Conditions: Lupus Nephritis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 126
Healthy volunteers: no

Brief summary:
This Phase II study will compare the efficacy and safety of obinutuzumab plus mycophenolate mofetil (MMF)/mycophenolic acid (MPA) with placebo plus MMF/MPA in participants with proliferative LN.

Detailed description:

Arms:
arm 1: Participants will receive obinutuzumab 1000 milligrams (mg) intravenous (IV) infusion on Days 1, 15, 168, and 182 along with MMF/MPA at a starting dose of 1500 mg/day (or equivalent) administered orally in 2 or 3 divided doses. MMF/MPA dose will be up titrated to a target dose of 2.0 - 2.5 grams per day (g/day) (or equivalent). Investigators, at their discretion, may use MPA as a substitute for MMF, with a 360 mg dose being equivalent to a 500 mg dose of MMF. During screening or at randomization, if clinically indicated, participants may receive 750-1000 mg methylprednisolone IV once daily for up to 3 days to treat underlying LN clinical activity. Participants will receive 0.5 mg/kg oral prednisone, tapering this prednisone dose, per protocol, starting on Day 16 and reducing the prednisone dosage to 7.5 mg/day by Week 12. arm 2: Participants will receive placebo matching to obinutuzumab IV infusion on Days 1, 15, 168, and 182 along with MMF/MPA at a starting dose of 1500 mg/day (or equivalent) administered orally in 2 or 3 divided doses. MMF/MPA dose will be up titrated to a target dose of 2.0 - 2.5 g/day (or equivalent). Investigators, at their discretion, may use MPA as a substitute for MMF, with a 360 mg dose being equivalent to a 500 mg dose of MMF. During screening or at randomization, if clinically indicated, participants may receive 750-1000 mg methylprednisolone IV once daily for up to 3 days to treat underlying LN clinical activity. Participants will receive 0.5 mg/kg oral prednisone, tapering this prednisone dose, per protocol, starting on Day 16 and reducing the prednisone dosage to 7.5 mg/day by Week 12.

Interventions: intervention 1: Mycophenolate Mofetil/Mycophenolic Acid intervention 2: Obinutuzumab intervention 3: Placebo intervention 4: Methylprednisolone intervention 5: Prednisone
Intervention descriptions: intervention 1: MMF/MPA will be administered as per schedule specified in the respective arm. intervention 2: Obinutuzumab will be administered as per schedule specified in the respective arm. intervention 3: Placebo matching to obinutuzumab will be administered as per schedule specified in the respective arm. intervention 4: Methylprednisolone IV will be administered as per schedule specified in the respective arm. intervention 5: Prednisone will be administered as per schedule specified in the respective arm.

Protocol document:
Prot_004.pdf: 
Official Title: 
A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study 
to Evaluate the Safety and Efficacy of Obinutuzumab in Patients With 
ISN/RPS 2003 Class III or IV Lupus Nephritis 
NCT Number: 
NCT02550652 
Document Date: 
Protocol Version 4: 18-April-2023 


CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  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 an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
Protocol WA29748, Version 4 
PROTOCOL 
TITLE: 
A RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, MULTI-CENTER STUDY 
TO EVALUATE THE SAFETY AND EFFICACY OF 
OBINUTUZUMAB IN PATIENTS WITH ISN/RPS 
2003 CLASS III OR IV LUPUS NEPHRITIS 
PROTOCOL NUMBER: WA29748 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2015-002022-39 
IND NUMBER: 
125,054 
TEST PRODUCT: 
Obinutuzumab (GA101; RO5072759) 
NCT NUMBER: 
NCT02550652 
SPONSOR: 
F. Hoffmann-La Roche Ltd
APPROVAL DATE: 
See electronic signature and date stamp on the final 
page of this document.  


Obinutuzumab—F. Hoffmann-La Roche Ltd 
2/Protocol WA29748, Version 4 
PROTOCOL HISTORY 
Protocol 
Version 
Date Final 
4 
See electronic date stamp on final page. 
3 
2 February 2016 
2 
24 July 2015 
1 
6 May 2015 
 


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
3/Protocol WA29748, Version 4 
PROTOCOL AMENDMENT, VERSION 4: 
RATIONALE 
Protocol WA29748 has been amended primarily to update the details for the end of the 
study.  Substantial changes to the protocol, along with a rationale for each change, are 
summarized below: 
 
Personal identifiable information (i.e., name and telephone number) for the Medical 
Monitors has been removed from the protocol (front matter and Section 5.4.1).  
Medical Monitor contact information has been replaced with a sentence indicating 
that this information will be provided separately to sites. 
 
The description of the end of study has been updated to emphasize that it is defined 
as the last patient’s last visit at Week 104 when B-cell follow-up (BCFU) visits for all 
patients will end. This represents a minimum of 78 weeks (~18 months) of safety 
follow-up after the last dose of study drug to assess the occurrence of adverse 
events and to enable an assessment of peripheral blood CD19+ B cell return.  An 
analysis of the relationship between obinutuzumab exposure and B-cell count for 
patients with Lupus Nephritis (LN) in this study (WA29748) who have already 
completed 18-months of follow-up has been performed and shows that the vast 
majority of patients recovered or repleted their B-cells by 18 months after their last 
obinutuzumab dose, while a small percentage of patients experienced prolonged B-
cell depletion.  During the extended B-cell depeletion period, the safety profile of 
patients under follow-up was consistent with the overall safety profile observed up 
until Week 104. This finding is in-line with considerable experience with other anti-
CD20 antibodies with the same mechanism of action in sutoimmune diseases  
(Section 3.2). 
 
The reporting of the term “sudden death” has been updated to also require the 
presumed cause of death (Section 5.3.5.8). 
 
Adverse event reporting for hospitalization has been clarified (Section 5.3.5.11). 
 
The Sponsor record retention policy has been clarified (Section 7.5). 
 
A description of the technical and organizational security measures taken to protect 
personal data has been added to align with CTR requirements (Section 8.4). 
 
The process for reviewing and handling protocol deviations has been updated per 
internal standard operating procedures (Section 9.2). 
 
Due to certain local requirements and an alignment of Sponsor process, it has been 
clarified that summaries of clinical study results may be available in health authority 
databases for public access in addition to redacted Clinical Study Reports 
(Section 9.5). 
 
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. 


Obinutuzumab—F. Hoffmann-La Roche Ltd 
4/Protocol WA29748, Version 4 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11 
PROTOCOL SYNOPSIS .................................................................................... 12 
1. 
BACKGROUND ............................................................................ 24 
1.1 
Background on Lupus Nephritis ............................................... 24 
1.2 
Background on Obinutuzumab ................................................ 26 
1.3 
Study Rationale and Benefit-Risk Assessment ........................ 27 
2. 
OBJECTIVES ................................................................................ 32 
2.1 
Efficacy Objectives .................................................................. 32 
2.2 
Safety Objectives ..................................................................... 32 
2.3 
Pharmacodynamic Objective ................................................... 32 
2.4 
Pharmacokinetic Objectives..................................................... 32 
2.5 
Patient-Reported Outcome Objective ...................................... 32 
2.6 
Exploratory Objectives ............................................................. 33 
3. 
STUDY DESIGN ........................................................................... 33 
3.1 
Description of Study ................................................................. 33 
3.2 
End of Study ............................................................................ 35 
3.3 
Rationale for Study Design ...................................................... 35 
3.3.1 
Rationale for Obinutuzumab Dose and Schedule .................... 35 
3.3.2 
Rationale for Patient Population .............................................. 36 
3.3.3 
Rationale for Control Group ..................................................... 36 
3.3.4 
Rationale for Biomarker Assessments ..................................... 36 
3.4 
Outcome Measures ................................................................. 37 
3.4.1 
Efficacy Outcome Measures .................................................... 37 
3.4.2 
Safety Outcome Measures ...................................................... 38 
3.4.3 
Pharmacodynamic Outcome Measure ..................................... 39 
3.4.4 
Pharmacokinetic Outcome Measures ...................................... 39 
3.4.5 
Patient-Reported Outcome Measure ....................................... 39 
3.4.6 
Exploratory Outcome Measures .............................................. 39 
4. 
MATERIALS AND METHODS ...................................................... 41 
4.1 
Patients .................................................................................... 41 


 
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4.1.1 
Inclusion Criteria ...................................................................... 41 
4.1.2 
Exclusion Criteria ..................................................................... 42 
4.2 
Method of Treatment Assignment and Blinding ....................... 44 
4.3 
Study Treatment ...................................................................... 45 
4.3.1 
Formulation, Packaging, and Handling .................................... 45 
4.3.1.1 
Obinutuzumab and Placebo..................................................... 45 
4.3.1.2 
Methylprednisolone and Placebo ............................................. 45 
4.3.1.3 
Mycophenolate Mofetil/Mycophenolic Acid .............................. 45 
4.3.2 
Dosage, Administration, and Compliance ................................ 46 
4.3.2.1 
Obinutuzumab and Placebo..................................................... 46 
4.3.2.2 
Mycophenolate Mofetil/Mycophenolic Acid .............................. 48 
4.3.2.3 
Corticosteroid Administration ................................................... 49 
4.3.3 
Dosage Modification ................................................................ 51 
4.3.4 
Investigational Medicinal Product Accountability ..................... 52 
4.3.5 
Post-Study Access to Obinutuzumab ...................................... 52 
4.4 
Concomitant Therapy .............................................................. 53 
4.4.1 
Permitted Therapy ................................................................... 53 
4.4.1.1 
Other Concomitant Therapy..................................................... 53 
4.4.1.2 
Withdrawal of Immunosuppression after Week 52 ................... 55 
4.4.2 
Concomitant Therapy and Clinical Practice ............................. 55 
4.4.3 
Immunization during Peripheral B-Cell Depletion .................... 55 
4.4.4 
Prohibited Therapy .................................................................. 56 
4.5 
Study Assessments ................................................................. 57 
4.5.1 
Informed Consent Forms and Screening Log .......................... 57 
4.5.2 
Medical History and Demographic Data .................................. 57 
4.5.3 
Physical Examinations ............................................................. 57 
4.5.4 
Vital Signs ................................................................................ 58 
4.5.5 
Systemic Lupus Erythematosus Disease Activity Index 
(SELENA-SLEDAI) Assessment .............................................. 58 
4.5.6 
Systemic Lupus International Collaborating Clinics/ 
American College of Rheumatology Damage Index for 
Systemic Lupus Erythematosus ............................................... 58 
4.5.7 
Glucocorticoid Toxicity Change Index ...................................... 58 
4.5.8 
Laboratory, Biomarker, and Other Biological Samples ............ 58 


 
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4.5.9 
Electrocardiograms .................................................................. 60 
4.5.10 
Patient- and Physician-Reported Outcomes ............................ 60 
4.5.11 
Samples for Roche Clinical Repository .................................... 61 
4.5.11.1 
Overview of the Roche Clinical Repository .............................. 61 
4.5.11.2 
Approval by the Institutional Review Board or Ethics 
Committee ............................................................................... 61 
4.5.11.3 
Sample Collection .................................................................... 61 
4.5.11.4 
Confidentiality .......................................................................... 62 
4.5.11.5 
Consent to Participate in the Roche Clinical Repository .......... 63 
4.5.11.6 
Withdrawal from the Roche Clinical Repository ....................... 63 
4.5.11.7 
Monitoring and Oversight ......................................................... 63 
4.6 
Patient, Treatment, Study, and Site Discontinuation ................ 64 
4.6.1 
Patient Discontinuation ............................................................ 64 
4.6.2 
Study Treatment Discontinuation ............................................. 64 
4.6.3 
Study and Site Discontinuation ................................................ 65 
5. 
ASSESSMENT OF SAFETY ......................................................... 65 
5.1 
Safety Plan .............................................................................. 65 
5.1.1 
Infusion-Related Reactions ...................................................... 65 
5.1.2 
Infections ................................................................................. 66 
5.1.2.1 
Hepatitis B Reactivation ........................................................... 66 
5.1.2.2 
Progressive Multifocal Leukoencephalopathy .......................... 67 
5.1.3 
Immunizations .......................................................................... 67 
5.1.4 
Neutropenia ............................................................................. 67 
5.1.5 
Thrombocytopenia ................................................................... 67 
5.1.6 
B-Cell Depletion and Recovery ................................................ 67 
5.1.6.1 
Obinutuzumab Monotherapy - NHL and CLL Patients ............. 68 
5.1.6.2 
Obinutuzumab in Combination with Chemotherapy - CLL 
Patients .................................................................................... 68 
5.1.7 
Immunoglobulin Depletion and Recovery ................................ 68 
5.1.8 
Gastrointestinal Perforations.................................................... 69 
5.1.9 
Management of Specific Adverse Events ................................ 69 
5.2 
Safety Parameters and Definitions .......................................... 72 
5.2.1 
Adverse Events ........................................................................ 72 


 
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5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) .................................................................................. 72 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ...................................................... 73 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 74 
5.3.1 
Adverse Event Reporting Period .............................................. 74 
5.3.2 
Eliciting Adverse Event Information ......................................... 74 
5.3.3 
Assessment of Severity of Adverse Events ............................. 74 
5.3.4 
Assessment of Causality of Adverse Events............................ 75 
5.3.5 
Procedures for Recording Adverse Events .............................. 76 
5.3.5.1 
Infusion-Related Reactions ...................................................... 76 
5.3.5.2 
Diagnosis versus Signs and Symptoms ................................... 76 
5.3.5.3 
Adverse Events That Are Secondary to Other Events ............. 77 
5.3.5.4 
Persistent or Recurrent Adverse Events .................................. 77 
5.3.5.5 
Abnormal Laboratory Values ................................................... 78 
5.3.5.6 
Abnormal Vital Sign Values ..................................................... 78 
5.3.5.7 
Abnormal Liver Function Tests ................................................ 79 
5.3.5.8 
Deaths ..................................................................................... 79 
5.3.5.9 
Preexisting Medical Conditions ................................................ 80 
5.3.5.10 
Lack of Efficacy or Worsening of Systemic Lupus 
Erythematosus ......................................................................... 80 
5.3.5.11 
Hospitalization or Prolonged Hospitalization ............................ 80 
5.3.5.12 
Adverse Events Associated with an Overdose or Error in 
Drug Administration ................................................................. 81 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................... 81 
5.4.1 
Emergency Medical Contacts .................................................. 82 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest .......................................... 82 
5.4.2.1 
Events That Occur prior to Study Drug Initiation ...................... 82 
5.4.2.2 
Events That Occur after Study Drug Initiation .......................... 82 
5.4.3 
Reporting Requirements for Pregnancies ................................ 82 
5.4.3.1 
Pregnancies in Female Patients .............................................. 82 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................... 83 


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
8/Protocol WA29748, Version 4 
5.4.3.3 
Abortions.................................................................................. 83 
5.4.3.4 
Congenital Anomalies/Birth Defects ........................................ 83 
5.5 
Follow-Up of Patients after Adverse Events............................. 84 
5.5.1 
Investigator Follow-Up ............................................................. 84 
5.5.2 
Sponsor Follow-Up .................................................................. 84 
5.6 
Post-Study Adverse Events ..................................................... 84 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............... 84 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ......... 85 
6.1 
Determination of Sample Size ................................................. 85 
6.2 
Summaries of Conduct of Study .............................................. 86 
6.3 
Summaries of Treatment Group Comparability ........................ 86 
6.4 
Efficacy Analyses ..................................................................... 86 
6.4.1 
Primary Efficacy Endpoint ........................................................ 86 
6.4.2 
Secondary Efficacy Endpoints ................................................. 87 
6.4.3 
Exploratory Efficacy Endpoints ................................................ 88 
6.5 
Safety Analyses ....................................................................... 88 
6.5.1 
Adverse Events ........................................................................ 88 
6.5.2 
Deaths ..................................................................................... 88 
6.5.3 
Laboratory Tests ...................................................................... 88 
6.5.4 
Vital Signs ................................................................................ 89 
6.6 
Pharmacodynamic Analyses .................................................... 89 
6.7 
Pharmacokinetic Analyses ....................................................... 89 
6.8 
Patient- and Physician-Reported Outcome Analyses .............. 90 
6.9 
Exploratory Analyses ............................................................... 90 
6.10 
Interim Analyses ...................................................................... 91 
6.10.1 
Planned Interim Analyses ........................................................ 91 
6.10.1.1 
Pharmacodynamic Futility Interim Analysis: ............................ 91 
6.10.1.2 
Renal Response Interim Analysis: ........................................... 91 
7. 
DATA COLLECTION AND MANAGEMENT ................................. 92 
7.1 
Data Quality Assurance ........................................................... 92 
7.2 
Electronic Case Report Forms ................................................. 92 
7.3 
Source Data Documentation .................................................... 92 


 
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7.4 
Use of Computerized Systems ................................................ 93 
7.5 
Retention of Records ............................................................... 93 
8. 
ETHICAL CONSIDERATIONS ...................................................... 94 
8.1 
Compliance with Laws and Regulations .................................. 94 
8.2 
Informed Consent .................................................................... 94 
8.3 
Institutional Review Board or Ethics Committee ...................... 95 
8.4 
Confidentiality .......................................................................... 96 
8.5 
Financial Disclosure ................................................................. 96 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ....................................................................... 96 
9.1 
Study Documentation .............................................................. 96 
9.2 
Protocol Deviations .................................................................. 97 
9.3 
Site Inspections ....................................................................... 97 
9.4 
Administrative Structure ........................................................... 97 
9.5 
Dissemination of Data and Protection of Trade Secrets .......... 97 
9.6 
Protocol Amendments ............................................................. 98 
10. 
REFERENCES.............................................................................. 99 
 
 
LIST OF TABLES 
Table 1 
International Society of Nephrology/Renal Pathology Society 
2003 Classification of Lupus Nephritis ........................................ 25 
Table 2 
Administration of Obinutuzumab Infusions .................................. 47 
Table 3 
Management of Infusion-Related Reactions ............................... 48 
Table 4 
Antimalarial Medications ............................................................. 53 
Table 5 
Suggested Dose Ranges for Angiotensin-Converting 
Enzyme Inhibitors and Angiotensin-Receptor Blockers .............. 54 
Table 6 
Guidelines for Management of Specific Adverse Events ............ 70 
Table 7 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 75 
Table 8 
Causal Attribution Guidance ....................................................... 76 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 34 


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
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LIST OF APPENDICES 
Appendix 1 
 Schedule of Assessments ........................................................ 104 
Appendix 2 
 Follow-Up and B-Cell Follow-Up Assessments ........................ 108 
Appendix 3 
International Society of Nephrology/Renal Pathology Society 
(ISN/RPS)  2003 Classification of Lupus Nephritis ................... 109 
Appendix 4 
 Guidelines for Mycophenolate Mofetil (or Equivalent) Dosing .. 113 
Appendix 5 
 Initial Prednisone/Prednisolone Tapering Schedule ................. 115 
Appendix 6 
 Criteria for Classification of Systemic Lupus Erythematosus ... 118 
Appendix 7 
 Study Drug Administration ....................................................... 120 
Appendix 8 
 Corticosteroid Equivalence Chart ............................................. 123 
Appendix 9 
 Instructions for Collecting and Analyzing Urine Samples ......... 124 
Appendix 10 
 Systemic Lupus International Collaborating Clinics/ 
American College of Rheumatology (SLICC/ACR) ................... 127 
Appendix 11 
 Subject’s Global Assessment ................................................... 130 
Appendix 12 
 Physician’s Global Assessment ............................................... 131 
Appendix 13 
 Systemic Lupus Erythematosus Disease Activity Index-2K ..... 132 
Appendix 14 
 Glucocorticoid Toxicity Change Index ...................................... 133 


Obinutuzumab—F. Hoffmann-La Roche Ltd 
11/Protocol WA29748, Version 4 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, MULTI-CENTER STUDY 
TO EVALUATE THE SAFETY AND EFFICACY OF 
OBINUTUZUMAB IN PATIENTS WITH ISN/RPS 
2003 CLASS III OR IV LUPUS NEPHRITIS 
PROTOCOL NUMBER: WA29748 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2015-002022-39 
IND NUMBER: 
125,054 
NCT NUMBER: 
NCT02550652 
TEST PRODUCT: 
Obinutuzumab (GA101; RO5072759) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy as 
instructed by your local study monitor. 
 


