 new 
cases were reported in the United States, with more than 19,000 deaths. 
In Italy, it has been estimated that one in every 44 males and one in every 62 females 
will develop NHL, and that one in every 106 and one in every 152, respectively for the 
two sexes, will die of the disease (AIRTUM Working Group. 2009). 
The majority of NHLs (also known as malignant lymphoma) are of B-cell origin and are 
characterized by the expression of a membrane antigen, CD20, which is important in cell 
cycle initiation and differentiation (Anderson et al. 1984). NHL can be divided into 
aggressive and indolent NHL. Indolent NHLs are a heterogeneous group of malignant 
lymphomas and account for about one-third of all NHLs. 
Follicular lymphoma (FL) is the second most common lymphoma and is the most 
common subtype of indolent B-cell lymphomas diagnosed in the United States and 
Western Europe, accounting for approximately 35% of all NHLs, and 70% of indolent 
lymphomas (Swerdlow et al. 2008). The median age of diagnosis is at 65 years and the 
incidence is slightly increased among relatives of persons with FL (Goldin et al. 2009). 
FL associated with follicle centre B cells that typically contain the BCL2 chromosome 
trans location t(14:18), leading to overexpression of the intracellular anti-apoptotic 
protein Bcl-2. 
Patients with FL are usually at diagnoses at an advances state of the disease. They 
generally present with asymptomatic lymphadenopathy, with waxing and waning present 
for years. Bone marrow involvement is present in 70% of patients, whereas involvement 
of other normal organs is uncommon. Less than 20% of patients present with B 
symptoms and also less than 20% of patients present with an increased serum lactate 
dehydrogenase (LDH) (Freedman 2015). 
The clinical course of indolent NHL is characterized by remission and relapse (Gallagher 
et al. 1986). The disease initially responds to radiation and/or immunochemotherapy with 
conventional agents, but patients eventually suffer multiple relapses distinguished by 
increasing refractoriness and decreasing duration of response in subsequent lines of 
therapy. Patients with advance-stage disease are not usually cured with conventional 
treatment and ultimately die from recurrent disease or treatment-related toxicity. 
Patients who are diagnosed without symptoms can be observed without treatment (so-
called watchful waiting) for several years. However, treatment is required when the 
patient presents with symptoms at diagnosis or develops symptoms during observation 
(Izutsu 2014). 

 
 
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Treatment modalities for FL include chemotherapy, radiotherapy and immunotherapy 
against CD20, and stem cell transplantation, but a standard treatment approach for FL 
has not been established. 
For FL patients requiring treatment, immunochemotherapy with rituximab, a monoclonal 
antibody directed against CD20, plus chemotherapy has demonstrated improvements in 
response rates, progression-free survival (PFS), and overall survival compared with 
chemotherapy alone (Hiddemann et al. 2005; Herold et al. 2007; Marcus et al. 2008; 
Salles et al. 2008). Rituximab in combination with chemotherapy (e.g., CHOP 
[cyclophosphamide, doxorubicin, vincristine, and prednisone], CVP [cyclophosphamide, 
vincristine, and prednisone], or purine analogue–based schemes such as those with 
fludarabine or bendamustine) for newly diagnosed patients with advanced Stage III and 
IV disease requiring treatment is strongly supported by International Guidelines (Dreyling 
2009; Zelenetz et al. 2010). 
In addition to immunochemotherapy induction, randomized clinical trials have also 
demonstrated the benefit of maintenance rituximab in responding patients in both 
previously untreated and relapsed FL (van Oers et al. 2006; van Oers et al. 2010; Salles 
et al, 2011). 
Currently, the first-line treatment for FL is rituximab in combination with chemotherapy, 
followed by maintenance therapy with rituximab every two months for two years, as 
demonstrated by results of the PRIMA study (Salles et al, 2011). This regimen had 
determined a satisfactory result in most of treated patients, with a 10-year progression-
free survival of 51%. 
Despite these encouraging results, therapy for FL is not curative and presents with a 
chronic course (i.e. remitting-relapsing), with progressively shorter remissions and with 
increased risk of developing a transformation of the disease, i.e. the transition from an 
indolent malignant lymphoma to a more aggressive type of lymphoma. Patients who 
have an early disease progression (within 24 months) will have a more aggressive 
course and a shorter survival, and will be treated with more therapeutic lines, than those 
patients without an early progression. The majority of patients will ultimately die from 
progressive disease. Therefore, the introduction of new agents that may potentially alter 
the natural history of the disease is of great interest. 
Background on Obinutuzumab 
Obinutuzumab is a recombinant monoclonal humanised and glycoengineered Type II 
anti-CD20 antibody of the IgG1 isotype. It specifically targets the extracellular loop of the 
CD20 transmembrane antigen on the surface of non-malignant and malignant pre-B and 
mature B-lymphocytes, but not on haematopoietic stem cells, pro-B-cells, normal plasma 
cells or other normal tissue. Glycoengineering of the Fc part of Obinutuzumab results in 
higher affinity for FcɣRIII receptors on immune effector cells such as natural killer (NK) 
cells, macrophages and monocytes as compared to non-glycoengineered antibodies.  

 
 
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In nonclinical studies, Obinutuzumab induces direct cell death and mediates antibody 
dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis 
(ADCP) through recruitment of FcɣRIII positive immune effector cells. In addition, in vivo, 
Obinutuzumab mediates a low degree of complement dependent cytotoxicity (CDC). 
Compared to Type I antibodies, Obinutuzumab, a Type II antibody, is characterised by 
an enhanced direct cell death induction with a concomitant reduction in CDC at an 
equivalent dose. Obinutuzumab, as a glycoengineered antibody, is characterised by 
enhanced ADCC compared to non-glycoengineered antibodies at an equivalent dose. In 
animal models Obinutuzumab mediates potent B-cell depletion and antitumour efficacy. 
Furthermore, treatment with Obinutuzumab was able to control tumour growth when 
vehicle- and rituximab-treated tumours were not controlled (Mössner et al. 2010). 
Obinutuzumab has been evaluated in a wide-ranging program of clinical trials in patients 
with B-cell malignancies. Efficacy as monotherapy has been reported in patients with 
relapsed/refractory indolent and aggressive NHL (Salles et al. 2012; Salles et al. 2013) 
and in chronic lymphocytic leukemia (CLL) of B-cell origin (Cartron et al. 2014). 
Improved outcomes have also been noted when Obinutuzumab has been added to 
chemotherapy in patients with B-cell NHL (Radford et al. 2013). 
The Phase III GADOLIN trial tested the clinical efficacy of Obinutuzumab plus 
bendamustine followed by Obinutuzumab monotherapy in rituximab-refractory indolent 
NHL versus treatment with bendamustine alone. After a median follow-up time of 21.9 
months in the Obinutuzumab plus bendamustine group and 20.3 months in the 
bendamustine monotherapy group, PFS was significantly longer with Obinutuzumab plus 
bendamustine (median not reached [95% CI 22.5 months-not estimable]) than with 
bendamustine monotherapy (14.9 months [12.8-16.6]; hazard ratio (HR) 0.55 [95% CI 
0·40-0·74]; p=0·0001) (Sehn et al. 2016).  
A phase III study (the GALLIUM trial) compared the efficacy and safety of induction with 
Obinutuzumab, as compared with rituximab, each combined with chemotherapy, 
followed by maintenance therapy with the same monoclonal antibody, in patients with 
previously untreated indolent NHL (follicular lymphoma or marginal-zone lymphoma) 
(Marcus et al. 2017). A total of 601 patients in each group were randomised. After a 
median follow-up of 34.5 months, Obinutuzumab-based chemotherapy resulted in a 
significantly lower risk of progression, relapse, or death than rituximab-based 
chemotherapy (estimated 3-year rate of PFS, 80.0% vs. 73.3%; HR for progression, 
relapse, or death, 0.66; 95% CI, 0.51 to 0.85; p = 0.001). Response rates were similar in 
the two groups (88.5% in the Obinutuzumab group and 86.9% in the rituximab group). At 
a median follow-up of 41 months (Hiddeman et al. 2017), PFS was superior for 
Obinutuzumab plus chemotherapy over rituximab-based chemotherapy (overall HR, 0.68; 
95% CI, 0.54 to 0.87; p = 0.0016). At this follow-up, the median PFS has not yet been 
reached, and it is not expected to be reached based on statistical hypotheses. Therefore, 
it is expected that the GALLIUM study will improve the median PFS observed in the 
PRIMA study, in which patients received the same treatment scheme of that used in the 
control arm of the GALLIUM study (i.e. rituximab + chemotherapy followed by 

 
 
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maintenance therapy with rituximab). Furthermore, the evidence from the GALLIUM 
study has shown that patients with advanced FL (high or intermediate FLIPI score) 
treated with Obinutuzumab-based chemotherapy for 2 years have a reduction of 32% of 
risk of disease progression (Marcus et al. 2017). A further analysis (Seymour et al, 2018) 
of the progression of disease at 2 years (POD24) and its impact on overall survival (OS) 
has shown that treatment with Obinutuzumab plus chemotherapy was associated with a 
marked reduction of POD24 compared to rituximab-based chemotherapy and that 
POD24 was associated with poor prognosis, with mortality risk higher after earlier 
progression. 
Overall, Obinutuzumab has an acceptable safety profile as emerged from clinical trials. 
The major safety events were infusion-related reactions (IRRs) and hematologic adverse 
events (AEs), primarily neutropenia and infections. IRRs were the most common AEs 
throughout all clinical trials (Edelmann et al. 2016). They comprised of various symptoms 
such as hypotension or hypertension, tachycardia, dyspnea, pyrexia, chills, nausea, 
vomiting, diarrhea, flushing and headache coinciding with drug infusion. However, IRRs 
mainly occurred during the first infusion and almost always resolved with slowing or 
interrupting the infusion and/or upon steroid administration. Incidences of IRRs in clinical 
trials range between 64 and 86%, the majority of reactions being described as grades 1 
and 2. A relation between Obinutuzumab dose and intensity of the IRR was not 
observed. In the GALLIUM study (Marcus et al. 2017), adverse events of grade 3 to 5 
were more frequent in the Obinutuzumab group than in the rituximab group (74.6% vs. 
67.8%), as were serious adverse events (46.1% vs. 39.9%). The rates of adverse events 
resulting in death were similar in the two groups. The most common adverse events 
were infusion-related events that were considered by the investigators to be largely due 
to Obinutuzumab in 59.3% of patients and to rituximab in 48.9 % of patients. 
Obinutuzumab (Gazyvaro®), in combination with chlorambucil, is indicated for the 
treatment of adult patients with previously untreated CLL and with comorbidities making 
them unsuitable for full-dose fludarabine based therapy. From October 2017, 
Obinutuzumab is also indicated, in combination with bendamustine followed by 
Obinutuzumab monotherapy, for the treatment of patients with FL who relapsed after, or 
are refractory to, a rituximab-containing regimen. Obinutuzumab has also received the 
approval from the European Medicines Agency (EMA) for use in combination with 
chemotherapy, followed by Obinutuzumab maintenance therapy in patients with 
previously untreated advanced follicular lymphoma. 
4.1 
STUDY RATIONALE  
This observational study has been planned to evaluate the effectiveness of 
Obinutuzumab in combination with chemotherapy in previously untreated advanced FL 
patients, in the real world setting in Italy. 
The study will allow to collect real-life data in a significant number of Italian patients 
when compared to participants in pivotal studies of Gazyvaro and thus will allow to verify 