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
12/Protocol WA29748, Version 4 
PROTOCOL SYNOPSIS 
TITLE: 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
MULTI-CENTER STUDY TO EVALUATE THE SAFETY AND 
EFFICACY OF OBINUTUZUMAB IN PATIENTS WITH ISN/RPS 
2003 CLASS III OR IV LUPUS NEPHRITIS 
PROTOCOL NUMBER: 
WA29748 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2015-002022-39 
IND NUMBER: 
125,054 
NCT NUMBER: 
NCT02550652 
TEST PRODUCT: 
Obinutuzumab (GA101; RO5072759) 
PHASE: 
II 
INDICATION: 
ISN/RPS Class III or IV Lupus Nephritis 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
OBJECTIVES 
EFFICACY OBJECTIVES 
The primary efficacy objective for this study is as follows: 
 
To evaluate the efficacy of obinutuzumab compared with placebo in patients with 
International Society of Nephrology (ISN)/Renal Pathology Society (RPS) Class III or IV 
lupus nephritis (LN) as measured by complete renal response (CRR) at 52 weeks 
 
The secondary efficacy objectives for this study are as follows: 
 
To assess overall renal response (defined as CRR plus partial renal response [PRR]) 
 
To evaluate the ability of obinutuzumab to improve time-to-response (CRR plus PRR) over 
the course of 52 weeks 
 
SAFETY OBJECTIVES 
The safety objectives for this study are as follows: 
 
To evaluate the safety of obinutuzumab compared with placebo in patients with Class III or 
IV LN, focusing on the nature, frequency, and severity of serious and non-serious adverse 
events, as well as effects on laboratory values, vital signs, or other safety biomarkers 
 
To characterize the immunogenic potential of obinutuzumab by measuring human anti-drug 
antibodies and assessing their relationship with other outcome measures 
 
To fully characterize adverse events of special interest, including infusion reactions, 
infections, thrombocytopenia, and neutropenia 
 
PHARMACODYNAMIC OBJECTIVE 
The pharmacodynamic (PD) objective for this study is as follows: 
 
To compare changes in CD19 B cells in the peripheral blood following treatment with 
obinutuzumab versus placebo 
 


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
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PHARMACOKINETIC OBJECTIVES 
The pharmacokinetic (PK) objectives for this study are as follows: 
 
To characterize the pharmacokinetics of obinutuzumab in the LN population 
 
To assess potential PK interactions between obinutuzumab and concomitant medications, 
including mycophenolate mofetil (MMF) 
 
PATIENT-REPORTED OUTCOME OBJECTIVES 
The patient-reported outcome (PRO) objective for this study is as follows: 
 
To assess the change from baseline of the patient’s general health over the course of the 
study by use of the Subject’s Global Assessment 
 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are as follows: 
 
To evaluate pre-dose levels of exploratory biomarkers (which may include but are not 
limited to B-cell subsets and levels of protein and mRNA in serum, plasma, blood, and 
urine) and potential associations with outcome 
 
To evaluate changes in exploratory biomarkers (which may include but are not limited to 
B-cell subsets and levels of protein and mRNA in serum, plasma, blood, and urine) over 
time in patients dosed with obinutuzumab versus patients dosed with placebo 
 
To evaluate the occurrence of extrarenal flares 
 
To evaluate the impact of therapy on patient and physician-reported outcomes 
 
To assess damage through the Glucocorticoid Toxicity Change Index (GTCI) 
 
To assess renal biopsy histopathology (for the presence and depletion of B cells at the 
screening biopsy and from subsequent biopsies) 
 
Additional exploratory objectives and outcome measures will be included in a final Statistical 
Analysis Plan (SAP). 
STUDY DESIGN 
DESCRIPTION OF STUDY 
This Phase II study is a parallel-group, double-blind, randomized, placebo-controlled study 
comparing the efficacy and safety of obinutuzumab plus MMF with placebo plus MMF in Class 
III and IV patients with proliferative LN.  The Sponsor intends to enroll approximately 120 
patients diagnosed with ISN/RPS Class III or IV LN, with a diagnosis of systemic lupus 
erythematosus (SLE) based on current American College of Rheumatology (ACR) criteria (at 
least 4 criteria must be present, one of which must be a positive anti-nuclear antibody [ANA]), in 
centers throughout the world.  In addition to study treatment, patients will receive 
standard-of-care therapy with angiotensin-converting enzyme 
(ACE) inhibitors/angiotensin-IIreceptor blockers, MMF (dosed at 2.02.5 g/day) or 
mycophenolic acid (MPA) (dosed 14401800 mg/day), and a prednisone taper.  Patients must 
be 1875 years of age and have ISN/RPS 2003 Class III or IV proliferative LN as evidenced by 
renal biopsy performed within 6 months prior to or during screening and may have concomitant 
Class V disease (e.g., Class III/V or Class IV/V).  Patients with Class III (C) or Class IV (C) 
disease will be excluded because of the lower likelihood of response within these categories.  
Patients must exhibit significant proteinuria (urine protein to creatinine ratio  1.0 based on a 
24-hour urine collection).  Key exclusions will be evidence of severe renal impairment 
(estimated glomerular filtration rate [GFR]  30 mL/minute per 1.73 m2 of body surface area), 
end-stage renal disease requiring dialysis or transplantation, evidence of active infections, and 
other safety-related exclusions.  Patients will receive an initial 1000 mg of methylprednisolone 
intravenous (IV) prior to or during screening, and may receive up to a total of 3000 mg 
methylprednisolone IV prior to randomization for severe clinical activity according to guidelines 
of routine care for these patients.  Patients will receive 80 mg methylprednisolone (or 
methylprednisolone placebo) on the day of the obinutuzumab/placebo infusion to reduce 
infusion-related reactions.  Oral corticosteroids will be initiated at a dose of 0.5 mg/kg 
(maximum 60 mg/day) and will be reduced over 10 weeks.  This modified taper, from the 


 
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LUNAR study, will be initiated at a lower dose in recognition that prednisone doses above 
10 mg/day are associated with significant adverse events, including increased risk of 
cardiovascular events.  Prior experience with rituximab suggests that it can potentially enable 
complete and PRRs in the absence of oral prednisone or a prednisone taper, thus allowing the 
use of lower doses of corticosteroids as proposed in this Phase II protocol. 
Patients will be followed until at least Week 104, with the primary endpoint evaluation at Week 
52.  An interim analysis at 6 months will be performed to evaluate early differences in CRR.  All 
patients will have central reading of the renal biopsy histopathology and will also receive repeat 
renal biopsy as available on the basis of clinical status and local practice.  All patients will be 
evaluated by high-sensitivity flow cytometry (HSFC) to evaluate the ability of obinutuzumab to 
deplete circulating peripheral B cells, and an interim PD analysis will be performed to assess 
whether patients do not fully deplete peripheral CD19 B cells as anticipated.  These mechanistic 
studies and more intensive histopathologic reviews are intended to test the hypothesis that 
greater B-cell depletion in the target organ (kidney) and associated secondary lymphoid 
structures will translate into greater CRR rates. 
NUMBER OF PATIENTS 
The study will enroll approximately 120 patients with active ISN/RPS 2003 Class III or IV LN at 
approximately sixty centers in North America, South America, Europe, and selected other 
countries. 
TARGET POPULATION 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form 
 
Age 1875 years 
 
Ability to comply with the study protocol, in the investigator’s judgment 
 
Diagnosis of SLE, according to current ACR criteria (at least four criteria must be present, 
one of which must be a positive ANA) 
 
Diagnosis of ISN/RPS 2003 Class III or IV LN as evidenced by renal biopsy performed 
within 6 months prior to or during screening.  Patients may co-exhibit Class V disease in 
addition to either Class III or Class IV disease. 
 
Proteinuria (urine protein to creatinine ratio)  1.0, based on a 24-hour urine collection 
 
For women who are not postmenopausal ( 12 months of non-therapy-induced amenorrhea) 
or surgically sterile (absence of ovaries and/or uterus):  agreement to remain abstinent or 
use two adequate methods of contraception, including at least one method with a failure 
rate of  1% per year, during the treatment period and for at least 18 months after the last 
dose of study drug 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
Barrier methods must always be supplemented with the use of a spermicide. 
Examples of contraceptive methods with a failure rate of  1% per year include tubal 
ligation, male sterilization, hormonal implants, established, proper use of combined oral 
or injected hormonal contraceptives, and certain intrauterine devices. 
 
For men:  agreement to remain abstinent or use a condom plus an additional contraceptive 
method that together result in a failure rate of  1% per year during the treatment period and 
for at least 12 months after the last dose of study drug and agreement to refrain from 
donating sperm during this same period 
Men with a pregnant partner must agree to remain abstinent or use a condom for the 
duration of the pregnancy. 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 


 
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Patients must be willing to practice this method of contraception while taking MMF and 
for 90 days after stopping MMF. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Retinitis, poorly controlled seizure disorder, acute confusional state, myelitis, stroke or 
stroke syndrome, cerebellar ataxia, or dementia that is currently active and resulting from 
SLE 
 
Presence of rapidly progressive glomerulonephritis defined by 
The presence of crescent formation in  50% of glomeruli assessed on renal biopsy or 
Sustained doubling of serum creatinine within 12 weeks of screening or 
The investigator’s opinion that the patient has rapidly progressive glomerulonephritis. 
 
Severe renal impairment as defined by estimated GFR  30 mL/min or the need for dialysis 
or renal transplant 
 
Greater than 50% of glomeruli with sclerosis on renal biopsy 
 
Treatment with cyclophosphamide or calcineurin inhibitors within the 3 months prior to 
randomization 
 
Unstable disease with thrombocytopenia or at high risk for developing clinically significant 
bleeding or organ dysfunction requiring therapies such as plasmapheresis or acute blood or 
platelet transfusions 
 
Lack of peripheral venous access 
 
Pregnancy or lactation 
 
History of severe allergic or anaphylactic reactions to monoclonal antibodies or known 
hypersensitivity to any component of the obinutuzumab infusion 
 
Significant or uncontrolled medical disease in any organ system not related to SLE or LN, 
which, in the investigator’s opinion, would preclude patient participation 
 
Concomitant chronic conditions, excluding SLE, (e.g., asthma, Crohn’s disease) that 
required oral or systemic steroid use in the 52 weeks prior to screening 
 
Known HIV infection 
 
Known active infection of any kind (excluding fungal infection of nail beds) or any major 
episode of infection requiring hospitalization or treatment with IV anti-infectives within 
8 weeks of the screening visit or oral anti-infectives within 2 weeks prior to the screening 
visit 
 
History of serious recurrent or chronic infection 
 
History of cancer, including solid tumors, hematological malignancies, and carcinoma in situ 
(except basal cell carcinomas of the skin that have been treated or excised and have 
resolved) 
 
Currently active alcohol or drug abuse or history of alcohol or drug abuse within 52 weeks 
prior to screening 
 
Major surgery requiring hospitalization within 4 weeks of randomization (excluding 
diagnostic surgery) 
 
Previous treatment with an anti-CD20targeted therapy within 12 months of randomization 
 
Previous treatment with a biologic B-celltargeted therapy (other than anti-CD20) within 
6 months of randomization 
 
Treatment with any investigational agent within 28 days of randomization or five half-lives of 
the investigational drug (whichever is longer) 
 
Receipt of a live vaccine within 28 days prior to screening 
 
Intolerance or contraindication to oral or IV corticosteroids 
 
Aspartate aminotransferase or alanine aminotransferase  2.5  upper limit of normal (ULN) 


 
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 
Amylase or lipase  2  ULN 
 
Neutrophils  1.5  103/L 
 
Positive hepatitis B surface antigen (HbSAg) or hepatitis C serology.  Patients who are 
HBsAg negative and hepatitis B core antibody positive with no detectable DNA will be 
allowed into the study but will require regular monitoring of hepatitis B virus DNA. 
 
Hemoglobin  7 g/dL, unless caused by autoimmune hemolytic anemia resulting from SLE 
 
Platelet count  10,000/L 
 
Positive serum human chorionic gonadotropin measured prior to the first obinutuzumab 
infusion 
 
Known intolerance to MMF and MPA 
 
LENGTH OF STUDY 
The study will follow all patients for a minimum of 78 weeks after the last infusion of 
obinutuzumab at Day 182.  In consideration of recruitment and follow-up (independent of B-Cell 
follow-up [BCFU]), the length of study is estimated to be greater than 36 months.  Patients may 
enter BCFU and continue to be evaluated for safety on a limited basis. 
END OF STUDY 
The end of this study is defined as the last patient’s last visit at Week 104. This has been 
selected to enable 78 weeks (~18 months) of safety follow-up after the last dose of study drug 
to assess the occurrence of adverse events and to enable an assessment of peripheral blood 
CD19+ B cell return. 
Additional B-cell follow-up (BCFU) visits will occur until patients have achieved their baseline 
CD19+ count or achieved 25 cells/μL CD19+ count (the lower limit of normal (LLN) of CD19+ B 
cells for this lupus population), whichever occurs first.  B-cell follow-up (BCFU) visits for all 
patients will end when the last patient has completed ~18 months of safety follow-up from the 
last dose of blinded obinutuzumab infusion. 
Patients who receive additional therapies that reduce peripheral B-cell counts will not be 
included in BCFU. 
OUTCOME MEASURES 
PRIMARY EFFICACY OUTCOME MEASURE 
The primary efficacy outcome measure is the proportion of patients who achieve a CRR, 
evaluated at 52 weeks. 
CRR is defined by attainment of all of the following: 
 
Normalization of serum creatinine as evidenced by the following: 
Serum creatinine  the ULN range of central laboratory values if baseline (Day 1) serum 
creatinine is above the ULN 
Serum creatinine  15% above baseline and  the ULN range of central laboratory 
values if baseline (Day 1) serum creatinine is  the ULN range of central laboratory 
values 
 
Inactive urinary sediment (as evidenced by  10 RBCs/high-power field (HPF) and the 
absence of red cell casts) 
 
Urinary protein to creatinine ratio  0.5 
 
SECONDARY EFFICACY OUTCOME MEASURES  
The secondary efficacy outcome measures are the following: 
 
Proportional analysis of patients who achieve an overall response at Week 52 (CRR  PRR) 
 
Time to overall response (CRR  PRR) over the course of 52 weeks 
 
Percent reduction or increase from baseline and mean andmedian assessments of 
biomarkers of LN disease activity (e.g., reduction in anti-dsDNA antibody levels, increase 
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 
Proportion of patients that achieve a PRR at Week 52 as defined by attainment of all of the 
following: 
Serum creatinine  15% above baseline value 
No urinary red cell casts and either RBCs/HPF  50% above baseline or  10 RBCs/HPF 
50% improvement in the urine protein to creatinine ratio, with one of the following 
conditions met: 
If the baseline urine protein to creatinine ratio is  3.0, then a urine protein to 
creatinine ratio of  1.0 
If the baseline protein to creatinine ratio is  3.0, then a urine protein to creatinine 
ratio of  3.0 
 
Proportion of patients who achieve a CRR at Week 24 
 
Time to CRR, over the course of 52 weeks. 
 