 
 
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in routine practice (after physician hands-on) the effectiveness and safety management 
in 50 reference sites all over the country.  
The stratification factors selected to this study are different from those presented in 
pivotal trials as the label allows to treat patients in a wider setting than the clinical trials 
eligibility criteria. This stratification will also allow to understand the profile of patients 
that are treated with Obinutuzumab in Italy.  
As described above, Obinutuzumab has granted approval for use in combination with 
chemotherapy, followed by Obinutuzumab maintenance therapy in patients with 
previously untreated advanced FL. Thus, the study will include patients with untreated 
advanced FL for which the physician has decided to use Obinutuzumab according to the 
approved SmPC. These patients will be treated according to the approved scheme, i.e. 
Obinutuzumab will be administered according to the approved SmPC in association with 
a chemotherapy regimen during induction, and alone during maintenance treatment.   
Patients enrolled in this study may benefit from treatment with Obinutuzumab. However, 
the assignment of the patients to any therapeutic strategy and thus also to treatment 
with Obinutuzumab is not decided in advance based the study protocol and is clearly 
separated from the possibility or decision to include the patients in the study. Therefore, 
the treating physician will make all treatment decisions according to his/her regular 
practice independent of this study. During the study, patient will undergo clinical visits as 
planned by the treating physician, according to standard clinical practice.  
Although Obinutuzumab has resulted to be generally well tolerated, IRRs have been 
reported with the use of the product, however occurring predominantly during infusion of 
the first 1,000 mg. These events will be closely monitored during the study and 
appropriate measures for prevention of IRRs (adequate glucocorticoid, oral 
analgesic/anti-histamine, omission of antihypertensive medicine in the morning of the 
first infusion, and the Cycle 1 Day 1 dose administered over 2 days) will be used in the 
study to reduce the incidence of IRRs, as scheduled in the current SmPC of the product. 
All AEs will be duly monitored in the study and appropriate measures (including the 
discontinuation of treatment with Obinutuzumab) will be implemented for the protection 
of patients’ healthcare.  
Therefore, treatment with Obinotuzumab offers the potential for clinical benefit in 
patients with untreated advanced FL for which the treating physician has decided to start 
treatment with Obinotuzumab.  
Patients will be fully informed of the potential risks in taking part in this study, and 
investigators will make a careful assessment of the potential benefits and risks of 
Obinutuzumab, by monitoring the clinical status of the patient and the potential 
occurrence of AEs events and toxicities. 
Therefore, the current evidence on the efficacy and safety of Obinutuzumab 
administered according to the therapeutic indication for the drug in patients with 

 
 
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untreated advanced FL suggest that the benefits that can be achieved from the 
participation in this observational study will outweigh the potential risks.   
This trial will be conducted in compliance with the Declaration of Helsinki (1964 and 
amendments) current with the Good Pharmacoepidemiology Practice (GPP) published 
by the International Society of Pharmacoepidemiology (ISPE) and all other applicable 
laws and regulations. 
For information on the condition under observation and on the Obinutuzumab please 
refer to the Investigator's Brochure and to the most recent version of the Summary of 
Product Characteristics (SmPC) of Gazyvaro®, i.e. the brand name of Obinutuzumab, for 
further details on nonclinical and clinical studies. 
5. 
RESEARCH QUESTION AND OBJECTIVES 
5.1 
RESEARCH QUESTION  
This study will evaluate the effectiveness and safety of Obinutuzumab in patients with 
previously untreated advanced follicular lymphoma (FL) treated with Obinutuzumab in 
routine clinical care.   
5.2 
OBJECTIVES 
5.2.1 
Effectiveness Objectives 
The primary effectiveness objective of this study is as follows: 
 
To evaluate the effectiveness of Obinutuzumab in combination with chemotherapy in 
previously untreated advanced follicular lymphoma (FL) patients, in the real world 
setting as measured by the proportion of patients relapsed within 24 months from 
start of therapy (POD24). 
The secondary effectiveness objectives of this study are as follows: 
 
To evaluate the progression free survival (PFS) at 2 and 3 years; 
 
To evaluate the overall and complete response rates at mid and end of induction, 
and during and after maintenance therapy (including the complete response rate at 
30 months [CR30]), as per clinical practice, with and without 18F-
fluorodeoxyglucose−positron emission tomography (FDG-PET); 
 
To describe patient/disease characteristics and the second line regimens prescribed 
for patients who progressed after first line therapy during the overall study duration 
and within 24 months from start of therapy (POD24); 
 
To explore the effectiveness of Obinutuzumab in different patient subgroups, 
stratified by follicular lymphoma International Prognostic Index (FLIPI) – intermediate 
and high, ECOG performance status (PS), age at study entry, chemotherapy 
backbone choice, hepatitis infection (history of past/resolved infection or latent HBV 
after prophylaxis as per standard treatment guidelines), presence of autoimmune 
disease, history of renal failure and liver failure. 
 

 
 
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5.2.2 
Safety Objectives 
The safety objectives of this study are as follows:  
 
To evaluate the safety of Obinutuzumab in a real-world setting.  
 
5.2.3 
Other Objectives  
 
To describe the treatment pattern in first and second line of treatment; 
 
To evaluate methods applied to tumour and response evaluations according to used 
guidelines and clinical practice;  
 
To evaluate the FDG-PET response at end of induction and end of maintenance, as 
per clinical practice;  
 
To evaluate the Quality of life;  
 
To evaluate the presence of B symptoms;  
 
To explore effectiveness of Obinutuzumab in real world setting; 
 
To explore prescription profile 
 
To explore COVID-19 impact on therapy adherence 
 
6. 
RESEARCH METHODS 
6.1 
STUDY DESIGN 
This is a retrospective and prospective primary data collection and secondary data use, 
non-interventional, multi-center study designed to assess real-world effectiveness and 
safety of Obinutuzumab in previously untreated advanced FL patients, prescribed in first 
line with Obinutuzumab and chemotherapy, according to existing label.  
The study will be conducted in approximately 50 Italian centers distributed all across the 
country and will collect data during treatment with Obinutuzumab and up to 3.5 years 
following the start of the treatment. Since the study is observational, the treating 
physician will make all treatment decisions according to his/her regular practice 
independent of this study. No treatment regimen is mandated by this protocol.  
Patients should be included after the start of treatment, including newly diagnosed FL 
patients. Patients included should have performed at least 2 cycles of induction 
treatment with Obinutuzumab and chemotherapy within 1 year from beginning of 
treatment. 
During the treatment with Obinutuzumab, patient data will be collected at the clinical 
visits planned by the treating physician, including retrospective data of cycles performed 
before enrolment, baseline data and medical history, as detailed in Section 6.4.21. The 
collection of retrospective data will be those generated from the start of treatment with 
Obinotuzumab to study entry. 

 
 
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A data collection overview is provided in Appendix 2. 
6.1.2 
Rationale for Study Design  
This will be an open-label, multicenter, national, non-interventional study. This was 
considered as the most appropriate design to evaluate the efficacy and safety of 
Obinutuzumab, administered during with chemotherapy during the induction phase and 
as monotherapy during the maintenance phase, according to the posology and method 
of administration approved in the current SmPc of Gazyvaro®, in patients with untreated 
advanced FL. 
6.1.3 
Number of Patients Observed in the Study 
Approximately 300 patients will take part in this study. 
6.1.4 
Sites  
This study will be conducted at approximately 50 sites in Italy. 
Additional centers may be added or substituted if underperforming. 
6.2 
POPULATION 
The patient population taking part in the study will comprise patients aged ≥ 18 years 
with untreated advanced FL. 
Patients must meet the following criteria for study entry: 
1. Signed Informed consent according to local regulations, after performing at least 2 
cycles of induction treatment with Obinutuzumab and chemotherapy, within 1 year 
from beginning of treatment; 
2. Age ≥ 18 years;  
Patients who meet any of the following criteria will be excluded from study entry: 
1. Any contraindications to Obinutuzumab therapy according to local label for specific 
indication; 
2. Concomitant participation in an interventional clinical study; 
3. 
Patients not receiving treatment for untreated follicular lymphoma with 
Obinutuzumab according to standard of care and in line with the current summary of 
product characteristics (SmPC)/local labeling  
 
6.2.1 
Rationale for Patient Population 
The patient population taking part in the study will comprise patients aged ≥ 18 years in 
first treatment for advanced FL, in which Obinutuzumab are administered in combination 
with chemotherapy during the induction phase, followed by Obinutuzumab maintenance 
therapy. This indication and treatment scheme is that approved by the EMA as per EU 
countries agency and AIFA as per Italian local agency. 

 
 
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6.2.2 
Recruitment Procedure  
No specific procedures for recruitment (e.g. advertisements, published information or 
other) were used for the study. 
The Principal Investigator or a co-investigator in each investigational site will verify the 
eligibility of each patient for the participation in the study based on adherence to 
inclusion/exclusion criteria. Eligible patients who signed the ICF were then included in 
the study. 
6.2.3 
Dosage, Administration, and Compliance 
Dosing and treatment duration of any studied medicinal products collected as parts of 
this non-interventional study are at the discretion of the physician in accordance with 
local clinical practice and local labelling. 
6.2.4 
Concomitant Medication and Treatment  
Concomitant medication prescribed for concomitant diseases and treatment for 
untreated advanced FL at the beginning of the observation period or introduced during 
the observation period will be documented in the eCRF from start of therapy with 
Obinutuzumab until discontinuation of the treatment, if applicable. 
6.3 
VARIABLES 
Only variables, obtained according to routine clinical practice (with exception of quality of 
life questionnaires) and collected according to the study objectives can and should be 
documented in this study. 
6.3.1 
Primary Effectiveness Variable 
Progression of disease at 2 years (POD24), defined as the time from the date of 
treatment initiation with Obinutuzumab until the first documented progression of disease 
or death due to disease progression, whichever occurs first, within 24 months from the 
start of treatment with Obinutuzumab. Patients who have no disease progression and 
have not died due to disease progression or who are lost to follow-up at the time of 
analysis will be censored at the date of last tumor assessment where no progression 
was documented or the last date of follow-up for disease, whichever is last. Patients 
without post-baseline tumor assessments will be censored at the time of their baseline 
visit unless death due to disease progression occurs prior to their first scheduled tumor 
assessment. Patients who die for reasons not related to the disease progression within 
24 months from the treatment start with Obinutuzumab will be excluded from the 
statistical analysis of the endpoint. 
Moreover, the POD24 will be also analyzed as binary variables. Number and percentage 
of patients with its 95% confidence interval for POD24 will be calculated. 
 