Proportion of patients that achieve a modified CRR (mCRR1) at Week 52 employing the 
primaryefficacy measure definition and removing the urinary sediment analysis criteria 
mCRR1 is defined by attainment of normalization of serum creatinine as evidenced by 
the following: 
Serum creatinine  the ULN range of central laboratory values if baseline (Day 1) 
serum creatinine is above the ULN 
Serum creatinine  15% above baseline and  the ULN range of central laboratory 
values if baseline (Day 1) serum creatinine  the ULN range of central laboratory 
values 
Urinary protein to creatinine ratio  0.5 
 
Proportion of patients that achieve a second modified CRR (mCRR2) at Week 52 as 
defined by attainment of the following: 
Normalization of serum creatinine as evidenced by the following: 
Serum creatinine  15% above baseline if baseline (Day 1) serum creatinine is 
above the normal range of the central laboratory values or  the ULN range of 
central laboratory values if baseline (Day 1) serum creatinine is  the ULN range of 
central laboratory values 
Inactive urinary sediment (as evidenced by  10 RBCs/HPF and the absence of red cell 
casts) 
Urinary protein to creatinine ratio  0.5 
 
Proportion of patients that achieve a third modified CRR (mCRR3) at Week 52 as defined 
by attainment of the following: 
Normalization of serum creatine as evidenced by serum creatinine  the ULN range of 
central laboratory values 
Urinary protein to creatinine ratio  0.5 
 
The hierarchical ordering of the secondary endpoints will be pre-specified in the SAP. 
SAFETY OUTCOME MEASURES 
The safety outcome measures for this study are as follows: 
 
Incidence, type, and severity of adverse events 
 
Abnormal vital signs 
 
Abnormal laboratory values 
 
Safety will be monitored through regular physical examinations, vital signs, hematologic and 
chemistry laboratory tests, urinalyses, and incidence and severity of adverse events.  In 
addition, the following will be examined: 
 
Circulating B cells, T cells, neutrophils and other cell populations 
 
Plasma immunoglobulins (total Ig, IgG, IgM, and IgA) 


 
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 
Record of menses 
 
Pregnancy 
 
Antibody titers for mumps, rubella, Varicella, tetanus, influenza, and Streptococcus 
pneumoniae 
 
PHARMACODYNAMIC OUTCOME MEASURE 
The primary PD outcome measure for this study is as follows: 
 
Changes in levels of circulating CD19 B-cells relative to baseline 
 
PHARMACOKINETIC OUTCOME MEASURES 
The obinutuzumab PK outcome measures for this study are as follows: 
Non-linear mixed-effects modeling (with software NONMEM) will be used to analyze the dose-
concentrationtime data of obinutuzumab.  The PK profile data will be used to further develop a 
PK model, including the effect of major covariates (e.g., sex, race/ethnicity, weight, biochemical 
and hematological parameters at baseline, degree of underlying disease), on the main 
parameters (e.g., clearance).  The derivation of individual measures of exposure, such as area 
under the concentration-time curve and maximum concentration observed will depend on the 
final PK model used for this analysis.  Results of this analysis may be reported separately.  
Serum obinutuzumab will be summarized (mean, minimum, maximum, SD, and geometric 
mean) and reported within this study.  
Exploratory graphical analyses will be performed to assess whether the occurrences of serious 
adverse events and abnormalities in the safety laboratory parameters in patients treated with 
obinutuzumab can be attributed to obinutuzumab exposure.  Also, exploratory 
graphical analyses will be performed to assess whether the variability in response can be 
attributed to the variability in obinutuzumab exposure.  Relevant observed relationships 
between exposure and safety parameters may be further characterized using different 
approaches such as logistic regression analysis and indirect response modeling.  
Additional PK and PD analyses may be conducted as appropriate. 
PATIENT-REPORTED OUTCOME MEASURE 
The PRO measure for this study is as follows: 
 
Subject’s Global Assessment 
This visual analog scale (VAS) will be captured in screening, at the baseline visit, and at 
several timepoints during study conduct. 
 
EXPLORATORY OUTCOME MEASURES 
The exploratory outcome measures for this study are as follows: 
 
Changes in levels of circulating B-cell subsets relative to baseline  
 
Changes in levels of exploratory biomarkers, which may include but are not limited to levels 
of protein and mRNA in serum, plasma, blood, and urine, relative to baseline  
 
Proportion of patients experiencing a Systemic Lupus Erythematosus Disease Activity 
Index-2K flare 
 
Proportion of patients experiencing a renal flare over 52 weeks and 104 weeks 
 
Proportion of patients achieving CRR, mCRR1, mCRR2, and mCRR3 at additional 
timepoints, including Week 12 and Week 36 
 
Physician’s Global Assessment 
This VAS will be captured in screening, at the baseline visit, and at several timepoints 
during study conduct. 
 
GTCI 
 
Renal biopsy evaluations 
 


 
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INVESTIGATIONAL MEDICINAL PRODUCTS 
TEST PRODUCT (INVESTIGATIONAL DRUG) 
The test product for this study is obinutuzumab and will be administered by IV infusion at a dose 
of 1000 mg on Days 1, 15, 168, and 182.  The study drug will be administered in a hospital or 
clinic environment where full resuscitation facilities are immediately available and under close 
supervision of the investigator or designee.  After the end of the first infusion, the IV line will 
remain in place for at least 2 hours to enable administration of IV drugs if necessary.  If no 
adverse events occur during this period of time, the IV line may be removed.  For subsequent 
infusions, access through an IV line should remain in place for at least 30 minutes from the end 
of the infusion, and if no adverse events occur after 30 minutes, the IV access may be removed. 
COMPARATOR (PLACEBO) 
The obinutuzumab placebo (corresponding to the obinutuzumab1000-mg dose) will be 
administered by IV infusion on Days 1, 15, 168, and 182.  The placebo will be administered in a 
hospital or clinic environment where full resuscitation facilities are immediately available and 
under close supervision of the investigator or designee.  After the end of the first infusion, the IV 
line will remain in place for at least 2 hours to enable administration of IV drugs if necessary.  If 
no adverse events occur during this period of time, the IV line may be removed.  For 
subsequent infusions, access through an IV line should remain in place for at least 30 minutes 
from the end of the infusion, and if no adverse events occur after 30 minutes, the IV access may 
be removed. 
NON-INVESTIGATIONAL MEDICINAL PRODUCTS 
After screening, patients who were not already receiving MMF or MPA will receive 1500 mg/day 
(or equivalent) in divided doses (23 times/day), and all patient doses will be titrated upward to 
a target dose of 2.02.5 g/day (or equivalent) in divided doses (23 times/day) by Week 4, as 
tolerated.  If reductions in dose are necessary, decreases will be allowed in 250500 mg (or 
equivalent) decrements.  During screening or at randomization, if clinically indicated, patients 
may receive 7501000 mg methylprednisolone IV once daily for up to 3 days to treat underlying 
LN clinical activity.  Patients will receive 0.5 mg/kg oral prednisone, tapering this prednisone 
dose, per protocol, starting on Day 16 and reducing the prednisone dosage to 7.5 mg/day by 
Week 12. 
Prior to each infusion of either study drug or placebo, patients should receive prophylactic 
treatment with acetaminophen (6501000 mg) and diphenhydramine (50 mg; or equivalent dose 
of a similar agent) by mouth, given 3060 minutes before the start of the infusion period.  The 
patients who are receiving obinutuzumab will receive 80 mg methylprednisolone IV and patients 
who are receiving placebo will receive placebo-methylprednisolone IV given 3060 minutes 
before the start of the obinutuzumab/placebo infusion. 
CONCOMITANT THERAPY AND CLINICAL PRACTICE 
Patients who are not already taking vitamin D (800 IU/day) and calcium supplements 
(1200 mg/day of calcium citrate or 1500 mg/day of calcium carbonate) will begin taking these 
supplements at randomization.  All patients will take either an ACE inhibitor or an 
angiotensin-receptor blocker titrated to adequate blood pressure control as recommended by 
the National Kidney Foundation for chronic kidney disease. 
Other agents that affect proteinuria will not be allowed to be initiated during the study.  These 
include but are not limited to the following: 
 
Non-dihydropyridine calcium antagonists 
 
Dihydropyridine calcium antagonists 
 
Aldosterone antagonists 
 
Direct renin antagonists 
 
STATISTICAL METHODS 
All efficacy outcomes will be analyzed according to the modified intent-to-treat principle and will 
include all randomized patients who have received any amount of study drug.  Patients will be 
grouped according to randomized (assigned) treatment, rather than treatment received. 


 
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Treatment period data will be locked after all patients have completed the Week 52 visit.  The 
primary efficacy and safety analyses will be performed on data for all patients through the Week 
52 assessments or early discontinuation. 
Safety assessments will be performed on patients who receive study medication.  In all safety 
analyses, patients will be grouped according to the treatment that patients actually received 
rather than the treatment assigned. 
The primary and secondary efficacy analyses will include all randomized patients who received 
any study medication, with patients grouped according to the treatment assigned at 
randomization. 
PRIMARY ANALYSIS 
The primary assessment of efficacy of obinutuzumab, to induce a clinically significant 
improvement in renal function in patients with ISN/RPS 2003 class III or IV LN, will be assessed 
by attainment of CRR. 
CRR is defined as achievement of all of the following: 
 
Normalization of serum creatinine as evidenced by the following: 
Serum creatinine  the ULN range of central laboratory values if the baseline (Day 1) 
serum creatinine is above the ULN 
Serum creatinine  15% above baseline and  the ULN range of central laboratory 
values if baseline (Day 1) serum creatinine is  the ULN range of central laboratory 
values 
 
Inactive urinary sediment (as evidenced by  10 RBCs/HPF and the absence of red cell 
casts) 
 
Urinary protein to creatinine ratio  0.5 
 
Any patient who switches to rescue medication prior to Week 52 will be considered a 
non-responder. 
The proportions of patients achieving CRR across treatment groups will be compared using a 
Cochrane-Mantel-Haenzel (CMH) test with race (Afro-Caribbean/African American versus 
others) and region (United States versus non-United States) as stratification factors.  If the test 
result is in favor of the obinutuzumab group at   0.1-level (one-sided), it will be concluded that 
there is a shift toward better renal response associated with the obinutuzumab group. 
DETERMINATION OF SAMPLE SIZE   
This Phase II study is a proof-of-concept study that is designed to detect an improvement in 
CRR.  The primary efficacy endpoint of this study is the proportion of patients that achieve CRR. 
It is estimated that approximately 30% of patients with proliferative LN who are receiving MMF 
(or equivalent) will achieve a CRR at Week 52 and that the addition of obinutuzumab to MMF 
(or equivalent) will induce an overall CRR rate of 50% at Week 52.  On the basis of these 
assumptions, a total of 120 patients randomized to obinutuzumab- and placebo-treated groups 
in a 1:1 ratio (60 patients in each of the obinutuzumab- and placebo-treated groups) will yield 
approximately 83% power at the two-sided   0.2 significance level using a CMH test, 
assuming the same CRR proportions across the strata. 
INTERIM ANALYSES 
Pharmacodynamic Futility Interim Analysis 
Given the rationale for this study, including the results from the LUNAR and BELONG studies, 
an interim analysis for futility is planned on the basis of CD19 B-cell counts after 30 patients 
have been assigned to the obinutuzumab arm and have had their Day 28 blood CD19 B-cell 
counts assessed by HSFC. 
The effect of rituximab on CD19 B-cell counts has been measured by HSFC in an investigator-
sponsored study in which peripheral B-cell depletion below the lower limit of quantification 
(LLOQ) of the assay occurred in 46% of patients.  Slightly less than half of these rituximab-
treated patients with full peripheral B-cell depletion achieved a major clinical response, with the 
remainder of the patients having partial clinical responses.  Therefore, it is hypothesized that an 
improved outcome over rituximab is achievable for a LN patient population with full peripheral B-
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peripheral depletion.  To test the hypothesis in this study, we will require at least 50% of the 
obinutuzumab-treated patients to have peripheral B-cell depletion below the LLOQ of the HSFC 
assay in order to have a realistic chance of a positive primary endpoint analysis for the 
treatment arm.  Quantification of the link between this biomarker and the study’s primary 
analysis has not been established; therefore predictive probabilities for study statistical 
significance cannot be provided.  Consequently, the study will be terminated if the 5% one-sided 
Clopper-Pearson upper confidence limit for the proportion of patients who achieve B-cell 
depletion is not greater than 0.5.  Assuming that there are 30 patients at the time of the interim 
analysis, this will effectively require that  11 obinutuzumab patients have complete B-cell 
depletion below the LLOQ of the HSFC assay at the time of the interim analysis. 
The interim analysis will be performed by the independent Data Monitoring Committee (iDMC), 
which may recommend that the study be stopped for futility if the futility criterion is satisfied.  
Additional criteria for recommending that the study be stopped for futility may be added to the 
iDMC Charter. 
As this interim analysis will only result in termination of the study due to futility, and not for 
efficacy, an adjustment to the -level is not required.  Although the outcome of the interim 
analysis may reduce the power of this study to below the estimated 83%, a sample size 
adjustment has not been made. 
Renal Response Interim Analysis 
The iDMC will conduct an interim efficacy analysis to evaluate renal response when the last 
patient has achieved the 6-month visit.  The interim analysis will be performed and interpreted 
by members of the iDMC, who may recommend to the Sponsor the initiation of future study 
planning, according to rules outlined in the iDMC Charter.  If the iDMC does recommend that 
future study planning can begin, then the summary of renal response data at Week 24 will be 
shared with appropriate Sponsor senior management personnel who will be unblinded at the 
treatment group level. 
This interim analysis is for planning purposes only and will have no impact on the progression of 
this study.  Consequently, an adjustment to the -level is not required. 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ACE 
angiotensin-converting enzyme 
ACR 
American College of Rheumatology 
ADA 
anti-drug antibody 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
ALMS 
Aspreva Lupus Management Study 
ANA 
anti-nuclear antibody 
ARB 
angiotensin-receptor blocker 
AUC 
area under the concentration–time curve 
BAFF 
B-cell activating factor 
BCFU 
B-cell follow-up 
CDC 
complement-dependent cytotoxicity 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum concentration observed 
CMH 
Cochrane-Mantel-Haenzel 
CRR 
complete renal response 
EC 
Ethics Committee 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ESRD 
end-stage renal disease 
GC 
germinal center 
GFR 
glomerular filtration rate 
GI 
gastrointestinal 
GTCI 
Glucocorticoid Toxicity Change Index 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HPF 
high-power field 
HSFC 
high-sensitivity flow cytometry 
ICH 
International Conference on Harmonisation 
iDMC 
independent Data Monitoring Committee 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
ISN 
International Society of Nephrology 
IV 
intravenous 


 
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Abbreviation 
Definition 
IxRS 
interactive voice/Web response system 
LLN 
lower limit of normal 
LLOQ 
lower limit of quantification 
LN 
lupus nephritis 
mAb 
monoclonal antibody 
mCRR1 
modified complete renal response 
mCRR2 
second modified complete renal response  
mCRR3 
third modified complete renal response 
MMF 
mycophenolate mofetil 
MOA 
mechanism of action 
MPA 
mycophenolic acid 
NaCl 
sodium chloride 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events  
NHL 
non-Hodgkin’s lymphoma 
NK 
natural killer 
NSAID 
nonsteroidal anti-inflammatory drug 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PML 
progressive multifocal leukoencephalopathy 
PRO 
patient-reported outcome 
PRR 
partial renal response 
RCR 
Roche Clinical Repository 
RPS 
Renal Pathology Society 
SAP 
Statistical Analysis Plan 
SLE 
systemic lupus erythematosus 
SLEDAI 
Systemic Lupus Erythematosus Disease Activity Index 
SLICC 
Systemic Lupus International Collaborating Clinics 
TI 
tubulointerstitial inflammation 
ULN 
upper limit of normal 
VAS 
visual analog scale 
 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON LUPUS NEPHRITIS 
Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease that occurs 
primarily in women of childbearing age.  It is characterized by multisystem involvement 
and immunological abnormalities, and much of the tissue damage is thought to occur 
through autoantibody formation and immune complex deposition.  The disease is 
heterogeneous in its clinical presentation, course, and prognosis.  However, most 
patients present with joint involvement, skin rashes, mouth ulcers, Raynaud’s 
phenomenon, and/or severe fatigue.  Inflammation of pericardial and pleural tissues may 
also be present.  The most serious manifestations include CNS and renal involvement, 
which correlate with poor outcomes that include temporary or permanent disability or 
death.  Typically, the disease follows a relapsing-remitting course with intermittent 
periods of disease activity (flare) interspersed with periods of relative quiescence. 
The incidence and prevalence of SLE varies with sex, race, and ethnicity.  The 
estimated prevalence of SLE in the United States ranges between 65 and 155 per 
100,000 (Walsh et al. 2001; Ward 2004; Naleway et al. 2005; Chakravarty et al. 2007; 
Molina et al. 2007; Sacks et al. 2010; Feldman et al. 2013; Furst et al. 2013; 
Lim et al. 2014).  In adulthood, approximately nine times as many women as men are 
affected.  The disease has a higher incidence and worse outcome among 
African-Americans, Afro-Caribbeans, Hispanics, and Asians compared with Caucasians. 
Medications for the successful treatment of SLE as measured by long-term remission 
are limited, and only one new medication for SLE treatment has been approved in more 
than 50 years (Burness and McCormack 2011).  Analgesics and nonsteroidal 
anti-inflammatory drugs (NSAIDs) provide partial symptomatic relief.  Anti-malarial drugs 
are generally well tolerated by patients with SLE and appear to have a beneficial effect 
on the prevention of lupus flares, increasing long-term survival, and possibly 
ameliorating certain types of organ damage (Ruiz-Irastorza et al. 2009).  However, these 
agents are generally regarded as having insufficient efficacy for moderate to severe 
manifestations of SLE. 
The mainstays of therapy for more significant manifestations of SLE are corticosteroids 
and off-label use of immunosuppressive drugs (e.g., methotrexate, mycophenolic acid 
[MPA] [as either mycophenolate mofetil (MMF) or Myfortic (MPA as sodium salt)], 
azathioprine, and cyclophosphamide), which have profound and diverse effects on the 
immune system in patients with lupus.  However, the use of these immunosuppressant 
agents is limited by their safety profiles.  Corticosteroids, for example, are effective for 
many of the manifestations of SLE but have significant short- and long-term adverse 
effects, including infections, osteoporosis, hyperglycemia, and hyperlipidemia. 
Lupus nephritis (LN) is a common manifestation of SLE and continues to be a major 
cause of morbidity and mortality in this patient population.  Of unselected patients with 


 
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SLE, 25%50% have abnormalities of urine or renal function early in the course of their 
disease, and up to 60% of adults and 80% of children may eventually develop overt
renal abnormalities (Cameron 1999).  Proteinuria is the most common feature of LN, 
often in the nephrotic range, and is frequently accompanied by a worsening of renal 
function.  The clinical course of LN varies from mild subclinical disease to an aggressive 
course that may progress to end-stage renal disease (ESRD) (Flanc et al. 2004).  This is 
particularly concerning because patients with LN, despite having a decrease in clinical 
lupus activity after they begin renal replacement therapy, have been noted to have
poorer outcomes than other patients with non-lupus causes of ESRD (Lee et al. 2003).
The nature and severity of the clinical features do not always predict the underlying 
histological severity, and renal biopsy is necessary for a precise diagnosis.  The findings 
from a consensus conference in 2002 on renal pathology in LN were adopted by the 
International Society of Nephrology (ISN) and the Renal Pathology Society (RPS)
leading to the ISN/RPS 2003 classification system (Weening et al. 2004).  This 
classification scheme grades LN on the basis of histological features seen using light 
microscopy (see Table 1).
Table 1 
International Society of Nephrology/Renal Pathology Society
2003 Classification of Lupus Nephritis
Class I 
Minimal mesangial LN
Class II 
Mesangial proliferative LN
Class III 
Focal LN ( 50% of glomeruli)
III (A):  active lesions
III (A/C):  active and chronic lesions 
III (C):  chronic lesions
Class IV 
Diffuse LN ( 50% glomeruli)
Diffuse segmental (IV-S) or global (IV-G) LN 
IV (A):  active lesions
IV (A/C):  active and chronic lesions
IV (C):  chronic lesions
Class V 
Membranous LN
Class VI 
Advanced sclerosing LN ( 90% globally sclerosed glomeruli without
residual activity)
LN  lupus nephritis.
Note:  Class V may occur in combination with Class III or IV, in which case both will be 
diagnosed.
Source:  Markowitz GS, D’Agati VD. The ISN/RPS 2003 classification of lupus nephritis: an 
assessment at 3 years. Kidney Int 2007;71:491–5.
 