 
 
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6.3.2 
Secondary Effectiveness Variable  
 Progression free survival (PFS) at 2 and 3 years, defined as the time from the date of 
treatment initiation until the first documented progression of disease measured by 
routine clinical care or death from any cause, whichever occurs first. Patients who 
have no disease progression and have not died or who are lost to follow-up at the 
time of analysis will be censored at the date of last tumor assessment where no 
progression was documented or the last date of follow-up for disease, whichever is 
last. Patients without post-baseline tumor assessments will be censored at the time of 
their baseline visit unless death occurs prior to their first scheduled tumor assessment; 
 Time to next treatment (TTNT), defined as the Time to initiation of subsequent 
systemic anti-cancer therapy following initiation of Obinutuzumab containing therapy. 
Patients not starting a subsequent systemic anti-cancer therapy will be censored at 
the date of the last study visit;  
 Overall survival (OS), defined as the time from initiation of study treatment to death 
from any cause. Patients who still alive at the time of analysis and patients who are 
lost to follow-up will be censored at their last time known to be alive;  
 Correlation between POD24 and OS; 
 TTLCB, defined as the time from first dose to loss of clinical benefit as assessed by 
the treating physician (single or multiple reasons possible: e.g. disease progression, 
deterioration in ECOG PS, death, other). Patients who do not loss clinical benefit will 
be censored at the date of the last study visit. Patients without post-baseline tumor 
assessments will be censored at the time of their baseline visit unless death occurs 
prior to their first scheduled tumor assessment; 
 Overall response rate (ORR); 
 Complete response (CR); 
 Complete response at 30 months (CR30); 
 Duration of response (DoR) measured per clinical practice, defined as the time from 
first documentation of CR or partial response (PR) (whichever occurs first) until 
disease progression, as evaluated by the physician according to routine clinical 
practice or death. Patients who have no disease progression and have not died or 
who are lost to follow-up at the time of analysis will be censored at the date of last 
tumor assessment where no progression was documented or the last date of follow-
up for disease, whichever is last; 
 Time to response, defined as the time from first dose of Obinutuzumab to first 
documented response as assessed in clinical routine. Patients without response at 
the time of analysis and patients who are lost to follow-up will be censored at the date 
of their last tumour assessment. Patients without post-baseline tumor assessments 
will be censored at the time of their baseline visit unless death occurs prior to their 
first scheduled tumor assessment; 

 
 
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 Rate of patients with stable disease (SD); 
 Effectiveness of Obinutuzumab in different patient subgroups, stratified by FLIPI 
(intermediate/high), ECOG-PS, age at study entry, hepatitis infection (history of 
past/resolved infection or latent HBV after prophylaxis as per standard treatment 
guidelines), chemotherapy backbone choice, presence of autoimmune disease, 
history of renal failure and liver failure; 
 FDG-PET response at end of induction and end of maintenance, as per clinical 
practice. When PET is not performed, the alternative routine tumor assessment 
method will be collected.  
 
6.3.3 
Safety Variables 
 Incidence, nature, seriousness, severity and relatedness of all adverse events (AEs) 
and serious adverse events (SAEs); 
 Infusion related reactions (IRRs) management at each center as per clinical practice; 
 Clinical laboratory abnormalities;  
 Adverse events of special interest (AESI); 
 Vital signs. 
 
6.3.4 
Other Variables of Interest  
 Patient/disease characteristics: age, sex, ECOG PS, Ann Arbor staging, FLIPI 
(intermediate/high), medical history and history of FL, comorbidities, physical 
examination and vital signs; 
 Treatment pattern: 
- 
Time from diagnosis to start of treatment with Obinutuzumab; 
- 
Duration of treatment with Obinutuzumab;  
- 
Dose modifications;  
- 
Treatment discontinuation; 
- 
Prophylaxis medications; 
- 
Type of chemotherapy chosen in association with Obinutuzumab; 
- 
Second line regimens prescribed for patients who progressed within two years 
after starting first line therapy; 
- 
Time to initiation of subsequent systemic anti-lymphoma therapy following 
initiation of Obinutuzumab containing therapy; 
- 
Adherence to treatments 
 Quality of life: EuroQol 5-Dimension Questionnaire, 5-level version (EQ-5D-5L); 
Functional Assessment of Chronic illness Therapy-Lymphoma (FACT-Lym); 

 
 
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 Presence of B symptoms; 
 Concomitant medication prescribed or in current use from the start of therapy with 
Obinutuzumab until discontinuation of the treatment. 
 effectiveness of Obinutuzumab in real word setting; 
 prescription profile 
 COVID-19 impact on therapy adherence 
 
6.4 
DATA SOURCES 
6.4.1 
Collection of Data on the CRF 
Patients’ data will be recorded on eCRFs. The degree of detail and completeness of 
data collected is dependent on local clinical practice. Data from patient notes should be 
entered on the CRF as soon as they become available. Data entered in the eCRF will 
not act as source documents.  
6.4.2 
Data Collected during the Observation Period 
During therapy with Obinutuzumab, laboratory assessments are routinely performed in 
accordance with current guidelines and local standard of care. When performed during 
the observational period, available results that represent an adverse event in according 
to CTCAE vs. 5, relevant symptom/signal of an event or abnormal laboratory finding that 
results in a change of the treatment in study will be documented in the eCRF. Most data 
will be documented during the treatment period when the respective assessments are 
usually performed according to standard of care. The proposed assessments and 
suggested timings for assessments in the protocol/observational plan are not mandatory. 
It is up to the treating physician to perform and document the assessments as performed 
in the real clinical setting. 
In the routine care setting, patients are seen regularly by their treating physicians either 
for treatment or for regular assessment after treatment. Thus, no study-specific visits or 
evaluations are required by this protocol. 
Tumor assessments collected in eCRF will comprise the following periods as available: 
 
Baseline tumor assessment 
 
During induction: 
- 
Mid induction: tumor assessment performed between cycle 2 and cycle 4 after 
the start of treatments 
- 
End induction: tumor assessment performed at the day of cycle 6 /8 ( or when 
induction is early discontinued) until 2 month later 
 
After induction treatment:  
- 
1 year after the start of treatment (from 10 to 14 months after the start of 
treatment) 

 
 
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- 
2 years after the start of treatment (from 22 to 26 months after the start of 
treatment)  
- 
3 years after the start of treatment (from 34 to 40 months after the start of 
treatment) 
- 
1 year after end of maintenance as applicable  
 
Any tumor assessment, and the method used that shows disease progression, CR or 
CRu during induction or maintenance. 
The lack of tumor assessments in those periods are not a protocol deviation as clinical 
practice should be followed. 
Since the enrolment of patients into the study will occur after the treatment has already 
started (Patients included should have performed at least 2 cycles of induction treatment 
with Obinutuzumab but no later than the completion of 1 year of the treatment with 
Obinutuzumab), a retrospective data collection is expected. 
Retrospective data applicable to the study includes but not limits to the following 
information available before ICF signature (enrolment): 
 
Information regarding previous cycles performed with Obinutuzumab and 
chemotherapy (at least 2 cycles and no longer than 1 year of treatment) 
 
Safety data    
 
Baseline condition (before start of the treatment)  
 
Medical history  
 
Relevant laboratory exams 
 
Concomitant medication and procedures 
 
Diagnostic information  
 
Tumor assessments and cancer history 
 
Imaging exams 
 
Demographic Data 
 
Physical exams, performance status and FLIPI classification 
Data will be collected as availability in source document.  
Safety data will be provided as aggregate data for retrospective visits. Minimal 
information such as the event term, seriousness classification and reason, relationship 
and duration of the event will be collected as available. For prospective data collection of 
safety, additional variables will be collected as available, such as grade, outcome, 
concomitant treatment, background causality, onset and end date. 
Quality of life will be evaluated by means of the EuroQol 5-Dimension Questionnaire, 5-
level version (EQ-5D-5L), and of the Functional Assessment of Chronic illness Therapy-
Lymphoma (FACT-Lym). 

 
 
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The EuroQol 5-Dimension Questionnaire, 5-level version (EQ-5D-5L) (Appendix 4), is a 
validated self-report health status questionnaire that is used to calculate a health status 
utility score for use in health economic analyses (EuroQol Group 1990; Brooks 1996; 
Herdman et al. 2011).  
The Functional Assessment of Chronic illness Therapy-Lymphoma (FACT-Lym) 
(Webster et al, 2005) (Appendix 5) is used to assess quality of life in patients with 
various forms of lymphoma. It contains 42 items (questions) covering quality of life, 
common lymphoma symptoms and treatment side-effects. The questionnaire begins with 
the Functional Assessment of Cancer Therapy - General (FACT-G), which contains 27 
items covering four core quality of life subscales: Physical Wellbeing (7 items), 
Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The 
FACT-Lym also includes an Additional Concerns subscale (15 items), addressing issues 
typically experienced by lymphoma patients. Some of the issues covered include pain, 
itching, night sweats, trouble sleeping, fatigue and trouble concentrating. The FACT-Lym 
also asks patients about their concerns about lumps and swelling, fevers, infections, 
weight, appetite, emotional stability and treatment. 
To ensure instrument validity and that data standards meet health authority 
requirements, questionnaires scheduled for administration during a clinic visit will be 
completed in their entirety by the patient prior to the performance of non-PRO 
assessments and the treatment administration of study treatment (where applicable). 
 
Patients will use an electronic PRO (ePRO) device to capture PRO data on the same 
day of clinic visits. The ePRO device and/or instructions for completing the PRO 
questionnaires electronically will be provided by the investigator staff. The data will be 
transmitted via a pre-specified transmission method (e.g., web or wireless) automatically 
after entry to a centralized database at the ePRO vendor. The data can be accessed by 
the appropriate sponsor study personnel securely via the Internet. 
 
In case patient is not able to complete the electronic questionnaires, e.g. due to 
technical issues, the PRO data will be completed by patient in paper records and later 
transferred into the electronic system by site staff. In case any survival follow-up contact 
is conducted by phone or in case of patient’s compromised reading ability (e.g illiterate 
patients/ vision issues, etc) the PRO data for that visit will be collected in an 
interview performed by a trained site staff (via telephone or face-to-face, depending on 
how visit occurs), recorded in paper records (source document) and then transferred in 
electronic system. 
PRO questionnaires (FACT-Lym, EQ-5D) should be administered on Day 1 of alternate 
cycles during induction treatment period and at each cycle during manteinace treatment 
period. PRO Questionnaires should be administered on Day 1 of the cycle prior to any 
treatment and assessments, i.e. PRO questionnaires should be collected only when 

 
 
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corresponding to a treatment cycle. PRO questionnaires should also be administered at 
first visit after reporting disease progression. 
Please see Appendix 2 for the data collection overview (as per standard of care). 
6.4.3 
Data Collected at Study Completion 
For patients who complete the observation period, the study completion visit should be 
documented. 
Please see Appendix 2 for the data collection overview at the study completion visit. 
6.4.4 
Safety Data Collection 
Clinical AEs, serious and non-serious, will be recorded in the eCRF during the total 
observation period, with physician’s assessment of severity (mild, moderate, severe or in 
oncology studies using the National Cancer Institute [NCI] Common Terminology Criteria 
for Adverse Events [CTCAE]) and relationship to therapy (i.e., related or unrelated) as 
described in Appendix 3. 
6.5 
PATIENT, STUDY AND SITE DISCONTINUATION 
6.5.1 
Patient Discontinuation 
Patients have the right at any time and for any reason to withdraw their consent that their 
data are collected and used for the study. Reasons for discontinuation of treatment with 
the medicinal product or withdrawal from the study may include, but are not limited to, 
the following: 
 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues to receive study treatment; 
 
Investigator or Sponsor determines it is in the best interest of the patient; 
 
Pregnancy; 
 
Symptomatic deterioration attributed to disease progression; 
 
Intolerable toxicity related to Obinutuzumab, as determined by the investigator to be 
unacceptable given the individual patient’s potential response to therapy and 
severity of the event;  
 
Any medical condition that may jeopardize the patient’s safety if he or she continues 
on study treatment;  
 
Confirmed disease progression per investigator assessment; 
 
Patient withdrawal of consent at any time; 
 
Patient is lost to follow-up. 
 

 
 
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6.5.2 
Discontinuation from Treatment with Studied Medicinal 
Product 
The decision for discontinuation from treatment lies with the treating physician in 
agreement with the patient’s decision and is not regulated by this protocol.  
The primary reason for early treatment discontinuation should be documented on the 
appropriate eCRF page. Every effort should be made to obtain information on patients 
who discontinue treatment. 
Patients who discontinue treatment for reasons other than disease progression should 
continue to have its data collected for radiological assessment and minimal residual 
disease as collected by clinical practice until disease progression. Data of new anti-
cancer therapy within 3.5 years after first line and survival status should also be 
collected as available.   
6.5.3 
Withdrawal from Study 
Every effort should be made to obtain information on patients who withdraw from the 
study. The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF page. Patients will not be followed for any reason after consent has 
been withdrawn. Patients who withdraw from the study will not be replaced.  
6.5.4 
Study and Site Discontinuation 
The sponsor has the right to terminate this study at any time. Reasons for terminating 
the study may include, but are not limited to, the following: 
 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients; 
 
Patient enrolment is unsatisfactory. 
The sponsor will notify the physician if the study is placed on hold, or if decided to 
discontinue the study. 
The sponsor has the right to replace a site at any time. Reasons for replacing a site may 
include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the Guidelines for Good Pharmacoepidemiological Practices 
(GPP) or any other pertinent local law or guideline 
 
6.6 
DATA MANAGEMENT 
6.6.1 
Data Quality Assurance 
A contract research organization (CRO) will be responsible for the data management of 
this study, including quality checking of the data. Data entered manually will be collected 
via electronic data capture (EDC). Sites will be responsible for data entry into the EDC 

 
 
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system. In the event of discrepant data, site will be request data to clarify the 
discrepancy in the EDC system. 
The contract research organization (CRO) Data Management will identify and implement 
the most effective data acquisition and management strategy for the clinical trial protocol 
and deliver datasets which support the protocol objectives. The CRO will produce eCRF 
specifications for the study based on their own templates including quality checking to be 
performed on the data.  
Patient data will be entered into the eCRF and combined with data provided from other 
sources (e.g., ePRO data) in a validated data system. Clinical data management will be 
performed in accordance with applicable CRO standards and data cleaning procedures 
with the objective of removing errors and inconsistencies in the data which would 
otherwise impact on the analysis and reporting objectives, or the credibility of the Clinical 
Study Report. Adverse events and concomitant medications terms will be coded using 
validated dictionaries.  
The eCRFs and correction documentation will be maintained in the EDC system audit 
trail. System backups for data stored at the CRO and records retention for the study data 
will be consistent with the CRO standard procedures. 
The study data should be verified by the Clinical Research Associate (CRA), i.e. the 
study monitor, with the original data, thereafter all the records and clinical records of the 
subjects could be accessible. The investigator should allow the access to patient clinical 
records and the original data should be available for all the study duration. Also the 
subjects and parents/legal representatives should allow the access to their own clinical 
records; such condition is cleared and authorized when the subjects supply their 
authorization for the participation to the clinical study. 
To ensure instrument validity and that data standards meet health authority 
requirements, questionnaires scheduled for administration during a clinic visit will be 
completed in their entirety by the patient prior to the performance of non-PRO 
assessments and the administration of study treatment (where applicable). 
Patients will use an electronic PRO (ePRO) device to capture PRO data on the same 
day of clinic visits. ePRO data collection will be performed by the patients through a 
dedicated app installed on smartphone. The data will be transmitted via a pre-specified 
transmission method (e.g., web or wireless) automatically after entry to a centralized 
database at the ePRO vendor. In case application in smartphone cannot be used, ePRO 
data might be completed by patients directly in web-application at a computer available 
at site. The data can be accessed by the appropriate sponsor study personnel securely 
via the Internet. 

 
 
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In case patient is not able to complete the electronic questionnaires, e.g due to technical 
issues, the PRO data will be completed by patient in paper records and later transferred 
into the electronic system by site staff.  
6.6.2 
Electronic Case Report Forms 
Clinical data will be captured using a study specific eCRF using a validated and Code of 
Federal Regulations (CFR) Part 11 compliant electronic data capture (EDC) system. 
Sites will receive training and have access to a manual for appropriate eCRF completion. 
 
All eCRFs should be completed by designated trained site staff. eCRFs should be 
reviewed and electronically signed and dated by the physician or a designee. 
At the end of the study, the physician will receive the data related to patients from his or 
her site in an electronically readable format (e.g., on a compact disc).  Data must be kept 
with the study records. Acknowledgement of receipt of the data is required. 
6.6.3 
Source Data Documentation  
Site Operations Representative will perform ongoing SDV as defined in the Clinical 
Monitoring Plan to confirm that critical protocol data (i.e., source data) entered in the 
CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in the clinical study. 
Before study initiation, the types of source documents that contain study-relevant 
information will be clearly defined in the Clinical Monitoring Plan. The Clinical Monitoring 
Plan defines which kind of source data – if available from clinical routine - can be used 
for documentation into CRF. No additional source data creation beyond routine is 
allowed.  
Source documents that are required to verify the validity and completeness of data 
entered in the CRF must not be obliterated or destroyed and must be retained per the 
policy for retention of records described in Section 6.8.4. 
To facilitate SDV, the physicians and institutions must provide the marketing 
authorization holder direct access to applicable source documents and reports for 

 
 
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trial-related monitoring, marketing authorization holder audits, and IRB/EC review.  The 
participating sites must also allow inspection by applicable health authorities. 
6.7 
STATISTICAL CONSIDERATIONS 
A detailed description of the statistical methods that will be used for the primary and 
secondary analyses will be provided in the Statistical Analysis Plan (SAP). 
The statistical analysis will be performed using the R system.SAS System version 9.4 or 
higher. 
This is not a hypothesis testing study but an exploratory study with predefined precision 
of estimates for key efficacy and safety parameters; there are no formal statistical 
hypotheses tests to be tested, and there will be no adjustments for multiplicity of 
endpoints or within-subgroups comparisons. 
As when entering in the initial patient’s treatment/pre-treatment data are collected 
retrospectively, missing data might occur in the retrospective period as well the 
distribution of missing data might be different across the participating investigational 
sites. 
Data will be summarized using appropriate descriptive statistics. Categorical data will be 
presented as frequencies and percentages. For continuous data, arithmetic mean, 
standard deviation (STD), median, minimum, and maximum will be presented. The 95% 
confidence interval of the observed proportions (calculated using either the Clopper-
Pearson methodology, or the Poisson distribution, for frequencies below 10%) will be 
provided. 
6.7.1 
Effectiveness Analyses  
Effectiveness analysis population includes all patients who are enrolled and have 
received at least two cycles of Obinutuzumab.    
In general, the time to endpoint will be defined as an interval between the date of 
enrolment (date of first visit) and date of first occurrence of the event. For patients who 
are event free, the censoring time will be calculated as a time interval between date of 
enrolment and the patient`s final contact with available data concerning the event. The 
estimates and graphical presentation will be performed via Kaplan-Meier approach.  
Logistic regression will be performed on the rate of endpoints in order to test the impact 
of covariates, i.e. age, sex, ECOG PS, Ann Arbor staging, FLIPI, hepatitis infection 
(history of past/ resolved infection or latent HBV after prophylaxis as per standard 
treatment guidelines), chemotherapy backbone choice, medical history and history of FL, 
comorbidities. The list of the covariates to be included in the multivariate models will be 
detailed and justified in the statistical analysis plan document. 

 
 
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Exploratory analysis between different medical treatments given or subgroup analysis 
will be performed using Cox regression model and including relevant covariates. The list 
of the covariates to be included in the multivariate models will be detailed and justified in 
the statistical analysis plan document.  
Further analyses will be performed to investigate different types of bias that might be 
present in this type of study design, e.g. time-dependent confounding, informative 
censoring, informative treatment changes/discontinuations, heterogeneity of results, and 
how to handle missing data. 
Corresponding 95% confidence intervals (CIs) will be provided for all statistical estimates. 
Primary endpoint 
The primary endpoint is progression of disease at 2 years (POD24). 
POD24 will be analyzed according to the survival analysis methods. The quartiles with 
their 95% confidence interval (estimated using Kaplan-Meier methods and Greenwood’s 
formula) will be presented. Kaplan-Meier plots with a 95% CI will be prepared. Estimates 
for the survivor function will be obtained by the Kaplan-Meier approach. 
Moreover, the POD24 will be analyzed as binary variable. Number and percentage of 
patients with its 95% confidence interval for POD24 will be calculated. 
Logistic regression analysis will be performed to assess which variables are predictive of 
POD24. To identify factors associated with POD24, logistic regression analysis will be 
performed with backwards selection (removing factors with P > 0.05). Univariable 
associations between factors and POD24 will be calculated by using the Chi-square test. 
In the analysis of POD24 will be excluded patients who die within 24 months from the 
treatment start with Obinutuzumab for reasons not related to the disease progression.  
Secondary endpoints 
Time-to-event outcomes (PFS at 2 and 3 years, TTNT, OS, TTLCB, duration of 
response, and time to response) will be analyzed according to the survival analysis 
methods. The quartiles will their 95% confidence interval (estimated using Kaplan-Meier 
methods and Greenwood’s formula) will be presented. Kaplan-Meier plots with a 95% CI 
will be prepared. Estimates for the survivor functions for all time to event endpoints will 
be obtained by the Kaplan-Meier approach. 
Cox regression analysis will be used to assess which variables are predictive of OS as 
well as to evaluate the association between early POD and OS from a risk-defining 

 
 
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event, that is, survival from time of POD for early progressors or from 2 years after 
diagnosis.  
Response rates (ORR, CR, CR30 and rate of patients with stable disease) will be 
presented with the number and proportions of responders and non-responders together 
with two-sided, 95% Clopper-Pearson CIs. 
Exploratory endpoints 
All exploratory endpoints will be analyzed using descriptive statistics only. 
6.7.2 
Safety Analyses 
Safety analysis population includes all patients who are enrolled.    
Adverse events are those with start date beyond or equal to the date of first 
administration of Obinutuzumab and until 185 days after the last Obinutuzumab dose 
intake or until starting a new anti-cancer therapy (whichever occurs first). After this 
period AEs that are believed to be related to prior study drug treatment will be collected. 
All adverse events will be assigned to a Preferred Term (PT) and will be classified by 
primary System Organ Class (SOC) according to the MedDRA thesaurus version 22 or 
higher. 
Adverse events will be reported on a per-patient basis within Preferred Term. This mean 
that even if a patient will report the same event repeatedly (i.e. events mapped to the 
preferred term) the event will be counted only once. In the latter case the event will be 
assigned the worst CTCAE severity and the strongest relationship to the study drug. The 
earliest date will regard as start date of the event and the latest date will regard as stop 
date of the event. 
Data will be listed by study site, patient number, and study day. Events occurring on or 
after treatment on Day 1 (treatment-emergent adverse events - TEAEs) will be 
summarized by mapped term, appropriate thesaurus levels, and NCI CTCAE v5.0 grade. 
In addition, SAEs, including deaths, will be listed separately and summarized. AEs 
leading to treatment discontinuation will be listed.  
Infusion related reactions (IRRs) and adverse events of special interest (AESI) will be 
summarized by descriptive statistics and will be listed. 
Relevant laboratory and vital signs data will be displayed by time, with NCI CTCAE 
Grade 3 and 4 values identified, where appropriate. Additionally, all laboratory data will 
be summarized by grade with use of NCI CTCAE v5.0. 