 
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Cyclophosphamide, MMF or MPA, and azathioprine, along with corticosteroids, have 
been used in the treatment of proliferative Class III/IV LN with varying degrees of
success and varying adverse effects (Houssiau et al. 2004).  Cyclophosphamide
became a dominant standard of care in the 1980s, yet acute and dose-limited toxicity 
prompted the investigation of lower-dose regimens such as the Euro-lupus regimen 
(Houssiau et al. 2002).  Toxicity also prompted the search for new therapies, including 
MMF (Chan et al. 2000; Ginzler et al. 2005), and a study that directly compared the two 
therapies (Contreras et al. 2004).  Given the organ-threatening severity of LN, 
placebo-controlled studies were not considered to be appropriate to prove the efficacy of 
either agent, and both cyclophosphamide and MMF became unapproved standards of 
care (Hahn et al. 2012).
A major advance in the treatment of patients with LN was the demonstration that MMF 
was comparable in efficacy and safety to cyclophosphamide in the Aspreva Lupus 
Management Study (ALMS) (Appel et al. 2009) and potentially superior to azathioprine
in remission maintenance (Dooley et al. 2011).  These critical studies solidified the place 
of MMF as a potentially effective therapy for LN, although MMF was not found to be 
superior to cyclophosphamide.  Both MMF and cyclophosphamide are considered to be 
first-line therapies for the treatment of patients with proliferative LN, as outlined in the 
American College of Rheumatology (ACR) Lupus Nephritis Guidelines
(Hahn et al. 2012).
As a measure of unmet need, the risk of mortality remains elevated for patients with 
lupus.  In the modern era, on the basis of a multisite international cohort of 9500 patients 
with lupus, the standardized mortality ratio was 2.4, with particularly high mortality seen 
with renal disease (Bernatsky et al. 2006). Among patients with LN, 10%-30% of 
patients progress to ESRD despite aggressive immunosuppressive therapy
(Costenbader et al. 2011).  Whereas these outcomes have improved over the past
30 years, continued risk of treatment failure remains (as defined by death, ESRD, 
sustained doubling of serum creatinine, LN flare, or need for rescue medications), which 
ranges 14.5%-20.1% per 100 patient-years over the course of follow-up
(Dooley et al. 2011; Rovin et al. 2012).
1.2 
BACKGROUND ON OBINUTUZUMAB
Obinutuzumab (also known as GAZYVA or GA101) is a recombinant, monoclonal, 
humanized, and glycoengineered type II CD20 antibody of the IgG1 isotype that 
specifically targets the extracellular loop of the CD20 transmembrane antigen that is 
expressed on the surface of non-malignant and malignant pre-B and mature
B lymphocytes but not on hematopoietic stem cells, pro-B cells, normal plasma cells, or 
other normal tissue (Mössner et al. 2010; Niederfellner et al. 2011; Klein et al. 2013). 
Glycoengineering of the Fc portion of obinutuzumab results in a higher affinity for 
FcgRIII receptors on immune effector cells such as natural killer (NK) cells and 
macrophages/monocytes (Mössner et al. 2010).


 
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Obinutuzumab in combination with chlorambucil is currently approved in multiple 
countries worldwide for the treatment of patients with previously untreated chronic 
lymphocytic leukemia (CLL). 
Data from an estimated 3284 patients, up to 31 October 2014, are available for safety 
analysis of obinutuzumab in clinical studies.  These data include patients with CLL or 
non-Hodgkin’s lymphoma (NHL) from doses of 502000 mg in monotherapy or in 
combination with cyclophosphamide, doxorubicin, vincristine, and prednisone; 
fludarabine plus cyclophosphamide; bendamustine; or chlorambucil. 
Nonclinical in vitro studies show that obinutuzumab mediates superior induction of direct 
cell death and effector cell-mediated antibody-dependent cell-mediated cytotoxicity 
(ADCC) and antibody dependent cellular phagocytosis on a panel of NHL cell lines 
compared with the type I CD20 antibodies rituximab and ofatumumab.  Conversely, its 
potency to mediate complement-dependent cytotoxicity (CDC) is significantly reduced 
compared with these two antibodies.  In ex vivo autologous whole-blood B-cell depletion 
studies with blood from healthy volunteers as well as patients with CLL, obinutuzumab 
mediated superior B-cell depletion when compared with rituximab.  
These properties of obinutuzumab translated into superior anti-tumor efficacy in direct 
comparison with rituximab against a number of aggressive subcutaneous and 
disseminated NHL xenograft models.  The efficacious and optimal dose range of 
obinutuzumab in xenograft models ranged 1030 mg/kg, corresponding to trough levels 
of 300600 g/mL.  Treatment with obinutuzumab resulted in potent and superior 
depletion of B-cells in the peripheral blood and in lymphoid tissues of hCD20 transgenic 
mice and cynomolgus monkeys.  Vaccination studies in cynomolgus monkeys and 
human CD20 transgenic mice showed that the enhanced efficacy in terms of the B-cell 
depletion of obinutuzumab translated into suppression of de novo antibody responses 
but left the protective humoral memory responses intact. 
The data generated to date imply that obinutuzumab represents a novel therapeutic 
anti-CD20 antibody with outstanding efficacy compared with classical type I and 
non-ADCC-enhanced anti-CD20 antibodies, such as rituximab, ocrelizumab and 
ofatumumab. 
See the immunology Obinutuzumab Investigator's Brochure for additional details on 
nonclinical and clinical studies of obinutuzumab. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Multiple studies have demonstrated histopathologic involvement of B and T cells in LN 
pathogenesis.  A temporal model established from lupus-prone mice strains with 
nephritis suggests that autoantibodies and immune complexes deposit within the 
glomerular basement membrane of the kidney, fix complement, and cause local 
inflammation.  Lymphocytes, macrophages, and neutrophils migrate into the kidney and 


 
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establish continued tubulointerstitial inflammation (TI) that triggers proliferative 
mesangial changes in the glomeruli with resultant proteinuria, hematuria, and altered 
renal function.  This experimental nonclinical model demonstrates antibody-producing 
cells (APCs) that mature into plasma cells (Cassese et al. 2001).  As an organized 
immunologic reaction involving B cells, T cells, macrophages, and supporting dendritic 
cells becomes amplified, renal function further deteriorates and is fatal in multiple mouse 
models. 
The presence of B cells in LN has been better characterized over the past 10 years 
(Steinmetz et al. 2008; Lee and Ballow 2010).  Recently, Chang et al. (2011) published 
an extensive histopathologic review of LN biopsy samples from a longitudinal series of 
patients at the University of Chicago.  This review confirms the presence of B cells in LN 
biopsies and describes their organization into T:B-cell aggregates and germinal centers 
(GCs).  The review also confirmed that TI is an important pivotal variable and an 
independent risk factor in predicting renal outcomes in patients with LN (Hill et al. 2000; 
Alsuwaida et al. 2013).  On renal biopsy, the presence and degree of TI is prognostic 
and may identify those patients with LN who are at risk for progression to renal failure 
(Schwartz et al. 1982; Esdaile et al. 1989; Hsieh et al. 2011).  As such, TI is a central 
manifestation of LN that might arise from different pathogenic mechanisms from those 
implicated in glomerulonephritis, and it may serve as a potential therapeutic target in this 
disease. 
These data, demonstrating the presence of B cells in LN, implicate tertiary lymphoid 
neogenesis in the pathogenesis of lupus TI.  The presence of lymphoid-like structures 
strongly correlated with detectable tubular basement membrane immune complexes.  
These observations suggested that in LN, GCs, and T:B aggregates select for cells that 
locally secrete pathogenic antibodies in the tubulointerstitium.  Furthermore, the data 
indicated that such plasmablast foci are a usual feature of LN that is complicated by 
severe TI.  Although interstitial inflammation often correlates with the extent of 
glomerular injury in LN, there are several lines of evidence that these processes may be 
distinct.  Chang et al. (2011) hypothesized that identification of the in situ antigens and 
factors promoting local B-cell selection and expansion of organized immunological 
structures in the interstitium should yield important biomarkers and could lead to novel 
therapeutic strategies in LN.  Anti-vimentin autoantibodies are being investigated as a 
potentially pathogenic autoantibody produced by vimentin expression in the damaged 
interstitium (Kinloch et al. 2014).  
Genentech and Roche have experience conducting LN clinical studies with two 
anti-CD20 compounds:  rituximab and ocrelizumab.  Study U2790g (the LUNAR study; 
Rovin et al. 2012) was a randomized, parallel arm, add-on double-blind 
placebo-controlled study in patients with Class III and IV proliferative LN.  The study 
evaluated the regimen of rituximab plus MMF versus MMF in combination with 
methylprednisolone infusions and a prednisone taper and enrolled 144 adult patients in 
North and South America.  The study failed to meet its primary endpoint of overall 


 
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response (weighted toward complete renal response [CRR]); no major new safety 
signals were identified.  The LUNAR study determined that the combination of 
rituximab  MMF was more effective at reducing anti-dsDNA autoantibody levels and 
increasing complement levels than MMF alone.  In addition, there was a 15.3% increase 
of partial renal response (PRR) with rituximab, and fewer patients in the rituximab arm 
required rescue with cyclophosphamide (n  1) versus the MMF-alone arm (n  8).  A pre-
specified sub-analysis of African American patients (n  40) demonstrated that 70% of 
these patients responded (PRR  CRR) in the rituximab arm versus 45% in the 
MMF-alone arm (p  0.2) (Rao et al. 2012).  This analysis clarified that non-responders 
had higher mean serum creatinine levels, a higher degree of proteinuria, and higher 
mean blood pressure than did responders. 
The partial response observed in the LUNAR study, in addition to the multiple 
publications that suggest partial response in patients with more refractory disease 
(Lu et al. 2009; Jónsdóttir et al. 2010; Roccatello et al. 2011; Turner-Stokes et al. 2011; 
Díaz-Lagares et al. 2012; Gregersen and Jayne 2012; Furtado and Isenberg 2013), 
particularly with the combination of rituximab and cyclophosphamide (Ng et al. 2007), 
has suggested that rituximab has a place in the treatment of these patients and led to its 
incorporation into the ACR LN Treatment Guidelines in 2013 (Hahn et al. 2012).  This 
partial response difference along with the improvement in anti-dsDNA antibody and 
complement levels suggests that the drug has activity, but not at the level of CRR.  
These findings, in addition to lupus-related factors described below that might impair 
rituximab’s ability to deplete B cells in SLE, are consistent with the hypothesis that 
incomplete local B-cell depletion contributed to a partial response and that a more 
efficient B-cell depleting agent (obinutuzumab) might be associated with greater efficacy. 
A PRR improvement was also observed in a second company-sponsored study of LN, 
Study WA20500 (the BELONG study; Mysler et al. 2013).  The BELONG study was a 
Phase III dose-ranging study that evaluated ocrelizumab, a humanized anti-CD20 
monoclonal antibody (mAb) therapy with 35-fold greater ADCC than rituximab.  The 
BELONG study enrolled 350 patients in an international, double-blind, randomized, 
controlled dose-ranging study enrolling Class III and Class IV patients with LN who were 
treated with a background therapy of either MMF or Euro-Lupus-regimen 
cyclophosphamide (500 mg intravenous [IV] every 2 weeks  6 doses).  This study was 
terminated because of a minor imbalance of serious infectious events (largely confined 
to countries in Asia) and after the LUNAR study data became available, suggesting that 
the likelihood of a positive outcome had decreased significantly. 
There were several notable findings from the BELONG study.  Ocrelizumab was 
associated with a 12.2% increase in overall response (66.9%) across both doses and 
background treatments compared with controls (54.7%).  In the Euro-Lupus 
regimen-cyclophosphamidetreated patients, ocrelizumab was associated with a 22.7% 
increase in overall response (65.6%) across both doses compared with the control 
(42.9%).  Serious infectious events were clustered within the first 12 weeks of the study, 


 
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consistent with the time of maximal prednisone exposure.  Lastly, ocrelizumab was 
associated with a significant decrease in anti-dsDNA antibody levels and an 
improvement in complement levels compared with the controls.  These findings replicate 
the efficacy and immunologic outcomes from the LUNAR study and are consistent with 
the hypothesis that patients with LN are resistant to B-cell depletion and that anti-CD20 
therapy is associated with PRR. 
There are available data that demonstrate that achievement of CRR is prognostic of a 
good long-term outcome (Chen et al. 2008); however, across the LUNAR and BELONG 
studies, only 30%40% of patients were able to achieve CRR at 12 months.  In the 
LUNAR study (Rovin et al. 2012), 54% of the patients who were randomized to the 
high-dose MMF/high-dose prednisone arm achieved no response, defined as failure to 
achieve PRR or CRR or having met another definition of treatment failure.  Recently, 
efforts have been made to identify subsets of patients treated with either Euro-Lupus 
cyclophosphamide (Houssiau et al. 2004) or MMF (Dall’Era et al. 2011) who achieve a 
short-term favorable outcome and are of potentially lower unmet medical need.  The 
putative biomarkers from the ALMS database that predict good response are baseline 
C4 level, duration of diagnosis, baseline estimated glomerular filtration rate (GFR), early 
normalization of complement, and reduction of proteinuria by  25% from baseline 
(Dall’Era et al. 2011).  Other clinical prognostic factors such as non-Caucasian race, 
poor socioeconomic status, uncontrolled hypertension, high activity and chronicity score 
(on biopsy), baseline renal impairment, nephritic relapses, and poor initial therapy 
response have been associated with a poor outcome and thus higher unmet need.  With 
these factors in mind, a significantly high proportion of patients have poor prognostic 
factors and exhibit major unmet medical needs despite currently available therapies.  A 
recent review of 73 patients undergoing renal biopsy for LN concluded that persistence 
of interstitial inflammation is also associated with poor long-term outcome, yet few 
patients receive repeat renal biopsies, suggesting that unrecognized, uncontrolled 
inflammation may be present in many patients (Alsuwaida 2013).  Existing therapies 
have known toxicities that can limit their use, and prednisone toxicity is increasingly 
recognized as a major concern with standard induction regimens (Petri et al. 2014).  
Higher rates of CRR, faster achievement of CRR, improved tolerability of drugs, 
significant reduction of prednisone exposure, and reduction of flares in maintenance 
stages have currently not been achieved.  
The scientific rationale for the experimental use of obinutuzumab in LN is supported by 
multiple experiments that suggest that patients with SLE are resistant to B-cell depletion 
with rituximab, as described below.  SLE is considered a classic autoimmune disease 
marked by a loss of B-cell tolerance (Rahman and Isenberg 2008).  There are multiple 
publications that document the presence of B cells in active LN, both from experimental 
mouse models of lupus (Cassese et al. 2001) and also from more recent surveys of LN 
histopathology (Chang et al. 2011).  This evidence demonstrates a primary role for 


 
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B cells in disease pathogenesis; however, two studies using anti-CD20 therapies in LN 
(the LUNAR and BELONG studies) demonstrated only partial responses. 
Recent data suggest that B cells are resistant to and are incompletely depleted by 
rituximab in the peripheral blood of patients with SLE (Vital et al. 2011).  The explanation 
for this finding may be related to the putative mechanisms of actions (MOAs) of 
rituximabthe indirect depletion of CD20 B cells by ADCC and CDC and via apoptotic 
mechanisms, as well as new information that all three may be impaired in patients with 
lupus. 
ADCC and the interaction between the Fc portion of rituximab and the effector cell may 
be altered in SLE (Ahuja et al. 2011).  CDC may be impaired by the 
hypocomplementemic environment of LN, and the role of complement in B-cell depletion 
of patients with SLE has not been formally studied (Leffler et al. 2014).  Apoptotic 
defects are known to occur in SLE (Bouts et al. 2012), and this resistance to normal 
cellular death may translate to incomplete B-cell killing with rituximab via this 
mechanism.  In addition, the elevated human anti-chimeric antibody rates that were 
observed in the rituximab lupus studies and the early peripheral B-cell return that was 
repeatedly demonstrated in patients with SLE who were treated with rituximab is further 
evidence that rituximab may not have fully depleted B cells in these studies.  
Obinutuzumab is a humanized, type II anti-CD20 mAb that has been approved for CLL 
and was demonstrated in clinical studies to be superior to rituximab (Dooley et al. 2011).  
Obinutuzumab exhibits direct B-cell killing through a type II mechanism 
(Honeychurch et al. 2012) and has significantly higher ADCC compared with either 
rituximab or ocrelizumab, a type I humanized anti-CD20 mAb (see the Obinutuzumab 
Investigator’s Brochure).  Obinutuzumab has lower CDC and less dependence on 
complement for its MOA.  There are recent data that suggest that obinutuzumab may 
show depletion of B cells superior to rituximab in lupus-prone mouse models 
(unpublished data on file) and in patients with lupus (in an in vitro peripheral blood 
mononuclear cells analysis of B cells) (Reddy et al. 2014).  With consideration of these 
combined data, this scientific rationale supports the Phase II evaluation of obinutuzumab 
in patients with LN. 
Given the high unmet medical need of patients with LN for an improved CRR rate and 
therefore reduced risk of ESRD, achievement of this benefit is desirable.  The known risk 
of obinutuzumab, as characterized in the CLL-11 Stage 2 head-to-head study of 
obinutuzumab versus rituximab (Goede et al. 2014), suggests that its risk profile is 
comparable to rituximab, with the exception of worsened infusion-related reactions 
(IRRs).  In this setting, the benefit-risk assessment favors conducting this Phase II 
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2. 
OBJECTIVES 
2.1 
EFFICACY OBJECTIVES  
The primary efficacy objective for this study is as follows: 
 