 
 
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All medications reported will be coded using the WHO-DRL Dictionary version 2018 or 
higher and classified according to 3rd level ATC level subgroup and Preferred Term.  
For clinical laboratory parameters, where appropriate, the reported values will be 
converted into SI units and if needed boundary values for reference ranges will be 
converted as well. 
For each parameter the change from baseline to each post-baseline visit will be 
calculated. The ranges considered for such confront will be the local laboratory ranges 
values available at each individual site. 
The following vital signs, when performed as per clinical practice, will be captured in the 
eCRF: 
 
Systolic and diastolic blood pressure (mmHg) 
 
Heart rate (bpm) 
 
Body temperature (°C) 
For each variable the change from baseline to each post-baseline visit will be calculated. 
6.7.3 
Other AnalysesThe following other analyses will be performed: 
Use of Obinutuzumab in real world setting 
Descriptive statistics for the use of Obinutuzumab in the real world setting will be 
performed. 
At least the following conditions will be considered in the analysis: 
 
Not performing obinutuzumab administration on Day 8 and Day 15 in Cycle 1 
(without safety reasons)  
 
Maintenance period: administration of obinutizumab in an interval superior to 10 days 
from the expected date (every 2 months per label). NOTE: An analysis will be 
performed to assess if this condition will have impact on efficacy parameters (PFS/ 
POD24) and to explore the delay reason (COVID-19 or others) 
 
All the chemotherapy scheme used with Obinutuzumab in real world setting 
Prescription profile  
Obinutuzumab prescription profile and chemotherapy backbone choice by Italian region, 
age range, patient’s profile and site dimension (outlying sites/universities, etc.) 
Impact of COVID-19 

 
 
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 
Safety (infections and COVID-19 related events) 
 
Maintenance delay or interruption due to pandemic status 
 
Therapy interruption due to patient’s complications caused by COVID-19 
The results of biomarker analyses will be presented using descriptive statistics only. 
6.7.4 
Interim and Final Analyses and Timing of Analyses  
An interim analysis will be performed approximately one year after the first patient is 
included in the study in order to evaluate safety data, demographic data, FLIPI and 
treatment choices. 
A second interim analysis will be performed approximately two years after the first 
patient included in the study in order to evaluate safety and primary and secondary 
effectiveness data, and the impact of COVID-19 on the patient management.  
The results of the first two interim analysis will be compared.  
The final Analysis will be performed at the end of the study. 
6.7.5 
Determination of Sample size  
Sample size of this clinical study is selected based on feasibility. 
Sample size is justified for the primary effectiveness endpoint POD24 treated as binary 
variable. 
A sample size of 300 evaluable patients will allow estimation of the two-sided 95% 
confidence interval with a width equal to 7.9% (precision 3.95%) of the POD24 when the 
expected percentage is equal to 13%. 
The Clopper-Pearson’s formula has been used for the computation. 
Table 1 provides the actual width and the precision of the 95% CI and the 95% 
confidence limits for different percentages of POD24 when the sample size is equal to 
300 evaluable patients. 
Table 1 - POD24 rate and corresponding 95% Confidence Intervals 
POD24 
(%) 
Actual Width  
(%) 
Precision  
(%) 
95% Clopper-Pearson 
Exact CI (%) 
11% 
7.4 
3.70 
From 7.7 to 15.1 
13% 
7.9 
3.95 
From 9.4 to 17.3  
15% 
8.4 
4.20 
From 11.2 to 19.6 
17% 
8.8 
4.40 
From 12.9 to 21.7 

 
 
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Moreover, a sample size of 300 evaluable patients will allow estimation of the two-sided 
95% confidence interval with a width equal to 9.4% (precision 4.70%) of the PFS rate at 
3 years (treated as binary variable) when the expected percentage is equal to 80%. 
Table 2 provides the actual width and the precision of the 95% CI and the 95% 
confidence limits for different percentages of PFS at 3 years when the sample size is 
equal to 300 of evaluable patients. 

 
 
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Table 2 - PFS rate at 3 yrs and corresponding 95% Confidence Intervals 
PFS 
(%) 
Actual Width  
(%) 
Precision 
(%) 
95% Clopper-Pearson 
Exact CI (%) 
70% 
10.7 
5.35 
From 64.5 to 75.1 
75% 
10.1 
5.05 
From 69.7 to 79.8 
80% 
9.4 
4.70 
From 75.0 to 84.4 
85% 
8.4 
4.20 
From 80.4 to 88.8 
90% 
7.1 
3.55 
From 86.0 to 93.2 
Notes: From Gallium trial, PFS at 2 years has been estimated equal 
to 90% while PFS rate at 3 years to 80%.  
 
6.8 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
6.8.1 
Study Documentation 
The physician 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, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval. In addition, at the end of the study, the physician will receive the 
patient data, which include an audit trail containing a complete record of all changes to 
the data. 
The sponsor shall ensure that the dataset and statistical programs used for generating 
the data included in the final study report are kept in electronic format and are available 
for auditing and inspection. 
6.8.2 
Site Audits and Inspections  
The physician will permit the sponsor or representative to audit facilities and records 
relevant to this study. 
The physician will also permit national and local health authorities to inspect facilities 
and records relevant to this study. In case the site will receive a notice for an inspection 
from regulatory authority, the investigator will promptly inform the sponsor. 
6.8.3 
Use of Site Computerized SystemsPatient’s Report Outcome data 
will be completed by patients into a smartphone connected with a remote web-
application or directly into the web-application in a computer, available at site.  
When clinical observations are entered directly into a participating 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 

 
 
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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. 
6.8.4 
Retention of Records 
Archiving at the study site has to be for 15 years after final study report or first 
publication of study results, whichever comes later. 
Records and documents pertaining to the conduct of this study must be retained by the 
MAHphysician for at least 125 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 MAH. Written 
notification should be provided to the MAH prior to transferring any records to another 
party or moving them to another location. 
All supporting functional parties will comply with the sponsor procedures regarding 
archiving and record management. 
6.8.5 
Administrative Structure 
This trial will be sponsored and managed by Roche S.p.A. The Sponsor will provide 
clinical operations management, data management, and medical monitoring. 
Approximately 50 sites in Italy will participate to enrol approximately 300 patients. 
Enrolment will be competitive across sites.  
Enrolment will occur through an eCRF interactive web response system (IWRS) or 
similar system to capture electronically enrolled patients.  
Accredited Local laboratories will be used for routine monitoring; local laboratory ranges 
will be included in eCRF collected as applicable. 
6.9 
LIMITATIONS OF THE RESEARCH METHOD 
This study will be conducted in approximately 50 sites in Italy and will reflect the 
standard of care in place in the selected investigational study sites. Therefore, caution 
should be used in the generalisation of data collected in this study.  
Furthermore, the design of the trial may be associated with further limitations. As an 
example, the possible bias in patients’ selection due to the uncontrolled design of the 
trial may have impact on results. 
Finally, pooling of prospective and retrospective data collection will be done even though 
not equivalent and this needs to be taken into consideration when interpreting the results.  

 
 
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7. 
PROTECTION OF HUMAN SUBJECTS 
7.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the Guidelines for GPP published 
by the International Society of Pharmacoepidemiology (ISPE) and the laws and 
regulations of the country in which the research is conducted. 
7.2 
INFORMED CONSENT  
The sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) 
and the privacy form will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The sponsor must review and approve any 
proposed deviations from the sponsor's sample Informed Consent Forms or any 
alternate Consent Forms proposed by the site (collectively, the “Consent Forms”) before 
IRB/EC submission.  The final Consent Forms approved by the IRB/EC must be 
provided to the marketing authorization holder for archiving and for health authority 
submission purposes according to local requirements. 
The Consent and Privacy Forms must be signed and dated by the patient or the patient’s 
legally authorized representative before start of documentation of his or her data in the 
CRF.  The case history or clinical records for each patient shall document the informed 
consent process and that written informed consent was obtained prior to first 
documentation of this patient’s data in the CRF. 
By signing the form, the patient confirms that he/she has been informed about the study 
and agrees to pseudonymous data collection, pooling of data with similar scientific data 
(if applicable), and the possibility of monitoring activities. It is the accountability of the 
physician for ascertaining that the subject has comprehended the information and to 
obtain written informed consent from each patient participating in the study, after 
adequate explanation of the aims, methods, anticipated benefits, and potential hazards 
of the study. The physician must also explain that the patient is completely free to refuse 
to enter the study or to withdraw from it at any time, for any reason and without losing 
the benefit of any medical care to which the patient is entitled or is presently receiving. A 
copy of each signed and dated Consent Form must be provided to the patient or the 
patient’s legally authorized 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 Site Operations Representative at any time. 
7.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Site 
Operations Representative in consultation with the Scientific Responsible and reviewed 

 
 
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and approved by the IRB/EC before the study is initiated. In addition, any patient 
recruitment materials must be approved by the IRB/EC. 
In addition to the requirements for collecting and reporting all AEs, adverse events of 
special interest (AESI) and SAEs to the marketing authorization holder, physicians must 
comply with requirements for AE reporting to the local health authority and IRB/EC. 
7.4 
CONFIDENTIALITY 
The sponsor 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 datasets that are transmitted to any marketing 
authorization holder location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
The sponsor, including affiliates, collaborators and licensees may use study data labeled 
with the patient ID numbers.  Study data may also be shared with independent 
researchers or government agencies, but only after personal information that can identify 
the patient has been removed.  Patients’ study data may be combined with 
other patient’s data and/or linked to other data collected from the patients. Patients’ 
study data may be used to help better understand why people get diseases, how to best 
prevent, diagnose and treat diseases, and to develop and deliver access to new 
medicines, medical devices, and healthcare solutions to advance patient care.     
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 national and local health authorities, marketing authorization holder 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate. 
8. 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ 
ADVERSE REACTIONS 
8.1 
SAFETY REPORTING REQUIREMENTS FOR STUDIED 
MEDICINAL PRODUCTS 
8.1.1 
Safety Parameters and Definitions 
The reporting requirements in this section apply to all studied medicinal products. 
Products are not considered “studied” anymore after the end of the wash out period 

 
 
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following its discontinuation. For safety reporting requirements for non-studied medicinal 
products, see Section 8.2. 
Safety assessments will consist of monitoring and recording SAEs and non-serious AEs 
(including AEs of special interest), performing safety laboratory assessments, measuring 
vital signs, and conducting other tests that are deemed critical to the safety evaluation of 
the study as per standard medical practice.   
8.1.1.1 
Adverse Events 
According to the International Conference of Harmonisation (ICH), an AE is any 
untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical product, regardless of causal attribution.  An AE can therefore be any of 
the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Appendix 3 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
 
Any deterioration in a laboratory value or other clinical test (e.g., electrocardiogram 
[ECG], X-ray) that is associated with symptoms or leads to a change in study 
treatment or concomitant treatment or discontinuation from study medicine. 
 
8.1.1.2 
Assessment of Serious Adverse Events (Immediately 
Reportable to the Marketing Authorization Holder), Non-serious 
Adverse Events of Special Interest (AESI) and Other Non-
serious Adverse Events 
Serious Adverse Events 
An SAE is any AE that meets any of the following criteria: 
 
Is fatal (i.e., the AE actually causes or leads to death) 
 
Is life-threatening (NOTE:  The term “life-threatening” refers to an event in which the 
patient was at immediate risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.) 
 
Requires or prolongs inpatient hospitalization (see A) 
 
Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions) 
 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study medicine 

 
 
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 
Is a significant medical event in the physician’s judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of 
an AE (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE criteria; see 
Appendix 3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each AE recorded on 
the CRF (for detailed instructions, see Appendix 3). 
Adverse Events of Special Interest AEs of special interest for this study include the 
following: 
 
Tumor lysis syndrome (TLS), irrespective of causality 
 
Second malignancies 
 
Cases of potential medicine-induced liver injury that include an elevated ALT or AST 
in combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
law (see Appendix 3). 
 
Suspected transmission of an infectious agent by the study medicine, as defined 
below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection in a 
patient exposed to a medicinal product. This term only applies when a contamination 
of the study medicine is suspected 
Serious IRRs; 
Tumour lysis syndrome (irrespective of regulatory seriousness criteria); 
Serious neutropenia 
Serious infections; 
Hepatitis B reactivation while receiving the appropriate anti-viral therapy. 
 
Non-Serious Adverse Events other than Adverse Events of Special Interest 
All non-serious AEs (in addition to AEs of special interest) must be collected according 
to the appropriate level of MedDRA classification.  
The physicians are reminded of the possibility to report any adverse reactions (for which 
they suspect a causal role of a medicinal product) that come to their attention to the 

 
 
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marketing authorization holder of the suspected medicinal product, or to the concerned 
competent authorities via the national spontaneous reporting system. 
The Marketing Authorization Holder is responsible to submit adverse reactions to the 
competent regulatory authority. 
8.1.2 
Methods and Timing for Capturing and Assessing 
Safety Parameters 
The physician is accountable for ensuring that all AEs collected as per protocol (see 
Section 8.1.1.1 for definition) are recorded in the AE section of the CRF and reported 
to the marketing authorization holder in accordance with instructions provided in this 
section and in Section 8.1.3.  
For each AE recorded in the AE section of the CRF, the physician will make an 
assessment of seriousness (see Section 8.1.1.2), severity (see Appendix 3), and 
causality (see Appendix 3). 
8.1.2.1 
Adverse Event Reporting Period 
Qualified healthcare professionals (HCPs)  will seek information on AEs at each patient 
contact.  All AEs subject to the collecting and reporting requirements outlined in this 
protocol, whether reported by the patient or noted by study personnel, will be recorded in 
the patient’s medical record and in the AE section of the eCRF. 
Once the patient is enrolled in the study, AEs will be collected during the treatment with 
Obinutuzumab and until 185 days after the last Obinutuzumab dose or until starting a 
new anti-cancer therapy (whichever occurs first). It includes available data of adverse 
events that occurred between start of treatment and enrolment in the study 
(retrospective data collection)..  
After this period, AEs that are believed to be related to prior study drug treatment will be 
collected and should be notified to the competent authority in the Member State where 
the reactions occurred or to the marketing authorization holder of the suspected 
medicinal product, but not to both (to avoid duplicate reporting). 
8.1.2.2 
Procedures for Recording Adverse Events 
HCPs should use correct medical terminology/concepts and MedDRA coding when 
recording AEs in the AE section of the CRF.  Colloquialisms and abbreviations should be 
avoided. 
Only one AE term should be recorded in the event field of the CRF. 
See Appendix 3 for further specific instruction regarding:  
 
Infusion-Related Reactions   
 
Diagnosis versus signs and symptoms 

 
 
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 
Adverse Events occurring secondary to other Adverse Events 
 
Persistent or recurrent Adverse Events 
 
Abnormal Laboratory Values 
 
Abnormal Vital Sign Values 
 
Abnormal Liver Function Tests 
 
Deaths 
o All events with an outcome or consequence of death should be classified 
as serious adverse events (SAEs) and reported to the marketing 
authorization holder immediately. In certain circumstances, however, 
suspected adverse reactions with fatal outcome may not be subject to 
expedited reporting. (see Section 8.3). All deaths that occur during the 
protocol-specified AE reporting period, regardless of relationship to study 
medicine, must be recorded in the AE section of the CRF and 
immediately reported to the marketing authorization holder. Deaths that 
are clearly attributable to disease progression must not be reported as an 
AE 
 
Pre-existing Medical Conditions 
 
Lack of Therapeutic Efficacy  
 
Hospitalization or Prolonged Hospitalization 
 
Overdoses, Misuses, Abuses, Off-Label Use, Occupational Exposure, or Medication 
Error (SS: Special Situation) 
 
Quality Defects, Falsified Medicinal Products and Product Complaints 
 
Drug Interactions 
 
8.1.3 
Reporting Requirements from Healthcare Professional 
to Marketing Authorization Holder 
8.1.3.1 
Immediate Reporting Requirements from Healthcare 
Professional to Marketing Authorization Holder 
Certain events require immediate reporting to allow the Marketing Authorization Holder 
and the regulatory authorities to take appropriate measures to address potential new 
risks associated with the use of the medicine.  The HCP must report such events to the 
marketing authorization holder immediately; under no circumstances should reporting 
take place more than 24 hours after the HCP learns of the event.  The following is a list 
of events that the HCP must report to the marketing authorization holder within 24 hours 
after learning of the event, regardless of relationship to study medicine: 
 
SAEs 
 
Non-serious AESI 
 
Pregnancies 
 

 
 
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The HCP must report new significant follow-up information for these events to the 
marketing authorization holder immediately (i.e., no more than 24 hours after becoming 
aware of the information). New significant information includes the following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 
 
Change in causality based on new information 
 
Change in the event’s outcome, including recovery 
 
Additional narrative information on the clinical course of the event 
 
For reports of SAEs and non-serious AESI, including follow-up, HCPs should record all 
case details that can be gathered immediately (i.e., within 24 hours) in the AE page of 
the CRF and submit the report via the EDC system.  A report will be generated and sent 
to Roche Drug Safety by the EDC system. 
In the event that the EDC system is temporarily unavailable, please refer to Section 
8.1.3.3. 
HCPs must also comply with local requirements for reporting SAEs to the local health 
authority and IRB/EC. 
8.1.3.2 
Reporting Requirements for Non-Serious Adverse Events 
For all non-serious AEs, including follow-up reports, HCPs must record all case details 
that can be gathered within 30 calendar days of learning of the event on the AE section 
of the CRF and submit the report via the EDC system.  A report will be generated and 
sent to Roche Drug Safety to allow appropriate reporting to relevant competent 
authorities. 
In the event that the EDC system is temporarily unavailable, please refer to Section 
8.1.3.3. 
8.1.3.3 
If EDC System is Temporarily Unavailable  
In the event that the EDC system is temporarily unavailable, a completed paper 
reporting form and fax coversheet should be faxed/scanned to Roche Drug Safety or its 
designee immediately (i.e., no more than 24 hours after learning of the event) or within 
30 calendar days for non-serious AEs if not AESI, using the fax number or email address 
provided to physicians.  
Once the system is available again, all information should additionally be entered and 
submitted via the EDC system.  
8.1.3.4 
Reporting Requirements for Pregnancies/Breastfeeding  
 

 
 
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Pregnancies/Breastfeeding in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
physician if they become pregnant during the study or within 5 months after the last dose 
of medicine. A Pregnancy Report should be completed by the physician immediately (i.e., 
no more than 24 hours after learning of the pregnancy) and sent to Roche Drug Safety.  
Pregnancy should not be recorded on the AE eCRF. The physician should discontinue 
Obinutuzumab and counsel the patient, discussing the risks of the pregnancy and the 
possible effects on the fetus. Monitoring of the patient should continue until conclusion of 
the pregnancy. Any SAEs associated with the pregnancy (e.g., an event in the foetus, an 
event in the mother during or after the pregnancy, or a congenital anomaly/birth defect in 
the child) should be reported on the AE section of the eCRF.  
Suspected adverse reactions that occur in infants following exposure to a medicinal 
product from breast milk should be reported to Roche Drug Safety. 
Pregnancies in Female Partners of Male Patients Male patients will be instructed 
through the Informed Consent Form to immediately inform the physician if their partner 
becomes pregnant during the study or within 5 months after the last dose of study 
medicinal product.  A Pregnancy Report should be completed by the physician 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and sent to 
Roche Drug Safety.  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 
medicine.  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 physician will update the Pregnancy Report 
with additional information on the course and outcome of the pregnancy.  A physician 
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 fetus, to support an informed 
decision in cooperation with the treating physician and/or obstetrician. 
Abortions 
Any abortion should be classified as an SAE (as the marketing authorization holder 
considers abortions to be medically significant), recorded in the AE section of the eCRF, 
and reported to the marketing authorization holder immediately (i.e., no more than 
24 hours after learning of the event; see Section 8.1.3.1).  
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to the 
medicine should be classified as an SAE, recorded in the AE section of the eCRF, and 
reported to the marketing authorization holder immediately (i.e., no more than 24 hours 
after learning of the event; see Section 8.1.3.1). 