To evaluate the efficacy of obinutuzumab compared with placebo in patients with 
ISN/RPS Class III or IV LN as measured by CRR at 52 weeks 
 
The secondary efficacy objectives for this study are as follows: 
 
To assess overall renal response (defined as CRR plus PRR) 
 
To evaluate the ability of obinutuzumab to improve time-to-response (CRR plus 
PRR) over the course of 52 weeks 
 
2.2 
SAFETY OBJECTIVES 
The safety objectives for this study are as follows: 
 
To evaluate the safety of obinutuzumab compared with placebo in patients with 
Class III or IV LN, focusing on the nature, frequency, and severity of serious and 
non-serious adverse events, as well as effects on laboratory values, vital signs, or 
other safety biomarkers 
 
To characterize the immunogenic potential of obinutuzumab by measuring human 
anti-drug antibodies (ADAs) and assessing their relationship with other outcome 
measures 
 
To fully characterize adverse events of special interest, including infusion reactions, 
infections, thrombocytopenia, and neutropenia 
 
2.3 
PHARMACODYNAMIC OBJECTIVE 
The pharmacodynamic (PD) objective for this study is as follows: 
 
To compare changes in CD19 B cells in the peripheral blood following treatment 
with obinutuzumab versus placebo 
 
2.4 
PHARMACOKINETIC OBJECTIVES 
The pharmacokinetic (PK) objectives for this study are as follows: 
 
To characterize the pharmacokinetics of obinutuzumab in the LN population 
 
To assess potential PK interactions between obinutuzumab and concomitant 
medications, including MMF 
 
2.5 
PATIENT-REPORTED OUTCOME OBJECTIVE 
The patient-reported outcome (PRO) objective for this study is as follows: 
 
To assess the change from baseline of the patient’s general health over the course 
of the study by use of the Subject’s Global Assessment 
 


 
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2.6 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are as follows: 
 
To evaluate pre-dose levels of exploratory biomarkers (which may include but are 
not limited to B-cell subsets and levels of protein and mRNA in serum, plasma, 
blood, and urine) and potential associations with outcome 
 
To evaluate changes in exploratory biomarkers (which may include but are not 
limited to B-cell subsets and levels of protein and mRNA in serum, plasma, blood, 
and urine) over time in patients dosed with obinutuzumab versus patients dosed 
with placebo 
 
To evaluate the occurrence of extrarenal flares 
 
To evaluate the impact of therapy on patient and physician-reported outcomes 
 
To assess damage through the Glucocorticoid Toxicity Change Index (GTCI) 
 
To assess renal biopsy histopathology (for the presence and depletion of B cells at 
the screening biopsy and from subsequent biopsies) 
 
Additional exploratory objectives and outcome measures will be included in a final 
Statistical Analysis Plan (SAP). 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This Phase II study is a parallel-group, double-blind, randomized, placebo-controlled 
study comparing the efficacy and safety of obinutuzumab plus MMF with placebo plus 
MMF in Class III and IV patients with proliferative LN.  The Sponsor intends to enroll 
approximately 120 patients diagnosed with ISN/RPS Class III or IV LN, with a diagnosis 
of SLE based on current ACR criteria (at least 4 criteria must be present, one of which 
must be a positive anti-nuclear antibody [ANA]), in centers throughout the world.  In 
addition to study treatment, patients will receive standard-of-care therapy with 
angiotensin-converting enzyme (ACE) inhibitors/angiotensin-IIreceptor blockers, MMF 
(dosed at 2.02.5 g/day) or MPA (dosed 14401800 mg/day), and a prednisone taper.  
Patients must be 1875 years of age and have ISN/RPS 2003 Class III or IV proliferative 
LN (see Table 1) as evidenced by renal biopsy performed within 6 months prior to or 
during screening and may have concomitant Class V disease (e.g., Class III/V or 
Class IV/V).  Patients with Class III (C) or Class IV (C) disease will be excluded because 
of the lower likelihood of response within these categories.  Patients must exhibit 
significant proteinuria (urine protein to creatinine ratio  1.0 based on a 24-hour urine 
collection).  Key exclusions will be evidence of severe renal impairment (estimated GFR 
 30 mL/minute per 1.73 m2 of body surface area), ESRD requiring dialysis or 
transplantation, evidence of active infections, and other safety-related exclusions.  
Patients will receive an initial 1000 mg of methylprednisolone IV prior to or during 
screening, and may receive up to a total of 3000 mg methylprednisolone IV prior to 
randomization for severe clinical activity according to guidelines of routine care for these 


 
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patients.  Patients will receive 80 mg methylprednisolone (or methylprednisolone 
placebo) on the day of the obinutuzumab/placebo infusion to reduce IRRs.  Oral 
corticosteroids will be initiated at a dose of 0.5 mg/kg (maximum 60 mg/day) and will be 
reduced over 10 weeks (see Appendix 5).  This modified taper, from the LUNAR study, 
will be initiated at a lower dose in recognition that prednisone doses above 10 mg/day 
are associated with significant adverse events, including increased risk of cardiovascular 
events (Bichile and Petri 2014).  Prior experience with rituximab suggests that it can 
potentially enable complete and PRRs in the absence of oral prednisone or a prednisone 
taper, thus allowing the use of lower doses of corticosteroids as proposed in this Phase 
II protocol (Condon et al. 2013). 
Patients will be followed until at least Week 104, with the primary endpoint evaluation at 
Week 52.  An interim analysis at 6 months will be performed to evaluate early 
differences in CRR.  All patients will have central reading of the renal biopsy 
histopathology and will also receive repeat renal biopsy as available on the basis of 
clinical status and local practice.  All patients will be evaluated by high-sensitivity flow 
cytometry (HSFC) to evaluate the ability of obinutuzumab to deplete circulating 
peripheral B cells, and an interim PD analysis will be performed to assess whether 
patients do not fully deplete peripheral CD19 B cells as anticipated.  These mechanistic 
studies and more intensive histopathologic reviews are intended to test the hypothesis 
that greater B-cell depletion in the target organ (kidney) and associated secondary 
lymphoid structures will translate into greater CRR rates. 
Figure 1 Study Schema 
 
EP  endpoint; MMF  mycophenolate mofetil. 


 
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3.2 
END OF STUDY 
The end of this study is defined as the last patient’s last visit at Week 104. This has 
been selected to enable 78 weeks (~18 months) of safety follow-up after the last dose of 
study drug to assess the occurrence of adverse events and to enable an assessment of 
peripheral blood CD19+ B cell return. 
Additional B-cell follow-up (BCFU) visits will occur until patients have achieved their 
baseline CD19+ count or achieved 25 cells/μL CD19+ count (the lower limit of normal 
(LLN) of CD19+ B cells for this lupus population), whichever occurs first.  B-cell 
follow-up (BCFU) visits for all patients will end when the last patient has completed 
~18 months of safety follow-up from the last dose of blinded obinutuzumab infusion. 
 
Patients who receive additional therapies that reduce peripheral B-cell counts will not 
be included in BCFU. 
 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Obinutuzumab Dose and Schedule 
The Phase II dose selection for obinutuzumab is based on experimental documentation 
of the drug’s potency relative to rituximab in head-to-head in vitro nonclinical 
experiments and primate experiments and by partial efficacy demonstrated in the 
LUNAR study with rituximab.  The most relevant in vitro experiments demonstrated a 
5-to 50-fold greater ADCC potency for obinutuzumab in a Z138 lymphoma cell line 
experiment and in a nonclinical xenograft mouse tumor volume experiment 
(Mössner et al. 2010).  A related primate study (Mössner et al. 2010) evaluated the 
depletion of B cells in cynomolgous monkeys evaluating rituximab at 2  10 mg/kg versus 
obinutuzumab at 2  10 mg/kg and at 2  30 mg/kg.  This controlled experiment 
demonstrated a significantly greater B-cell depletion (CD40CD21) with obinutuzumab 
versus rituximab at the 2  10 mg/kg dose level in lymph nodes and splenic tissue, and 
no significant difference in depletion between the two obinutuzumab doses.  
Glycoengineered modifications resulting in significantly higher ADCC and the direct 
type II cell-killing mechanism translate into results from mouse and primate experiments 
that confirm greater potency for obinutuzumab.  These findings were confirmed in the 
CLL11 Stage 2 head-to-head study of obinutuzumab versus rituximab 
(Goede et al. 2014), which demonstrated greater progression-free survival and also 
greater minimal residual disease negativity for obinutuzumab even in protected 
micro-environments such as the bone marrow. 
In the LUNAR study, rituximab was dosed at 1000 mg on Days 1, 15, 168, and 182 with 
a PD goal of peripheral blood CD19 B-cell depletion by use of normal sensitivity flow 
cytometry up to and including Week 52, the primary endpoint of the study.  This dosing 
schema may not have accomplished the PD goal of B-cell depletion in the kidney, and 
the degree of B-cell depletion in the kidney remains unknown since routine renal 


 
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biopsies are not part of clinical practice and there are no existing blood or urine 
biomarkers capable of evaluating this question.  For these reasons, obinutuzumab will 
be studied at a comparable dose (1000 mg) and comparable interval (on Days 1, 15, 
168, and 182) to assess whether the achieved CRR differs from the CRR rate observed 
in the LUNAR Study. 
3.3.2 
Rationale for Patient Population 
The population to be enrolled in this protocol will be patients with ISN/RPS Class III or IV 
LN with active inflammatory processes as evidenced by a renal biopsy within 6 months 
of screening or during screening and elevated proteinuria.  Class III and IV LN was 
selected because these patients have proliferative disease, which has a poor prognosis 
and requires significant immunosuppressive therapy.  Patients with Class V 
membranous nephritis will be allowed protocol entry if the Class V membranous 
nephritis is detected on a renal biopsy and concurrent with Class III or IV disease.  
Patients entering the protocol may have either relapsing or newly diagnosed disease.  
The population selected for this study has the highest unmet medical needs, and prior 
data suggesting partial responses in this population with anti-CD20 mAbs rituximab and 
ocrelizumab suggest that enrollment is feasible and that a greater response may be 
achieved with the more potent drug obinutuzumab. 
3.3.3 
Rationale for Control Group 
Study WA29748 will be a placebo-controlled study provided on top of background 
immunosuppression with MMF.  Add-on study designs are appropriate in this population, 
and the provision of no background immunosuppression in a placebo-controlled study 
would represent inadequate therapy for a population at risk for severe renal damage. 
3.3.4 
Rationale for Biomarker Assessments  
The variability in response to previous B-cell targeting therapies in LN is incompletely 
understood.  This variability may reflect the heterogeneity of this disease as it relates to 
varying degrees of B-cell involvement among patients, but it may also point to 
incomplete B-cell depletion.  Predictive and PD biomarkers have the potential to 
differentiate between these possible explanations and will be collected in this study to 
improve understanding of any variability seen for clinical outcome to obinutuzumab 
treatment.  Predictive biomarker samples will be collected prior to dosing in an effort to 
identify those patients with B-cell driven pathogenesis who are most likely to respond to 
obinutuzumab.  PD biomarker assessment will evaluate the modulation of B-cell 
numbers and activity by obinutuzumab, and may additionally inform PK/PD modeling to 
support the dose and dose regimen.  As these biomarkers may also have prognostic 
value, their association with disease progression will also be explored. 


 
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3.4 
OUTCOME MEASURES 
3.4.1 
Efficacy Outcome Measures 
Primary Efficacy Outcome Measure 
The primary efficacy outcome measure is the proportion of patients who achieve a CRR, 
evaluated at 52 weeks. 
CRR is defined by attainment of all of the following: 
 
Normalization of serum creatinine as evidenced by the following: 
Serum creatinine  the upper limit of normal (ULN) range of central laboratory 
values if baseline (Day 1) serum creatinine is above the ULN 
Serum creatinine  15% above baseline and  the ULN range of central 
laboratory values if baseline (Day 1) serum creatinine is  the ULN range of 
central laboratory values 
 
Inactive urinary sediment (as evidenced by  10 RBCs/high-power field (HPF) and 
the absence of red cell casts) 
 
Urinary protein to creatinine ratio  0.5 
 
Secondary Efficacy Outcome Measures  
The secondary efficacy outcome measures are the following: 
 
Proportional analysis of patients who achieve an overall response at Week 52 
(CRR  PRR) 
 
Time to overall response (CRR  PRR) over the course of 52 weeks 
 
Percent reduction or increase from baseline and mean and median assessments of 
biomarkers of LN disease activity (e.g., reduction in anti-dsDNA antibody levels, 
increase C3 and C4 levels) 
 
Proportion of patients that achieve a PRR at Week 52 as defined by attainment of all 
of the following: 
Serum creatinine  15% above baseline value 
No urinary red cell casts and either RBCs/HPF  50% above baseline or  10 
RBCs/HPF 
50% improvement in the urine protein to creatinine ratio, with one of the following 
conditions met: 
If the baseline urine protein to creatinine ratio is  3.0, then a urine protein to 
creatinine ratio of  1.0 
If the baseline protein to creatinine ratio is  3.0, then a urine protein to 
creatinine ratio of  3.0 
 
Proportion of patients who achieve a CRR at Week 24 
 
Time to CRR, over the course of 52 weeks. 


 
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 
Proportion of patients that achieve a modified CRR (mCRR1) at Week 52 employing 
the primaryefficacy measure definition and removing the urinary sediment analysis 
criteria 
mCRR1 is defined by attainment of normalization of serum creatinine as 
evidenced by the following: 
Serum creatinine  the ULN range of central laboratory values if baseline 
(Day 1) serum creatinine is above the ULN 
Serum creatinine  15% above baseline and  the ULN range of central 
laboratory values if baseline (Day 1) serum creatinine  the ULN range of 
central laboratory values 
Urinary protein to creatinine ratio  0.5 
 
Proportion of patients that achieve a second modified CRR (mCRR2) at Week 52 as 
defined by attainment of the following: 
Normalization of serum creatinine as evidenced by the following: 
Serum creatinine  15% above baseline if baseline (Day 1) serum creatinine 
is above the normal range of the central laboratory values or  the ULN range 
of central laboratory values if baseline (Day 1) serum creatinine is  the ULN 
range of central laboratory values 
Inactive urinary sediment (as evidenced by  10 RBCs/HPF and the absence of 
red cell casts) 
Urinary protein to creatinine ratio  0.5 
 
Proportion of patients that achieve a third modified CRR (mCRR3) at Week 52 as 
defined by attainment of the following: 
Normalization of serum creatine as evidenced by serum creatinine  the ULN 
range of central laboratory values 
Urinary protein to creatinine ratio  0.5 
 
The hierarchical ordering of the secondary endpoints will be pre-specified in the SAP. 
3.4.2 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
 
Incidence, type, and severity of adverse events 
 
Abnormal vital signs 
 
Abnormal laboratory values 
 
Safety will be monitored through regular physical examinations, vital signs, hematologic 
and chemistry laboratory tests, urinalyses, and incidence and severity of adverse events.  
In addition, the following will be examined: 
 
Circulating B cells, T cells, neutrophils and other cell populations 
 
Plasma immunoglobulins (total Ig, IgG, IgM, and IgA) 


 
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 
Record of menses 
 
Pregnancy 
 
Antibody titers for mumps, rubella, Varicella, tetanus, influenza, and Streptococcus 
pneumoniae 
 
3.4.3 
Pharmacodynamic Outcome Measure 
The primary PD outcome measure for this study is as follows: 
 
Changes in levels of circulating CD19 B-cells relative to baseline 
 
3.4.4 
Pharmacokinetic Outcome Measures 
The obinutuzumab PK outcome measures for this study are as follows: 
Non-linear mixed-effects modeling (with software NONMEM) will be used to analyze the 
dose-concentrationtime data of obinutuzumab.  The PK profile data will be used to 
further develop a PK model, including the effect of major covariates (e.g., sex, 
race/ethnicity, weight, biochemical and hematological parameters at baseline, degree of 
underlying disease), on the main parameters (e.g., clearance).  The derivation of 
individual measures of exposure, such as area under the concentration-time curve 
(AUC) and maximum concentration observed (Cmax) will depend on the final PK model 
used for this analysis.  Results of this analysis may be reported separately.  Serum 
obinutuzumab will be summarized (mean, minimum, maximum, SD, and geometric 
mean) and reported within this study.  
Exploratory graphical analyses will be performed to assess whether the occurrences of 
serious adverse events and abnormalities in the safety laboratory parameters in 
patients treated with obinutuzumab can be attributed to obinutuzumab exposure.  
Also, exploratory graphical analyses will be performed to assess whether the 
variability in response can be attributed to the variability in obinutuzumab exposure.  
Relevant observed relationships between exposure and safety parameters may 
be further characterized using different approaches such as logistic regression analysis 
and indirect response modeling.  
Additional PK and PD analyses may be conducted as appropriate. 
3.4.5 
Patient-Reported Outcome Measure 
The PRO measure for this study is as follows: 
 
Subject’s Global Assessment 
This visual analog scale (VAS) will be captured in screening, at the baseline visit, 
and at several timepoints during study conduct. 
 