 
 
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8.1.3.5 
Reporting Requirements for Adverse Events originating from 
Patient Reported Outcomes  
Although physicians are not expected to review the PRO data, if HCP/study personnel 
becomes aware of a potential adverse event during review of the PRO questionnaire 
data, he/she will determine whether the criteria for an adverse event have been met and, 
if so, these must be reported using the Adverse Event eCRF. 
8.1.4 
Follow-Up of Patients after Adverse Events 
8.1.4.1 
HCP Follow-Up 
The HCP should follow each AE until the event has resolved to baseline grade or better, 
the event is assessed as stable by the HCP, the patient is lost to follow-up, or the patient 
withdraws consent.  Every effort should be made to follow all SAEs considered to be 
related to studied medicinal product until a final outcome can be reported. 
During the study period, resolution of AEs (with dates) should be documented in the AE 
section of the eCRF and in the patient’s medical record to facilitate SDV. 
All pregnancies reported during the study should be followed until pregnancy outcome.   
8.1.4.2 
Marketing Authorization Holder Follow-Up 
For all AEs, the MAH 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. AE follow-up should 
be documented in the AE section of the eCRF.  
8.2 
SAFETY REPORTING REQUIREMENTS FOR NON-STUDIED 
PRODUCTS 
Although adverse event information is not being actively solicited for non-studied 
products, the physician/consumers are reminded to report any adverse reactions (for 
which they suspect a causal role of a product) that come to their attention to the 
marketing authorization holder of the suspected product, or to the concerned competent 
authorities via the national spontaneous reporting system. 
In addition, the following should also be reported if occurring during exposure to a 
marketed medicinal product, even in the absence of adverse events: 
 
Pregnancy 
 
Breastfeeding 
 
Abnormal laboratory findings 
 
Overdose, abuse, misuse, off-label use, medication error or occupational exposure 
 
Reports of lack of efficacy 
 
Product quality defects and falsified medicinal products 

 
 
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 
Data related to a suspected transmission of an infectious agent via a medicinal 
product 
 
Drug interactions (including drug/drug, drug/food, drug/device and drug/alcohol) 
 
When a patient is not exposed to a marketed medicinal product, but the HCP/consumer 
becomes aware of the potential for a medication error, or an intercepted medication 
error, this should also be reported. 
8.3 
REPORTING OF PRODUCT COMPLAINTS WITHOUT ADVERSE 
EVENTS 
Report Roche product complaints without Adverse Events, where Product Complaint is 
any written or oral information received from a complainant that alleges deficiencies 
related to Identity, Quality, Safety, Strength, Purity, Reliability, Durability, Effectiveness, 
or Performance of a product after it has been released and distributed to the commercial 
market, to monza.complaint_office@roche.com. Reports can be done via mail, clearly 
stating the product, protocol number, description of the complaint. Report non-Roche-
product complaints as per local regulation.   
 
9. 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a study, the sponsor is dedicated to openly providing 
information on the study to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The sponsor will comply with all requirements 
for publication of study results. 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the physician must agree to submit all manuscripts or abstracts to the sponsor  
prior to submission for publication or presentation.  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 physician. 
In accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
center data. In this case, a coordinating physician 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 physician 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. 

 
 
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10. 
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Appendix 1  
List of Stand-Alone Documents Not Included in the Protocol 
 
List of contact details of responsible parties and all physicians are declared in Site 
Signature and Delegation of Responsibilities log of each site and will be archived in 
site’s file and sponsor’s file.    
 

 
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Appendix 2  
Data Collection Overview (as per Standard of Care) 
Data Collection  
(available data will be collected; no 
additional diagnostic or monitoring 
procedures will be applied to patients 
outside of routine clinical practice) 
Enrolment visit a 
 
Retrospective Data 
collection 
Prospective Data 
Collected during 
Treatment Period 
(Induction and 
maintenance period) 
Follow-up 
period b 
Informed consentc 
x 
 
 
 
Diagnosis confirmation (clinical 
stage, histology) 
 
x 
 
 
Target Population 
x 
x 
 
 
Medical history and demographic 
data 
 
x 
 
 
Concomitant 
treatments/medicationsd 
x 
X 
x 
 
Treatment with Obinutuzumab 
(x)c 
(x)c 
x 
 
Prophylaxis medication 
x 
x 
x 
 
Laboratory assessmentse 
x 
x 
x 
 
Pregnancy test 
xf 
xf 
xf 
 
Physical examination and Vital signs 
x 
x 
x 
 
ECOG 
x 
x 
x 
x 
B symptoms 
x 
x 
x 
x 
QoL (Quality of life: EuroQol 5-
Dimension Questionnaire, 5-level 
version (EQ-5D-5L); Functional 
Assessment of Chronic illness 
Therapy-Lymphoma (FACT-Lym) g  
x 
 
x 
x 
Chemotherapy regimen  
x 
x 
x 
 
AEs/SAEs/AESI/SSIRR/ADR 
x 
 
x 
xk 
Retrospective Safety data collection 
 
xh 
 
 
Tumor assessments 
x 
x 
x 
x 
Ann Arbor 
x 
x 
 
 
FLIPI score assessmenti 
x 
x 
 
 
BM evaluation  
x 
x 
x 
x 
Response ratej 
x 
x 
x 
x 
New anti-cancer therapy and survival 
status after end of treatment 
 
 
 
x 
a Items Concomitant treatments/medications, Treatment with obinutuzumab, Pregnancy test. Physical 
examination and Vital signs, Prophylaxis medication and Chemotherapy regimen apply only for patients still 
on treatment at the time of enrollment as part of their standard procedures for treatment. In case of patients 

 
 
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enrolled after treatment completion, these data will be collected as indicated in the Retrospective column 
and the prospective information will be collected as described in the Follow-up period. 
b Approximately one-year follow-up after last dose of Obinutuzumab administration, as per clinical practice, 
or for patients that early discontinue the treatment up to 3.5 years after first treatment administration or until 
withdrawal of consent, study termination by the Sponsor, or death, whichever occurs first, regardless of 
whether patients start a new anti-cancer therapy. For patients that discontinue treatment before completing 
induction or maintenance, the follow up parameters can be collected in accordance with current patient’s 
schedule visit and not every 2 months. Follow-up data will include at least tumor assessments, new anti-
lymphoma therapy informations, and safety data. 
 c Patients included should have performed at least 2 cycles of induction treatment with Obinutuzumab and 
chemotherapy, within 1 year from beginning of treatment                                                              
d Including any medication used by the patient from 7 days prior to starting treatment with obinutuzumab. 
e Laboratory tests will include: haematology (WBCs and differential count [at least neutrophils and 
monocyte %], RBCs, haemoglobin, haematocrit, platelet count) and blood chemistry (creatinine, beta-2 
microglobulin, LDH, AST, ALT). 
f Data collected if performed per clinical practice as clinically indicated. 
g QoL will be completed prospectively period, every 2 cycles in induction treatment phase and every 2 
months during maintenance treatment phase. For further instructions over QoL completion please refer to 
section 6.6.1. PRO questionnaires (FACT-Lym, EQ-5D) should be administered on Day 1 of alternate 
cycles during induction treatment period and at each cycle during manteinace treatment period. PRO 
Questionnaires should be administered on Day 1 of the cycle prior to any treatment and assessments, i.e. 
PRO questionnaires should be collected only when corresponding to a treatment cycle. PRO 
questionnaires should also be administered at first assessment after report of disease progression. 
h AEs/SAEs/AESI/SSIRR/ADR that occur prior ICF signature should be reported in eCRF as available; 
however only the event preferred term as per CTCAE vs 5.0 is required as Individual Case Safety Report 
are not applicable. Prospective safety that must be fully assessed and reported by study physician 
including assessment of seriousness (see Section 8.1.1.2), severity (see Appendix 3), and causality (see 
Appendix 3).   
i FLIPI score (age, number of nodal sites, LDH level, haemoglobin, stage) or FLIPI2 (age, beta-2 
microglobulin, bone marrow involvement, longest diameter of largest involved node, haemoglobin) 
collected at diagnosis. 
j Response will be collected at mid of the induction (between 10 and 14 weeks after the start of treatments), 
end of the induction (at the day of cycle 6 until 1 month later) during maintenance (1 year after the start of 
treatment, i.e. from 10 to 14 months after the start of treatment; 2 years after the start of treatment, i.e. from 
22 to 26 months after the start of treatment; 3 years after the start of treatment, i.e. from 34 to 38 months 
after the start of treatment), at the end of maintenance and at Follow-up as per clinical practice, as well as 
at any tumor assessment that shows disease progression, CR or CRu during induction or maintenance. 
The assessment of tumor response will be based on standard Cheson criteria and the Deauville 5-point 
scale (Appendix 6) (Younes et al. 2017). 
k All adverse events data available in medical records after start of the treatment should be reported until 
185 days after the last obinutuzumab dose or until starting a new anti-cancer therapy (whichever occurs 
first). After this period AEs that are believed to be related to prior study drug treatment will be collected.  
 

 
 
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Appendix 3  
Methods for Assessing and Recording Adverse Events 
3.1 Assessment of Severity of Adverse Events 
3.2  Assessment of Causality of Adverse Events 
3.3  Procedures for Recording Adverse Events 
 
Appendix 3.1  Assessment of Severity of Adverse Events 
The AE severity grading scale for the NCI CTCAE (v5.0) will be used for assessing AE 
severity.  The table below will be used for assessing severity for AEs that are not 
specifically listed in the NCI CTCAE. 
Adverse Event Severity Grading Scale 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to AE d 
Note:  Based on the NCI CTCAE (v5.0), which can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm 
a 
Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications,as performed by patients who are 
andnot bedridden. 
c If an event is assessed as a “significant medical event,” it must be reported as an SAE (see 
Section 8.1.3.1 for reporting Instructions), per the definition of SAE in Section 8.1.1.2. 
d Grade 4 and 5 events must be reported as SAEs (see Section 8.1.3.1 for reporting 
instructions), per the definition of SAE in Section 8.1.1.2. 
 
 

 
 
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Appendix 3.2  Assessment of Causality of Adverse Events 
For patients receiving combination therapy, causality will be assessed individually for 
each of the medicinal products. 
Physicians should use their knowledge of the patient, the circumstances surrounding the 
event, and an evaluation of any potential alternative causes to determine whether or not 
an AE is considered to be related to the study medicine, indicating “yes” or “no” 
accordingly.  The following guidance should be taken into consideration: 
Temporal relationship of event onset to the initiation of study medicine 
Course of the event, considering especially the effects of dose reduction, discontinuation 
of study medicine, or reintroduction of study medicine (when applicable) 
Known association of the event with the study medicine or with similar treatments 
Known association of the event with the disease under study 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
 
 

 
 
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Appendix 3.3  Procedures for recording Adverse Events 
 
Appendix 3.3.1  
Infusion-Related Reactions  
AEs that occur during or within 24 hours after study medicine administration and are 
judged to be related to studied medicinal product infusion should be captured as a 
diagnosis (e.g., "infusion-related reaction") in the AE section of the eCRF. If possible, 
avoid ambiguous terms such as "systemic reaction."  Associated signs and symptoms 
should be recorded on the dedicated Infusion-Related Reaction eCRF. If a patient 
experiences both a local and systemic reaction to the same dose of studied medicinal 
product, each reaction should be recorded separately in the AE section of the eCRF, 
with signs and symptoms also recorded separately on the dedicated Infusion-Related 
Reaction eCRF. 
 