3.4.6 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
 
Changes in levels of circulating B-cell subsets relative to baseline  


 
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 
Changes in levels of exploratory biomarkers, which may include but are not limited 
to levels of protein and mRNA in serum, plasma, blood, and urine, relative to 
baseline  
 
Proportion of patients experiencing a Systemic Lupus Erythematosus Disease 
Activity Index (SLEDAI)-2K flare 
 
Proportion of patients experiencing a renal flare over 52 weeks and 104 weeks 
 
Proportion of patients achieving CRR, mCRR1, mCRR2, and mCRR3 at additional 
timepoints, including Week 12 and Week 36 
 
Physician’s Global Assessment 
This VAS will be captured in screening, at the baseline visit, and at several 
timepoints during study conduct. 
 
GTCI 
 
Renal biopsy evaluations 
 
All patients will be asked to undergo an optional repeat renal biopsy after completion of 
the treatment portion of the study (after Week 52).  If a patient agrees to a repeat renal 
biopsy, one should be performed within 4 weeks of completion of the treatment portion 
of the study.  Biopsies performed at other times, for clinical reasons, will also be 
submitted for central review.  Because examination of the biopsy sample may potentially 
unblind the study treatment, investigators and study site personnel should examine the 
biopsy sample for routine histology to enable clinical decisions but should not review 
immunohistopathology results that evaluate the presence or absence of B cells or be 
informed of their results.  
It is important to ensure that patients’ renal biopsy samples are classified in a consistent 
manner.  As with other quantitative histopathology procedures, there can be significant 
inter-personal variation in the scoring of renal biopsy samples.  Therefore, the biopsy 
sample used for entry qualification will be collected (where possible) and sent for reading 
at a specialist review laboratory before being returned to the study site.  This will allow 
accurate analysis and will enhance the scientific credibility of the study.  Determination 
of eligibility, however, will be made based on the local renal biopsy review. 
The original microscopic sections from each patient’s biopsy sample will be re-read by a 
panel of renal histopathologists.  Additional slides for investigating disease 
characteristics are also requested as described in the Laboratory Manual.  The biopsy 
consensus evaluation process will be as follows: 
 
A panel of independent nephro-pathologists will be used for the study. 
 
A consensus reading of each renal biopsy will be made by two of the pathologists. 
 
Discrepancies will be resolved at periodic consensus meetings. 
 
However, reading at the specialist review laboratory is not required prior to study entry.  
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at the specialist review laboratory.  Lack of availability of a biopsy sample specimen will 
not preclude enrollment in the study, as long as the pathology report confirming eligibility 
is available.  Follow-up repeat biopsies may be performed as clinically required by the 
investigator and also provided for analysis by the centralized facility. 
All repeat biopsy samples will be read with a central reading methodology.  The baseline 
biopsy sample that was used to determine the eligibility of the patient will be sent to the 
central reading site, as this will allow comparison between pre- and post-treatment 
samples.  An operational manual that outlines processes for the acquisition of renal 
biopsy data will be implemented as part of this protocol. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
All patients will be screened for conformance with the following inclusion and exclusion 
criteria.  The study will enroll approximately 120 patients with active ISN/RPS 2003 
Class III or IV LN at approximately sixty centers in North America, South America, 
Europe, and selected other countries. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form 
 
Age 1875 years 
 
Ability to comply with the study protocol, in the investigator’s judgment 
 
Diagnosis of SLE, according to current ACR criteria (at least four criteria must be 
present, one of which must be a positive ANA) 
 
Diagnosis of ISN/RPS 2003 Class III or IV LN as evidenced by renal biopsy 
performed within 6 months prior to or during screening.  Patients may co-exhibit 
Class V disease in addition to either Class III or Class IV disease. 
 
Proteinuria (urine protein to creatinine ratio)  1.0, based on a 24-hour urine 
collection 
 
For women who are not postmenopausal ( 12 months of non-therapy-induced 
amenorrhea) or surgically sterile (absence of ovaries and/or uterus):  agreement to 
remain abstinent or use two adequate methods of contraception, including at least 
one method with a failure rate of  1% per year, during the treatment period and for 
at least 18 months after the last dose of study drug 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle 
of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception. 
Barrier methods must always be supplemented with the use of a spermicide. 


 
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Examples of contraceptive methods with a failure rate of  1% per year include 
tubal ligation, male sterilization, hormonal implants, established, proper use of 
combined oral or injected hormonal contraceptives, and certain intrauterine 
devices. 
 
For men:  agreement to remain abstinent or use a condom plus an additional 
contraceptive method that together result in a failure rate of  1% per year during the 
treatment period and for at least 12 months after the last dose of study drug and 
agreement to refrain from donating sperm during this same period 
Men with a pregnant partner must agree to remain abstinent or use a condom for 
the duration of the pregnancy. 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle 
of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception. 
Patients must be willing to practice this method of contraception while taking 
MMF and for 90 days after stopping MMF. 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Retinitis, poorly controlled seizure disorder, acute confusional state, myelitis, stroke 
or stroke syndrome, cerebellar ataxia, or dementia that is currently active and 
resulting from SLE 
 
Presence of rapidly progressive glomerulonephritis defined by 
The presence of crescent formation in  50% of glomeruli assessed on renal 
biopsy or 
Sustained doubling of serum creatinine within 12 weeks of screening or 
The investigator’s opinion that the patient has rapidly progressive 
glomerulonephritis. 
 
Severe renal impairment as defined by estimated GFR  30 mL/min or the need for 
dialysis or renal transplant 
 
Greater than 50% of glomeruli with sclerosis on renal biopsy 
 
Treatment with cyclophosphamide or calcineurin inhibitors within the 3 months prior 
to randomization 
 
Unstable disease with thrombocytopenia or at high risk for developing clinically 
significant bleeding or organ dysfunction requiring therapies such as 
plasmapheresis or acute blood or platelet transfusions 
 
Lack of peripheral venous access 
 
Pregnancy or lactation 
 
History of severe allergic or anaphylactic reactions to mAbs or known 
hypersensitivity to any component of the obinutuzumab infusion 


 
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 
Significant or uncontrolled medical disease in any organ system not related to SLE 
or LN, which, in the investigator’s opinion, would preclude patient participation 
 
Concomitant chronic conditions, excluding SLE, (e.g., asthma, Crohn’s disease) that 
required oral or systemic steroid use in the 52 weeks prior to screening 
 
Known HIV infection 
 
Known active infection of any kind (excluding fungal infection of nail beds) or any 
major episode of infection requiring hospitalization or treatment with IV 
anti-infectives within 8 weeks of the screening visit or oral anti-infectives within 
2 weeks prior to the screening visit 
 
History of serious recurrent or chronic infection 
 
History of cancer, including solid tumors, hematological malignancies, and 
carcinoma in situ (except basal cell carcinomas of the skin that have been treated or 
excised and have resolved) 
 
Currently active alcohol or drug abuse or history of alcohol or drug abuse within 
52 weeks prior to screening 
 
Major surgery requiring hospitalization within 4 weeks of randomization (excluding 
diagnostic surgery) 
 
Previous treatment with an anti-CD20targeted therapy within 12 months of 
randomization 
 
Previous treatment with a biologic B-celltargeted therapy (other than anti-CD20) 
within 6 months of randomization 
 
Treatment with any investigational agent within 28 days of randomization or five 
halflives of the investigational drug (whichever is longer) 
 
Receipt of a live vaccine within 28 days prior to screening 
 
Intolerance or contraindication to oral or IV corticosteroids 
 
Aspartate aminotransferase or alanine aminotransferase  2.5  ULN 
 
Amylase or lipase  2  ULN 
 
Neutrophils  1.5  103/L 
 
Positive hepatitis B surface antigen (HbSAg) or hepatitis C serology.  Patients who 
are HBsAg negative and hepatitis B core antibody (HBcAb) positive with no 
detectable DNA will be allowed into the study but will require regular monitoring of 
hepatitis B virus (HBV) DNA. 
 
Hemoglobin  7 g/dL, unless caused by autoimmune hemolytic anemia resulting 
from SLE 
 
Platelet count  10,000/L 
 
Positive serum human chorionic gonadotropin measured prior to the first 
obinutuzumab infusion 
 
Known intolerance to MMF and MPA 
 


 
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4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
The investigator or the investigator’s research staff will provide patient eligibility 
information through the interactive voice/Web response system (IxRS) at randomization.  
Each patient will be randomized and assigned a unique identification number.  As 
confirmation, the investigator will be provided with written verification of each patient’s 
registration. 
Patients will be randomized to receive obinutuzumab or placebo in a 1:1 ratio. 
The randomization of patients into treatment and control groups will be managed by a 
central IxRS vendor by use of a block design.  The factors for balancing between the 
treatment groups will be the following: 
 
Treatment balance within each race stratum for the following: 
Region (Afro Caribbean/African American versus others) 
United States versus non-U.S. sites 
 
Because it is important to maintain blinding to preserve the integrity of the data collected, 
all laboratory studies of blood specimens, with unblinding potential, will be performed by 
a central laboratory.  Therefore, site personnel and the Sponsor’s staff involved with the 
conduct of the study will not receive unblinded data related to peripheral B-cell counts, 
PK results, specific immunoglobulin levels, or ADA results during the study, as listed 
below, until all eligible patients have completed their Week 52 visit. 
While PK samples must be collected from patients assigned to the comparator arm to 
maintain the blinding of treatment assignment, PK assay results for these patients are 
generally not needed for the safe conduct or proper interpretation of this study.  Sponsor 
personnel responsible for performing PK assays will be unblinded to patients’ treatment 
assignments to identify appropriate PK samples to be analyzed.  Samples from patients 
who are assigned to the comparator arm will not be analyzed except by request (e.g., to 
evaluate a possible error in dosing). 
If unblinding is necessary for patient management (e.g., in the case of a serious adverse 
event for which patient management might be affected by knowledge of treatment 
assignment), the investigator will be able to break the treatment code by contacting the 
IxRS.  Treatment codes should not be broken except in emergency situations.  If the 
investigator wishes to know the identity of the study treatment for any other reason, he 
or she should contact the Medical Monitor directly.  The investigator should document 
and provide an explanation for any premature unblinding (e.g., accidental unblinding, 
unblinding due to a serious adverse event). 
For regulatory reporting purposes and if required by local health authorities, the Sponsor 
will break the treatment code for all serious, unexpected suspected adverse reactions 


 
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(see Section 5.7) that are considered by the investigator or Sponsor to be related to the 
study drug. 
4.3 
STUDY TREATMENT 
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Obinutuzumab and Placebo 
Obinutuzumab is provided as a single-dose, sterile liquid formulation in a 50-mL 
pharmaceutical grade glass vial containing a nominal 1000 mg of obinutuzumab 
(G3 material).  The formulated drug product consists of 25 mg/mL drug substance (G3) 
formulated in histidine, trehalose, and poloxamer 188.  The vials contain 41 mL (with 
2.5% overfill). 
Handling and Storage 
The recommended storage conditions for the obinutuzumab drug product are between 
2C and 8C and protected from light.  Chemical and physical in-use stability for 
obinutuzumab dilutions in 0.9% sodium chloride (NaCl) have been demonstrated for 
24 hours at 2C8C and at ambient temperature and ambient room lighting.  
The prepared diluted product should be used immediately.  If not used immediately, 
in-use storage times and conditions prior to use are the responsibility of the user and 
would normally not be longer than 24 hours at 2C8C.  Obinutuzumab should not be 
frozen or shaken.  It should be mixed gently.  All transfer procedures require strict 
adherence to aseptic techniques.  An additional in-line filter should not be used because 
of potential adsorption. 
For further details see the Obinutuzumab Investigator’s Brochure, pharmacy manual, 
and local prescribing information. 
The placebo employed in this study will be a generic placebo of normal saline, and the 
double-blinded format will utilize an unblinded pharmacist to enable delivery of 
obinutuzumab and obinutuzumab placebo. 
4.3.1.2 
Methylprednisolone and Placebo  
Methylprednisolone and methylprednisolone placebo may be reimbursed by the Sponsor 
as per local requirements.  Local supply of commercially available stock should be used 
or matching saline solution – prepared by the unblinded pharmacist to maintain the 
double blind status of the study.  For information on the formulation and handling of 
methylprednisolone, see the pharmacy manual and the local prescribing information for 
methylprednisolone. 
4.3.1.3 
Mycophenolate Mofetil/Mycophenolic Acid 
For information on the formulation of and the packaging and handling requirements for 
MMF and MPA, see the local prescribing information. 


 
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4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
Obinutuzumab and Placebo 
Obinutuzumab will be administered by IV infusion at a dose of 1000 mg on Days 1, 15, 
168, and 182. 
Obinutuzumab must be administered in a hospital or clinic environment where full 
resuscitation facilities are immediately available and under close supervision of the 
investigator or designee.  Although study drug may be administered on an outpatient 
basis, patients may be hospitalized for observation at the discretion of the investigator. 
See the Obinutuzumab Administration section below for detailed study drug 
administration instructions for the first infusions (Day 1) and subsequent infusions 
(Day 15, Day 168, and Day 182) of the two dosing intervals. 
Obinutuzumab vials are biologically and chemically stable at 2C8C (36F46F).  Do 
not use beyond the expiration date stamped on the carton.  Obinutuzumab should be 
protected from direct sunlight. 
For further details, see the immunology Obinutuzumab Investigator’s Brochure and the 
local prescribing information. 
Obinutuzumab Dose and Schedule 
Obinutuzumab will be administered by IV infusion as an absolute (flat) dose of 1000 mg 
for four infusions on Days 1, 15, 168, and 182.  Placebo infusion will be infused in the 
same volume and on the same scheduled days in the control arm. 
Obinutuzumab Preparation 
Obinutuzumab drug product that is intended for IV infusion is prepared by dilution of the 
drug product into an infusion bag containing 0.9% NaCl to the final drug concentration of 
4 mg/mL.  Using a 250-mL infusion bag containing 0.9% NaCl, withdraw and discard 
40 mL of the NaCl.  Withdraw 40 mL of obinutuzumab from a single glass vial and inject 
it into the infusion bag (discard any unused portion of obinutuzumab remaining in the 
vial).  Gently invert the infusion bag to mix the solution; do not shake. 
Administration sets with polyvinyl chloride, polyurethane, or polyethylene as product 
contact surface and IV bags with polyolefin, polypropylene, polyvinyl chloride, 
or polyethylene as product contact surface are compatible and may be used.  Use of a 
port or a peripherally inserted central catheter (PICC line) is acceptable. 
Do not use obinutuzumab beyond the expiration date stamped on the carton. 
Obinutuzumab Administration 
Obinutuzumab should be administered to patients in a clinical setting (inpatient or 
outpatient) where full emergency resuscitation facilities are immediately available and 
patients should be under close supervision of the investigator at all times.  Do not 


 
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administer as an IV push or bolus.  After the end of the first infusion, the IV line should 
remain in place for  2 hours in order to be able to administer IV drugs if necessary.  If no 
adverse events occur after 2 hours, the IV line may be removed.  For subsequent 
infusions, access through an IV line should remain in place for at least 30 minutes from 
the end of the infusion, and if no adverse events occur after 30 minutes, the IV access 
may be removed. 
Patients should receive prophylactic treatment with acetaminophen (6501000 mg) and 
diphenhydramine (50 mg; or equivalent dose of a similar agent) by mouth 3060 minutes 
prior to the study drug infusion.  Methylprednisolone 80 mg IV must be given 
3060 minutes prior to the start of infusions on Days 1, 15, 168, and 182. 
Patients who are administered an antihistamine (e.g., diphenhydramine) for the 
treatment or prevention of IRRs should be given appropriate warnings prior to the 
patients’ discharge about drowsiness and impairment of ability to drive. 
Instructions for administration of obinutuzumab infusions are provided in Table 2 and 
Appendix 7. 
Table 2 
Administration of Obinutuzumab Infusions 
First Infusion (Day 1) 
Subsequent Infusions (Days 15, 168, and 182) 
Begin infusion at an initial rate of 50 mg/hr. 
If no infusion reaction occurs, increase the 
infusion rate in 50-mg/hr increments every 
30 minutes to a maximum of 400 mg/hr. 
If an infusion reaction develops, stop or slow 
the infusion.  Administer infusion-reaction 
medications and supportive care in 
accordance with institutional protocol.  
Resume the infusion at a 50% reduction in 
rate (the rate being used at the time that the 
hypersensitivity or IRR occurred) if the 
reaction has resolved. 
If a patient experienced an infusion reaction 
during the prior infusion, start at the same rate 
as the first infusion (50 mg/hr) and follow those 
directions as noted. 
If the patient tolerated the prior infusion well, 
begin infusion at a rate of 100 mg/hr. 
If no infusion reaction occurs, increase the 
infusion rate in 100-mg/hr increments every 
30 minutes to a maximum of 400 mg/hr. 
If an infusion reaction develops, stop or slow 
the infusion.  Administer infusion-reaction 
medications and supportive care in accordance 
with institutional protocol.  Resume the infusion 
at a 50% reduction in rate (the rate being used 
at the time that the hypersensitivity or IRR 
occurred) if the reaction has resolved. 
IRR  infusion-related reaction. 
 


 
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Table 3 
Management of Infusion-Related Reactions 
Infusion-Related 
Symptoms a 
Grade 
Guidance 
12 
Slow or hold infusion. 
Give supportive treatment b. 
Upon symptom resolution, may resume infusion rate escalation at the 
investigator’s discretion c. 
3 
Discontinue infusion. 
Give supportive treatment b. 
Upon symptom resolution, may resume infusion rate escalation, at 
investigator discretion c. 
Note:  If the same adverse event recurs with the same severity, treatment 
must be permanently discontinued. 
4 
Discontinue infusion immediately, treat symptoms aggressively, and do 
not restart drug. 
IV  intravenous. 
Note:  These recommendations do not address life-threatening events, including 
anaphylaxis, for which all appropriate standard measures (including full resuscitation 
medications and equipment) must be available and should be used as clinically 
indicated.  For further details see Section 5.1.1. 
a Refer to National Cancer Institute Common Terminology Criteria for Adverse Events, v4.0, 
for the grading of symptoms.  This table does not refer to management of immunoglobulin 
E-mediated allergic reactions. 
b Supportive treatment:  Patients should be treated with acetaminophen/paracetamol and an 
antihistamine such as diphenhydramine if they have not been received in the last 4 hours. 
IV saline may be indicated.  For bronchospasm, urticaria, or dyspnea, patients may require 
antihistamines, oxygen, corticosteroids (e.g., 100 mg of IV prednisolone or equivalent), 
and/or bronchodilators.  For hypotension, patients may require vasopressors. 
c Infusion rate escalation after re-initiation:  Upon complete resolution of symptoms, the 
infusion may be resumed at 50% of the rate achieved prior to interruption. In the absence of 
infusion-related symptoms, the rate of infusion may be escalated in increments of 50 mg/hr 
every 30 minutes to a maximum rate of 400 mg/hr. 
 
4.3.2.2 
Mycophenolate Mofetil/Mycophenolic Acid 
All patients will either continue on or initiate use of MMF (or MPA) during screening or no 
later than Day 1.  The initial dosage will be 1500 mg/day by mouth (or equivalent), given 
in two or three divided doses and titrated upward to 2.02.5 g/day (or equivalent) in 
divided doses by Week 4.  The dose may be increased by 500 mg/wk (or equivalent), as 
tolerated up to a maximum dosage of 2.5 g/day (or equivalent).  Reductions, as outlined 
in Appendix 4, will be allowed because of adverse effects.  Investigators, at their 
discretion, may use MPA as a substitute for MMF, with a 360-mg dose being equivalent 
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Based on randomized controlled clinical studies, approximately 3040% of patients with 
LN may achieve a CRR with initial therapy with either cyclophosphamide or MMF in 
combination with corticosteroids (Dall’Era et al. 2011).  In this group, the benefit of 
added therapy may be minimal, and the risks of added therapy may be unwarranted.  
The investigator should assess whether eligible patients may benefit from an initial trial 
of standard-of-care therapy prior to enrollment into the study. 
For those patients who enter the study already receiving a dosage of MMF (or MPA) 
higher than 1500 mg/day (or equivalent), MMF (or MPA) will be titrated upward, as 
tolerated, to a goal of 2.5 g/day (or equivalent), given in divided doses, by Week 4.  A 
patient’s current dose of MMF (or equivalent) will be given in two or three divided doses 
and will be increased by 500 mg/wk (or equivalent) as tolerated.  Refer to Appendix 4 for 
further details. 
Use of MMF (or equivalent) during pregnancy is associated with increased risks of 
spontaneous abortion and congenital malformations, especially external ear and other 
facial abnormalities, including cleft lip and palate, and anomalies of the distal limbs, 
heart, esophagus, kidney, and nervous system.  Because of this, women of reproductive 
potential must be counseled regarding pregnancy prevention and planning and must use 
effective contraception prior to initiation of this therapy.   
Because MMF (or equivalent) may have an interaction with oral contraceptives that 
could theoretically decrease its effectiveness, if patients (or partners of patients) 
enrolling in this study use hormonal contraceptives as their primary method of 
contraception, these must be supplemented by either a barrier method of contraception 
or an intra-uterine contraceptive device (see Section 4.1.1, and MMF/MPA U.S. Package 
Insert). 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1. 
Any overdose or incorrect administration of MMF (or equivalent) should be noted on the 
MMF/MPA Administration electronic case report form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of MMF/MPA should be 
recorded on the Adverse Event eCRF. 
4.3.2.3 
Corticosteroid Administration 
Initial Study Corticosteroid Dose  
All patients will receive a combination of IV and oral corticosteroids as part of their initial 
therapy for LN.  Methylprednisolone (Solu-Medrol) will be implemented in this protocol 
for two purposes:  as part of the usual care for patients with active Class III or IV LN and 
also to reduce IRRs on the days of obinutuzumab/placebo infusions.  Up to three doses 
of IV methylprednisolone 1000 mg will be given on the basis of investigator judgment 
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screening or during the screening interval, and proper documentation of the number and 
date of infusions must occur. 
On Days 1, 15, 168, and 182, patients will receive 80mg IV methylprednisolone or 
placebo 3060 minutes prior to study drug infusion to prevent IRRs. 
Additionally, oral prednisone may be initiated before or during the screening interval, and 
a taper will commence on Day 16 of the protocol.  From Days 2 to 16, 0.50 mg/kg/day 
oral prednisone will be given (maximum dose of 60 mg), except on the day of 
IV methylprednisolone/placebo infusions, and will continue until Day 16.  From Day 16 
onward, a prednisone taper will commence as directed in Appendix 5.  See Appendix 8 
for list of corticosteroid equivalence. 
Corticosteroid Taper 
All patients will undergo a scheduled corticosteroid taper commencing on Day 16.  
Patients will fractionally reduce their prednisone dose over 10 weeks until the dose is 
7.5 mg/day by Week 12 (see Appendix 5).  Deviations from the scheduled primary 
prednisone taper for any reason other than SLE disease activity will confound 
interpretation, so every attempt should be made to adhere to the tapering schedule.  
After the 10 weeks of tapering, patients will continue on prednisone at 7.5 mg/day.  In 
patients whose disease is too clinically active for the patient to make the first step in their 
prednisone taper, as evidenced by active urinary sediment, rising serum creatinine, or 
moderate-to-severe extrarenal symptoms, these patients may continue to receive their 
initial prednisone dose for up to an additional 28 days.  Patients who have started their 
taper and whose disease is too clinically active to continue tapering, may, using the 
same criteria as above, remain at the taper dose achieved for up to an additional 
28 days.  The prednisone dose may not be increased beyond the taper dose achieved.  
Patients will be discouraged from making adjustments to their prednisone dose and 
should contact the investigator and be examined before altering the prednisone taper so 
that deviations from the schedule can be justified and its relationship to lupus activity can 
be ascertained. 
After patients complete their Week 52 visit, investigators at their discretion may taper the 
oral prednisone further, if they believe it is clinically warranted. 
Corticosteroid Dosing for Renal Flares 
To maintain consistency in the treatment of renal flares, retreatment with higher doses of 
corticosteroids is permitted if judged clinically appropriate by the investigator and if 
patients meet criteria for a renal flare (see Appendix 5).  Patients may be treated with 
prednisone (up to 0.5 mg/kg; not to exceed 60 mg/day) for 2 weeks.  Prednisone will 
then be tapered to achieve 10 mg/day within 6 weeks after the initial corticosteroid 
increase and may further be tapered to 7.5 mg/day at the discretion of the investigator.  
Patients who do not exhibit a response to the initial 2-week course of increased 
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treatment failures and will continue regular visits and will not receive additional study 
drug. 
Corticosteroid Dose Increases Due to Extrarenal Disease Flare 
Patients will be allowed to receive corticosteroids for emergent illness (trauma, severe 
asthma) or surgery, if clinically warranted; the corticosteroid use should be limited to a 
total of  7 days, if possible.  Investigators will be allowed to increase the prednisone 
dose by  2.5 mg/day to treat symptoms of adrenal insufficiency or corticosteroid 
withdrawal. 
Patients who experience a severe extrarenal SLE flare may receive treatment with 
additional oral corticosteroids, if judged clinically appropriate by the investigator (see 
Appendix 5).  These patients may be retreated with prednisone (up to 1.0 mg/kg) for up 
to 2 weeks on the basis of the severity of disease and organ system involvement and the 
dosage should be tapered to 7.5 mg/day, following a separate tapering schedule as 
listed in Appendix 5.  Patients experiencing a mild or moderate extrarenal flare may 
temporarily increase their prednisone dose by up to 20 mg per day and taper this dose 
over 4 weeks, if judged clinically appropriate by the investigator.  IV corticosteroids in 
equivalent doses are allowed if gastrointestinal (GI) involvement temporarily precludes 
treatment with oral corticosteroids.  Patients who do not show improvement in their 
symptoms after 2 weeks of increased corticosteroid treatment are considered to be 
nonresponsive to corticosteroids.  Efforts should be made to reduce corticosteroid 
exposure to the minimally effective level to reduce corticosteroid-associated toxicity. 
If patients require a new immunosuppressive drug (other than corticosteroids) for 
treatment of their extrarenal SLE flare, those patients will be counted as treatment 
failures and will not receive further study drug but will continue their protocol-mandated 
study visits.  
Any overdose or incorrect administration of prednisone or methylprednisolone should be 
noted on the Corticosteroid Administration eCRF.  Adverse events associated with an 
overdose or incorrect administration of corticosteroids should be recorded on the 
Adverse Event eCRF. 
4.3.3 
Dosage Modification 
Dose modification is not permitted during this study; however, the rate of infusion may 
be adjusted in the event of an IRR. 
If a patient experiences an IRR that requires interruption of the infusion and the 
investigator determines it should not be restarted, the patient should continue to be 
followed in the study for safety. 


 
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4.3.4 
Investigational Medicinal Product Accountability 
Obinutuzumab will be provided by the Sponsor.  The study site will acknowledge receipt 
of investigational medicinal products (IMPs) using the IxRS to confirm the shipment 
condition and content.  Any damaged shipments will be replaced.  Study sites will 
maintain adequate records for receipt and disposition of study drug and maintain 
adequate drug dispensing and return records for monitor inspection. 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log. 
4.3.5 
Post-Study Access to Obinutuzumab 
The Sponsor will offer post-study access to the study drug, obinutuzumab, free of charge 
to eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below. 
A patient will be eligible to receive study drug after completing the study if all of the 
following conditions are met: 
 
The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being  
 
There are no appropriate alternative treatments available to the patient 
 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 
A patient will not be eligible to receive study drug after completing the study if any of the 
following conditions are met: 
 
The study drug is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient) 
 
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for LN. 
 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for LN. 
 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country 
 


 
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The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
 
4.4 
CONCOMITANT THERAPY 
4.4.1 
Permitted Therapy 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
7 days prior to screening to the study completion/discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF. 
4.4.1.1 
Other Concomitant Therapy 
Antimalarial Medications 
Antimalarial medications may influence the development of subsequent lupus flares 
(Canadian Hydroxychloroquine Study Group 1991).  Patients taking antimalarial 
medications at study entry should maintain a constant dosage throughout the study.  
Patients not previously on antimalarial medications may be enrolled in the study but 
should not initiate antimalarial medications unless experiencing a disease flare that is 
unresponsive to corticosteroids.  Table 4 lists the antimalarial medications and dose 
ranges expected to be used during the course of the study. 
Table 4 
Antimalarial Medications 
Antimalarial Medication 
Dose Range (Oral) 
Hydroxychloroquine 
200400 mg daily 
Chloroquine 
500 mg every day or every other day 
Quinacrine 
100 mg every day 
 
Antihypertensive Therapy 
All patients who are not currently taking either an ACE inhibitor or an 
angiotensin-receptor blocker (ARB) should be started on one at screening.  Patients 
should be on either an ACE inhibitor or ARB for at least 10 days prior to randomization.  
Combination therapy with the two agents will not be allowed. 
During screening, every effort should be made to adequately control patients’ blood 
pressures.  The dose of the ACE inhibitor or ARB may be titrated upward to the 
maximum recommended dose in the current package insert to achieve adequate blood 
pressure control as recommended by the Eighth Report of the Joint National Committee 
on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (James 
et al. 2014).  If adequate blood pressure control is not achieved, patients may be started 
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(e.g., nondihydropyridine calcium channel blockers, aldosterone antagonists, direct renin 
antagonists).  Additional agents that specifically target the renin-angiotensin system 
cannot be initiated during the study.  Suggested dose ranges for specific ACE inhibitors 
and ARBs are listed in Table 5.   
ACE inhibitor and ARB therapy exposure during the second and third trimesters is 
known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull 
ossification retardation) and neonatal toxicity (renal failure, hypotension and 
hyperkalemia).  The use of ACE inhibitors and ARBs is not recommended during the first 
trimester of pregnancy and is contra-indicated during the 2nd and 3rd trimester of 
pregnancy. 
If patients are intolerant to ACE inhibitors and ARBs, they may use either a direct renin 
inhibitor or aldosterone antagonists, but not in combination. 
Table 5 
Suggested Dose Ranges for Angiotensin-Converting Enzyme 
Inhibitors and Angiotensin-Receptor Blockers 
ACE Inhibitor or 
ARB 
Dose Range (Oral) 
(mg/day) 
ACE inhibitors 
 
Benazepril 
1080 
Ramipril 
2.510 
Lisinopril 
1080 
Enalapril 
1040 
Quinapril 
1080 
Captopril 
75450 
Perindopril 
416 
Trandolapril 
18 
Moexipril 
7.530 
ARBs 
 
Eprosartan 
400600 
Valsartan 
80320 
Olmesartan 
2040 
Candesartan 
832 
Telmisartan 
2080 
Losartan 
25100 
Irbesartan 
75300 
ACE  angiotensin-converting enzyme; 
ARB  Angiotensin-Receptor Blockers. 
 


 
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Vitamins and Supplements 
Patients who are not already taking vitamin D (800 IU/day) and calcium supplements 
(1200 mg/day calcium citrate or 1500 mg/day calcium carbonate) should start taking 
these supplements during screening.  Investigators should follow current ACR guidelines 
for the prevention and treatment of glucocorticoid-induced osteoporosis (ACR 2001) or, 
for female patients in Canada  50 years of age, Canadian guidelines for the prevention 
and treatment of glucocorticoid-induced osteoporosis (Cheung et al. 2004). 
4.4.1.2 
Withdrawal of Immunosuppression after Week 52 
Patients who enter the Study Extension Period at Week 52 will remain on background 
standard-of-care immunosuppressant treatment until they have maintained their best 
achieved response, which must be at least an adequate clinical benefit for at least 
6 months.  After Week 52, the investigator may elect to continue MMF at a reduced dose 
or switch the patient to receive azathioprine at 2mg/kg/day on the basis of local practice.  
If this response is achieved and the patient’s condition is considered to be stable, an 
attempt may be made to reduce or discontinue immunosuppressive treatment while 
closely monitoring renal parameters. 
The following reduction strategy is recommended:  
Azathioprine:  Reduce by 50 mg/day every 4 weeks. 
MMF (or equivalent):  Reduce by 500 mg/day (or equivalent) every 4 weeks. 
 
Patients whose conditions deteriorate on withdrawal of background therapy in this phase 
may receive re-induction therapy, which can include high-dose corticosteroids, 
immunosuppressant treatment such as MMF/MPA or obinutuzumab, or a combination of 
these as considered appropriate by the investigator. 
After Week 52, any treatment changes are entirely at the discretion of the investigator. 
4.4.2 
Concomitant Therapy and Clinical Practice 
Concomitant medications such as HMG-coA-reductase inhibitors and bisphosphonates 
will be recorded but not initiated during the study unless considered clinically indicated 
by the treating investigator after discussion with the Medical Monitor.  If patients enter 
the study taking these medications, every effort will be made to keep their dosage stable 
to prevent confounding of study results. 
4.4.3 
Immunization during Peripheral B-Cell Depletion 
The efficacy and safety of immunization during periods of peripheral B-cell depletion 
have not been adequately studied.  It is recommended that a patient’s vaccination record 
and the need for immunization be carefully evaluated prior to receiving study drug.  For 
patients who are likely to require immunization in the foreseeable future, such as 
patients planning to travel to countries where specific immunization is required or 
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vaccination/booster must be given at least 28 days prior to randomization.  Review of a 
patient’s immunization status or need for the following vaccinations in advance of 
randomization is recommended:  tetanus; diphtheria; influenza; pneumococcus 
polysaccharide; Varicella; measles, mumps, and rubella (MMR); and hepatitis B 
vaccines. 
The safety and efficacy of immunization with a live or attenuated live vaccine in 
B cell-depleted patients are not known.  For this reason, the use of live or attenuated 
vaccines (e.g., measles, mumps, rubella, oral polio vaccine, Bacillus Calmette-Guérin 
[BCG], typhoid, yellow fever, vaccinia, or any other vaccines not yet licensed but 
belonging to this category) is specifically excluded for 28 days prior to screening through 
the end of study participation. 
Vaccines that do not contain live organisms (e.g., influenza, Pneumovax, tetanus) are 
not prohibited; however, vaccines received during peripheral B-cell depletion may be 
ineffective. 
4.4.4 
Prohibited Therapy 
Use of the following therapies is prohibited during the study: 
 
Investigational therapies from within 28 days or 5 half-lives of randomization 
(whichever is longer) and throughout the study 
 
Exposure to an anti-CD20 targeted biologic therapy from the 12 months prior to 
randomization and throughout the study 
 
Treatment with a biologic B-cell-targeted therapy other than anti-CD20 within 
6 months of randomization and throughout the study 
 
Live virus vaccines from 28 days before the screening visit and throughout the study 
 
NSAIDs, calcineurin inhibitors, or other nephrotoxic drugs during the study conduct 
 
The use of NSAIDs, with the exception of aspirin when used for cardiovascular 
protection, is prohibited in this study, given the potential effect of NSAIDs on renal 
function and proteinuria.  If patients are taking NSAIDs prior to enrollment, these 
medications must be discontinued during screening (at least 5 half-lives prior to 
randomization).  If the investigator believes that it is necessary to prescribe NSAIDs for a 
patient during the study, he or she should inform the Medical Monitor, and every attempt 
should be made to limit the use of NSAID treatment.  If used, the use of NSAIDs and 
other symptomatic medications that are both prescribed and available over the counter 
will be recorded at each visit.  Patients will be asked by the investigator whether these 
medications were used for a SLE-related symptom (e.g., pericarditis) or for symptoms 
not attributed to lupus (e.g., menstrual discomfort). 
Other immunosuppressive agents not specifically allowed in the study as described 
above will not be allowed during the study and must be discontinued during the 