Appendix 3.3.2  
Diagnosis versus Signs and Symptoms 
For AEs, other than infusion-related reactions (see Section 3.3.1) a diagnosis (if known) 
should be recorded in the AE section of the CRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases).  However, if a constellation of signs and/or symptoms cannot 
be medically characterized as a single diagnosis or syndrome at the time of reporting, 
each individual event should be recorded in the AE section of the CRF.  If a diagnosis is 
subsequently established, all previously reported AEs based on signs and symptoms 
should be nullified and replaced by one AE report based on the single diagnosis, with a 
starting date that corresponds to the starting date of the first symptom of the eventual 
diagnosis. 
Appendix 3.3.3  
Adverse Events Occurring Secondary to Other Events 
In general, AEs that are secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause, with the exception of severe or 
serious secondary events.  A medically significant secondary AE that is separated in 
time from the initiating event should be recorded as an independent event in the AE 
section of the CRF.  For example: 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, only 
vomiting should be reported on the CRF. 
If vomiting results in severe dehydration, both events should be reported separately on 
the CRF. 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the CRF. 
If dizziness leads to a fall and subsequent fracture, all three events should be reported 
separately on the CRF. 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the CRF. 
 

 
 
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All AEs should be recorded separately in the AE section of the CRF if it is unclear as to 
whether the events are associated. 
Appendix 3.3.4  
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient 
evaluation time points. Such events should only be recorded once in the AE section of 
the CRF.  The initial severity (intensity or grade) of the event will be recorded at the time 
the event is first reported.  If a persistent AE becomes more severe, the most extreme 
severity should also be recorded in the AE section of the CRF.  If the event becomes 
serious, it should be reported to the marketing authorization holder immediately (i.e., no 
more than 24 hours after learning that the event became serious; see Section 8.1.3.1 for 
reporting instructions).  The AE section of the CRF should be updated by changing the 
event from "non-serious" to "serious," providing the date that the event became serious, 
and completing all data fields related to SAEs. 
A recurrent AE is one that resolves between patient’s evaluation timepoints and 
subsequently recurs.  Each recurrence of an AE should be recorded separately in the 
AE section of the CRF. 
Appendix 3.3.5  
Abnormal Laboratory Values  
Not every laboratory abnormality qualifies as an AE.  A laboratory test result must be 
reported as an AE if it meets any of the following criteria: 
Is accompanied by clinical symptoms 
Results in a change in study treatment (e.g., dosage modification, treatment interruption, 
or treatment discontinuation) 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) or a 
change in concomitant therapy 
Is clinically significant in the physician’s judgment 
Note:  For oncology studies, certain abnormal values may not qualify as AEs. 
 
It is the physician’s responsibility to review all laboratory findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality 
should be classified as an AE. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5  the upper limit of normal [ULN] associated 
with cholestasis), only the diagnosis (i.e., cholestasis) should be recorded in the AE 
section of the eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded in the AE section of the CRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., “elevated 
potassium,” as opposed to “abnormal potassium”).  If the laboratory abnormality can be 

 
 
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characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the AE.  For example, an elevated serum potassium level of 7.0 mEq/L 
should be recorded as “hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once in the AE section of the eCRF (see Appendix 3.3.4 for 
details on recording persistent AEs). 
Appendix 3.3.6  
Abnormal Vital Sign Values  
Not every vital sign abnormality qualifies as an AE.  A vital sign result must be reported 
as an AE if it meets any of the following criteria: 
Is accompanied by clinical symptoms 
Results in a change in study treatment (e.g., dosage modification, treatment interruption, 
or treatment discontinuation) 
Results in a medical intervention or a change in concomitant therapy 
Is clinically significant in the physician’s judgment  
 
It is the physician’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an AE. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded in 
the AE section of the CRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once in the AE section of the CRF (see Appendix 3.3.4 for 
details on recording persistent AEs). 
Appendix 3.3.7  
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  the ULN) in combination with either an 
elevated total bilirubin ( 2  the ULN) or clinical jaundice in the absence of cholestasis 
or other causes of hyperbilirubinemia is considered to be an indicator of severe liver 
injury.  Therefore, physicians must report as an AE the occurrence of either of the 
following: 
Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin  2  the 
ULN 
Treatment-emergent ALT or AST  3  ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded in the AE section of the CRF (see Appendix 3.3.5) 
and reported to the marketing authorization holder immediately (i.e., no more than 

 
 
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24 hours after learning of the event) either as an SAE or a non-serious AE of special 
interest (see Section 8.1.3.1). 
Appendix 3.3.8  
Deaths 
All deaths that occur during the protocol-specified AE reporting period (see 
Section 8.1.2.1), regardless of relationship to study medicine, must be recorded in the 
AE section of the eCRF and immediately reported to the marketing authorization holder 
(see Section 8.1.3.1). 
Death should be considered an outcome and not a distinct event. The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the AE section of the CRF. Generally, only one such event should be 
reported. The term “sudden death” should only be used for the occurrence of an abrupt 
and unexpected death due to presumed cardiac causes in a patient with or without 
preexisting heart disease, within 1 hour after the onset of acute symptoms or, in the case 
of an unwitnessed death, within 24 hours after the patient was last seen alive and stable.  
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
“unexplained death” should be recorded on the AE section of the CRF. If the cause of 
death later becomes available (e.g., after autopsy), “unexplained death” should be 
replaced by the established cause of death. 
Appendix 3.3.9  
Preexisting Medical Conditions  
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions in the CRF. 
A preexisting medical condition should be recorded as an AE only if the frequency, 
severity, or character of the condition worsens during the study.  When recording such 
events in the AE section of the CRF, it is important to convey the concept that the 
preexisting condition has changed by including applicable descriptors (e.g., “more 
frequent headaches”). 
Appendix 3.3.10 
Lack of Therapeutic Efficacy  
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as AEs. These data will be captured as 
effectiveness assessment data only. In most cases, the expected pattern of progression 
will be based on standard criteria (i.e. Revised Response Criteria for Malignant 
Lymphoma [Cheson et al. 2007] and the Deauville 5-point scale [Meignan et al. 2009]). 
In rare cases, the determination of clinical progression will be based on symptomatic 
deterioration. However, every effort should be made to document progression through 
use of objective criteria. If there is any uncertainty as to whether an event is due to 
disease progression, it should be reported as an AE. This exception from reporting 
includes events of disease progression with a fatal outcome which are clearly 
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Appendix 3.3.11 
Hospitalization or Prolonged Hospitalization 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE (per the definition of SAE in Section 8.1.1.2), except as outlined 
below. 
The following hospitalization scenarios are not considered to be SAEs: 
Hospitalization for respite care 
Hospitalization for a preexisting condition provided that all of the following criteria are 
met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected normal 
progression of the disease. 
The patient has not suffered an AE. 
Hospitalization solely due to progression of the underlying cancer  
The following hospitalization scenarios are not considered to be SAEs but should be 
reported as AEs instead:  
Hospitalization that was necessary because of patient requirement for outpatient care 
outside of normal outpatient clinic operating hours 
 
Appendix 3.3.12 
Overdoses, Misuses, Abuses, Off-Label Use, 
Occupational Exposure, or Medication Error  
Any overdose, misuse, abuse, off-label use, occupational exposure, medication error 
(including intercepted or potential), or any other incorrect administration of medicine 
under observation should be noted in the Drug Administration section of the CRF as 
Special Situation (SS).  Any overdose, abuse, misuse, inadvertent/erroneous 
administration, medication error (including intercepted or potential), or occupational 
exposure reports must be forwarded to the marketing authorization holder with or without 
an AE. 
Reports with or without an AE should be forwarded to the marketing authorization holder 
as per non-serious timelines.  If the associated AE fulfills the seriousness criteria, the 
event should be reported to the marketing authorization holder immediately (i.e., no 
more than 24 hours after learning of the event, see Section 8.1.3.1). 
For the purpose of reporting cases of suspected adverse reactions, an occupational 
exposure to a medicine means an exposure to a medicine as a result of one’s 
professional or non-professional occupation. 
Appendix 3.3.13 
Quality Defects, Falsified Products and Products 
Complaints  
Reports of suspected or confirmed falsified product or quality defect of a product, with or 
without an associated AE, should be forwarded to the marketing authorization holder as 

 
 
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per non-serious timelines.  If the associated AE fulfills the seriousness criteria, the event 
should be reported to the marketing authorization holder immediately (i.e., no more than 
24 hours after learning of the event, see Section 8.1.3.1). 
Appendix 3.3.14 
Drug Interactions  
Reports of suspected or confirmed drug interactions, including drug/drug, drug/food, 
drug/device and drug/alcohol, should be forwarded to the marketing authorization holder 
as per non-serious timelines.  If the associated AE fulfills the seriousness criteria, the 
event should be reported to the marketing authorization holder immediately (i.e., no 
more than 24 hours after learning of the event, see Section 8.1.3.1). 

 
 
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Appendix 4  
EuroQol 5-Dimension Questionnaire, 5-level version (EQ-5D-5L) 
Sotto ciascun argomento, faccia una crocetta sulla casella (UNA SOLA) che descrive meglio la 
sua salute OGGI. 
CAPACITÀ DI MOVIMENTO 
 
Non ho difficoltà nel camminare 
 
Ho lievi difficoltà nel camminare 
 
Ho moderate difficoltà nel camminare 
 
Ho gravi difficoltà nel camminare 
 
Non sono in grado di camminare 
 
CURA DELLA PERSONA 
 
Non ho difficoltà nel lavarmi o vestirmi 
 
Ho lievi difficoltà nel lavarmi o vestirmi 
 
Ho moderate difficoltà nel lavarmi o vestirmi 
 
Ho gravi difficoltà nel lavarmi o vestirmi 
 
Non sono in grado di lavarmi o vestirmi 
 
ATTIVITÀ ABITUALI (per es. lavoro, studio, lavori domestici,attività 
familiari o di svago) 
 
Non ho difficoltà nello svolgimento delle attività abituali 
 
Ho lievi difficoltà nello svolgimento delle attività abituali 
 
Ho moderate difficoltà nello svolgimento delle attività abituali 
 
Ho gravi difficoltà nello svolgimento delle attività abituali 
 
Non sono in grado di svolgere le mie attività abituali 
 
DOLORE O FASTIDIO 
 
Non provo alcun dolore o fastidio 
 
Provo lieve dolore o fastidio 
 
Provo moderato dolore o fastidio 
 
Provo grave dolore o fastidio 
 
Provo estremo dolore o fastidio 
 
ANSIA O DEPRESSIONE 
 
Non sono ansioso/a o depresso/a 
 
Sono lievemente ansioso/a o depresso/a 
 
Sono moderatamente ansioso/a o depresso/a 
 
Sono gravemente ansioso/a o depresso/a 
 
Sono estremamente ansioso/a o depresso/a 
 

 
 
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La peggiore 
salute che può 
immaginare 
 
 
Vorremmo sapere quanto è buona o cattiva la sua salute OGGI. 
 
Questa è una scala numerata che va da 0 a 100. 
 
100 rappresenta la migliore salute che può immaginare. 
0 rappresenta la peggiore salute che può immaginare. 
 
Segni una X sul punto della scala per indicare com’è la sua salute 
OGGI. 
 
Poi, scriva nella casella qui sotto il numero che ha segnato sulla 
scala numerata. 
 
  
 
La migliore salute 
che può 
immaginare 
LA SUA SALUTE OGGI = 
10
0 
20
30
40
50
60
80
70
90
100
5 
15
25
35
45
55
75
65
85
95