 
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screening period when patients become eligible for study participation and fulfill 
exclusion criteria. 
4.5 
STUDY ASSESSMENTS 
See Appendix 1 for the schedule of assessments performed during the study. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomization.  The investigator will maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
4.5.2 
Medical History and Demographic Data 
Medical history includes clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
use of alcohol and drugs of abuse, and all medications (e.g., prescription drugs, 
over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used 
by the patient within 7 days prior to the screening visit. 
Demographic data will include age, sex, and self-reported race/ethnicity.  The collection 
of information on race is important in the context of this protocol because multiple 
studies have confirmed that patients with an African descent tend to have the worst 
prognosis for renal function.  For this reason, African heritage will be a stratification 
variable. 
4.5.3 
Physical Examinations 
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, and throat and the cardiovascular, dermatological, musculoskeletal, respiratory, 
GI, genitourinary, and neurological systems.  Any abnormality identified at baseline 
should be recorded on the General Medical History and Baseline Conditions eCRF. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF. 
A chest x-ray, if not done within 3 months prior to screening, will also be done at 
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4.5.4 
Vital Signs 
Vital signs will include measurements of respiratory rate, body temperature, pulse rate, 
and systolic and diastolic blood pressures while the patient is in a seated position for 
5 minutes.  The same arm for blood pressure measurements should be used 
consistently throughout the study, if possible. 
4.5.5 
Systemic Lupus Erythematosus Disease Activity Index 
(SELENA-SLEDAI) Assessment 
The SLEDAI-2K instrument (see Appendix 13) will be employed in this study to assess, 
at baseline, the occurrence of organ involvement other than the kidney.  It will be 
employed at regular visits and at unscheduled visits to capture changes in lupus-related 
disease activity after randomization.  The SLEDAI-2K instrument was selected for its 
ease of use, validation, and employment in the BELONG study.  SLEDAI-2K is assessed 
for the 10 days prior to the patient’s visit and has 24 items and a total score of 105. 
4.5.6 
Systemic Lupus International Collaborating Clinics/ American 
College of Rheumatology Damage Index for Systemic Lupus 
Erythematosus 
The Systemic Lupus International Collaborating Clinics (SLICC)/ACR Damage Index for 
SLE (see Appendix 10) will be utilized to assess organ damage as opposed to the 
collection of disease activity.  Damage is defined as non-reversible change not related to 
active inflammation. 
4.5.7 
Glucocorticoid Toxicity Change Index 
The GTCI is an exploratory standardized measure of damage related to use of 
glucocorticoids (see Appendix 14).  The GTCI will be incorporated into this study to 
better quantify the accrual of damage linked to corticosteroid use in patients with LN and 
may allow for an improved understanding of standard of care and patient phenotype. 
4.5.8 
Laboratory, Biomarker, and Other Biological Samples 
The following laboratory tests will be recorded at the timepoints indicated in the 
Schedule of Assessments (see Appendix 1). It is required that sample specimens be 
sent to the central laboratory at all study timepoints, with the exception of urinalysis and 
hematology samples collected for safety monitoring of MMF.  Full details of the sample 
handling can be found in the Laboratory Manual. 
The full laboratory assessments that will be assessed according to the study schedule of 
assessments are described below: 
 
Hematology:  To include CBC, hemoglobin, hematocrit, RBC, mean corpuscular 
volume, mean corpuscular hemoglobin, WBC (absolute and differential), and 
quantitative platelet count.  If a test is required to assess hemolytic anemia, it will be 
performed locally. 


 
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 
Blood chemistry:  AST/SGOT, ALT/SGPT, alkaline phosphatase, amylase, lipase, 
total protein, albumin, cholesterol, total bilirubin, urea, uric acid, creatinine, random 
glucose, potassium, sodium, chloride, calcium, phosphorus, lactic dehydrogenase, 
CPK and triglycerides. 
 
Urinalysis:  Including dipstick for blood, nitrite, protein, and glucose and urine 
microscopy.  Preferably, urinary protein to creatinine ratio should be performed on a 
first morning urine sample (see Appendix 9) 
 
24-hour urine collection:  To be analyzed for total protein, total creatinine, creatinine 
clearance, and protein to creatinine ratio.  To be performed at screening, 
randomization, and at Months 3, 6, 9, and 12. 
 
Flow cytometry:  B cell (including CD19, CD27, CD38, and IgD), T cell (CD3, 4, 8) 
and NK cells (CD16, CD56).  Flow cytometry results will remain blinded until the 
study is unblinded. 
 
Autoantibody profile:  To include ANA, anti-dsDNA, anti-Sm, anti-RNP, anti-Ro, 
antiLa, anti-C1q. 
 
Anti-ds-DNA antibody:  To be measured by ELISA at all visits as part of SLEDAI2K 
assessment 
 
Quantitative immunoglobulin:  Total Ig levels including IgG, IgM, and IgA isotypes 
 
Complement:  Including C3, C4, and CH50 
 
Antibody titers:  Measurement of antibody titers to common antigens (mumps, 
Varicella, rubella, tetanus, influenza, and S. pneumoniae) will be performed 
according to the schedule of assessments.  This information is used to assess the 
effect of obinutuzumab on specific humoral immunity to bacterial and viral antigens. 
 
Viral hepatitis:  Measurement of HBsAg, HBcAb, and hepatitis C antibody.  Patients 
who are HBsAg negative and HBcAb positive will also be evaluated for HBV DNA. 
 
Pregnancy test:  All women of childbearing potential (including those who have had 
a tubal ligation) will have a pregnancy test at each visit.  Positive test results will be 
confirmed with a serum pregnancy test.  The infusion must not be administered 
unless the pregnancy test is negative. 
 
Pharmacokinetics and ADA:  To be measured as outlined in the schedule of 
assessments. 
 
The following samples will be sent to the Sponsor or a designee for analysis: 
 
Cells from blood and urine for B-cell and lupus-related biomarkers, which may 
include but are not restricted to CD19 B cells and mRNA associated with B-cell 
activity 
 
Serum, plasma, and urine for B-cell and lupus-related biomarkers, which may 
include but are not restricted to B-cell activating factor (BAFF) 
 
Renal biopsy slides and/or formalin-fixed paraffin-embedded blocks for 
immunohistopathology assessment 
 


 
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Any leftover material from pharmacokinteics, ADA, and biomarker samples may be used 
for additional assay development and assay validation purposes during the development 
of study- or compound-related assays and exploratory research in addition to the 
mentioned intended uses.  These samples will be stored until the study results have 
been reported, with the exception of some blood, tissue, and urine samples that might 
be stored for 5 years after all study data have been collected.  For patients who agree to 
take part in optional long-term storage at Roche Clinical Repository (RCR), unused 
blood, urine, and kidney biopsy samples will be stored and destroyed no later than 
15 years after the date of final closure of the associated clinical database. 
4.5.9 
Electrocardiograms 
Twelve lead ECGs should be taken at the timepoints indicated in the schedule of 
assessments.  Lead placement should be as consistent as possible.  ECG recordings 
must be performed after the patient has been resting in a supine position for at least 
10 minutes.  All ECGs are to be obtained prior to other procedures scheduled at that 
same time (e.g., vital sign measurements, blood draws) and should not be obtained 
within 3 hours after any meal.  Circumstances that may induce changes in heart rate, 
including environmental distractions (e.g., television, radio, conversation) should be 
avoided during the pre-ECG resting period and during ECG recording. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site. 
If, at a particular post-dose timepoint, the mean QTcF is  500 ms and/or  60 ms 
longer than the baseline value, another ECG must be recorded, ideally within the next 
5 minutes, and ECG monitoring should continue until QTcF has stabilized on two 
successive ECGs.  The Medical Monitor should be notified.  Standard-of-care treatment 
may be instituted per the discretion of the investigator.  If a PK sample is not scheduled 
for that timepoint, an unscheduled PK sample should be obtained.  A decision on study 
drug discontinuation should be made, as described in Section 5.1.9.  The investigator 
should also evaluate the patient for potential concurrent risk factors (e.g., electrolyte 
abnormalities, co-medications known to prolong the QT interval, severe bradycardia). 
Comments generated automatically by the ECG machine should not be recorded unless 
confirmed by a physician.  An ECG is also required if the patient discontinues from the 
study. 
4.5.10 
Patient- and Physician-Reported Outcomes 
The Subject’s Global Assessment of Disease Activity is the patient’s overall assessment 
of his or her current disease activity will be measured on a 100 mm horizontal VAS.  The 
left-hand extreme of the line is described as “none” (symptom-free) and the right-hand 
extreme as “severe”. 


 
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The Physician’s Global Assessment of Disease Activity is the physician’s overall 
assessment of the patient’s current disease activity.  It is measured on a 100 mm 
horizontal VAS.  The left-hand extreme of the line is described as “none” (symptom-free) 
and the right-hand extreme as “severe”. 
4.5.11 
Samples for Roche Clinical Repository 
4.5.11.1 
Overview of the Roche Clinical Repository 
The RCR is a centrally administered group of facilities used for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection and analysis of RCR specimens will 
facilitate the rational design of new pharmaceutical agents and the development of 
diagnostic tests, which may allow for individualized drug therapy for patients in the 
future. 
Specimens for the RCR will be collected from patients who give specific consent to 
participate in this optional research. RCR specimens will be used to achieve the 
following objectives: 
 
To study the association of biomarkers with efficacy, adverse events, or disease 
progression 
 
To increase knowledge and understanding of disease biology 
 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.11.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site's Institutional Review Board or Ethics Committee (IRB/EC) 
and, if applicable, an appropriate regulatory body.  If a site has not been granted 
approval for RCR sampling, this section of the protocol (Section 4.5.11) will not be 
applicable at that site. 
4.5.11.3 
Sample Collection 
The following samples will be collected for research purposes, including but not limited 
to research on dynamic (non-inherited) biomarkers: 
 
Serum, plasma, and urine samples for research purposes, which may include but 
are not limited to research on biomarkers related to CD20 depletion, LN, SLE, or 
other autoimmune disease/inflammatory disorder 
 
Whole blood PAXgene samples for RNA extraction for research purposes, which 
may include but are not limited to research on biomarkers related to CD20 
depletion, LN, SLE, or other autoimmune disease/inflammatory disorder 


 
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 
Tissue samples from kidney biopsies for research on candidate biomarkers, which 
may include but are not limited to research on biomarkers related to 
CD20 depletion, LN, SLE, or other autoimmune disease/inflammatory disorder 
 
The following samples will be collected for research purposes, including but not limited 
to research on genetic (inherited) biomarkers related to obinutuzumab or LN: 
 
Whole blood samples for DNA extraction for research purposes, including but not 
limited to research on biomarkers related to CD20 depletion, LN, SLE, or other 
autoimmune disease/inflammatory disorder 
 
For all samples, dates of consent and specimen collection should be recorded on the 
associated RCR page of the eCRF.  For sampling procedures, storage conditions, and 
shipment instructions, see the laboratory manual. 
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below. 
4.5.11.4 
Confidentiality 
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is "double-coded" by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A "linking key" between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche's Legal Department, as applicable. 
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate. 
Patient medical information associated with RCR specimens 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. 


 
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Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless required by local law.  The aggregate results of 
any research conducted using RCR specimens will be available in accordance with the 
effective Roche policy on study data publication. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise. 
4.5.11.5 
Consent to Participate in the Roche Clinical Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RCR specimens.  
Patients who decline to participate will not provide a separate signature. 
The investigator should document whether or not the patient has given consent to 
participate by completing the RCR Research Sample Informed Consent eCRF. 
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research. 
4.5.11.6 
Withdrawal from the Roche Clinical Repository 
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the RCR Subject Withdrawal 
Form and, if the study is ongoing, must enter the date of withdrawal on the RCR 
Research Sample Withdrawal of Informed Consent eCRF.  The patient will be provided 
with instructions on how to withdraw consent after the study is closed.  A patient's 
withdrawal from Study WA29748 does not, by itself, constitute withdrawal of specimens 
from the RCR.  Likewise, a patient's withdrawal from the RCR does not constitute 
withdrawal from Study WA29748. 
4.5.11.7 
Monitoring and Oversight 
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 


 
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review, and health authority inspections by providing direct access to source data and 
documents related to the RCR samples. 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
The primary (and very uncommon) reason for withdrawal from the study should be the 
patient’s withdrawal of consent.  In addition, the investigator has the right to withdraw a 
patient from the study at any time.  Reasons for withdrawal from the study may include 
but are not limited to the following: 
 
Patient withdrawal of consent at any time 
 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
 
Investigator or Sponsor determines it is in the best interest of the patient 
 
Patient non-compliance, defined as the inability to comply with protocol procedures 
despite repeated interaction with the Principal Investigator 
 
If a patient wishes to withdraw from the study, a distinction should be made concerning 
withdrawal from experimental treatment and complete withdrawal from the study.  
Patients wishing to withdraw from treatment should continue to receive efficacy and 
safety evaluations in the 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.  However, patients will not be followed 
for any reason after consent has been withdrawn.  Patients who withdraw from the study 
will not be replaced. 
Patients who meet any of these criteria will not receive any additional study drug, but 
should be monitored for safety for at least 52 weeks after their last dose of study drug, 
unless they have withdrawn consent. 
4.6.2 
Study Treatment Discontinuation 
Patients must discontinue study treatment but remain in the study if they experience any 
of the following: 
 
Pregnancy 
 
Grade 4 IRRthe patient should be withdrawn from study treatment immediately 
 
Recurrence of Grade 3 IRR at rechallenge 
 
Grade 3 or 4 neutropenia that does not resolve to Grade  2 within 8 weeks 
 
Thrombocytopenia that does not resolve to Grade  2 within 8 weeks 
 
Hepatitis B reactivation despite the initiation of the appropriate anti-viral therapy 


 
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 
Receipt of rescue cyto-toxic therapy, including cyclophosphamide, an anti-CD20 
mAb other than Obinutuzumab, or other confounding investigational therapies used 
for the primary treatment of lupus or LN 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced, but they should continue protocol-mandated visits and procedures. 
4.6.3 
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 enrollment is unsatisfactory. 
 
Data recording is inaccurate or incomplete. 
 
Action is deemed necessary based on recommendations from the independent Data 
Monitoring Committee (iDMC). 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 
The Sponsor has the right to close a site at any time.  Reasons for closing 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 International Conference on Harmonisation (ICH) 
guidelines for Good Clinical Practice 
 
No study activity (i.e., all patients have completed and all obligations have been 
fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Obinutuzumab is currently approved in CLL and also has been used in clinical studies 
for other malignancies such as NHL but not for autoimmune diseases.  Thus, the entire 
safety profile is not known at this time.  The safety plan for this study is designed to 
ensure patient safety and will include specific eligibility criteria and monitoring 
assessments as detailed below. 
5.1.1 
Infusion-Related Reactions 
The most frequently observed adverse drug reactions in patients who received 
obinutuzumab during clinical studies in CLL and NHL were IRRs, which occurred 


 
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predominantly during infusion of the first 1000 mg.  In patients who received the 
combined measures for prevention of IRRs (adequate glucocorticoid, oral 
analgesic/antihistamine, omission of antihypertensive medication in the morning of the 
first infusion, and, for CLL patients only, the Cycle 1 Day 1 dose administered over 
2 days), a decreased incidence of all grade IRRs was observed.  The rates of 
Grades 34 IRRs (which were based on a relatively small number of patients) were 
similar before and after mitigation measures were implemented.  The incidence and 
severity of infusion-related symptoms decreased substantially after the first 1000 mg 
was infused, with most patients having no IRRs during subsequent administrations of 
obinutuzumab. 
In the majority of patients, IRRs were mild to moderate and could be managed by the 
slowing or temporary halting of the first infusion, but severe and life-threatening IRRs 
requiring symptomatic treatment have also been reported.  IRRs may be clinically 
indistinguishable from IgE-mediated allergic reactions (e.g., anaphylaxis).  
In studies where patients received either obinutuzumab or rituximab (another 
anti-CD-20), obinutuzumab patients appeared to have more IRRs compared to those 
receiving rituximab. 
Details regarding management of IRRs can be found in Section 5.1.9. 
5.1.2 
Infections 
Serious bacterial, fungal, and new or reactivated viral infections can occur during and 
following the completion of obinutuzumab therapy.  Fatal infections have been reported. 
Obinutuzumab is more potent in B-cell depletion than is rituximab; it is theoretically 
possible that there is an increased risk of infections with obinutuzumab compared with 
rituximab.  Study BO21004/CLL11 provides the most meaningful assessment of the 
possible risk of infection (Goede et al. 2014).  In Stage 1a (obinutuzumab  chlorambucil 
versus chlorambucil alone) and Stage 2 (obinutuzumab  chlorambucil versus 
rituximab  chlorambucil) of Study BO21004 in patients with CLL, the incidence of 
infections was similar between the treatment arms.  However, the chlorambucil arm 
compared with the obinutuzumab  chlorambucil arm showed a higher incidence of 
serious infections and deaths due to infection; the incidence of serious infections and 
fatal infections was similar in the obinutuzumab  chlorambucil and 
rituximab  chlorambucil arms.  To date, there is no clear evidence of a difference 
between rituximab and obinutuzumab regarding infections. 
5.1.2.1 
Hepatitis B Reactivation 
HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and 
death, can occur in patients treated with anti-CD20 antibodies, including obinutuzumab. 


 
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5.1.2.2 
Progressive Multifocal Leukoencephalopathy 
Progressive multifocal leukoencephalopathy (PML) has been reported in patients treated 
with obinutuzumab.  The diagnosis of PML should be considered in any patient that 
presents with new-onset or changes to preexisting neurologic manifestations.  The 
symptoms of PML are unspecific and can vary depending on the affected region of the 
brain.  Motor symptoms with corticospinal tract findings (e.g., muscular weakness, 
paralysis, and sensory disturbances), sensory abnormalities, cerebellar symptoms, and 
visual field defects are common.  Some signs/symptoms regarded as “cortical” (e.g., 
aphasia or visual-spatial disorientation) may occur.  Evaluation of PML includes but is 
not limited to consultation with a neurologist, brain MRI, and lumbar puncture 
(cerebrospinal fluid testing for John Cunningham [JC] viral DNA).  Therapy with 
obinutuzumab should be withheld during the investigation of potential PML and 
permanently discontinued in case of confirmed PML.  Discontinuation or reduction of any 
concomitant immunosuppressive therapy should also be considered.  The patient should 
be referred to a neurologist for the evaluation and treatment of PML. 
5.1.3 
Immunizations 
The safety of immunization with live or attenuated viral vaccines, following obinutuzumab 
therapy has not been studied, and vaccination with live virus vaccines is not 
recommended during treatment and until B-cell recovery. 
5.1.4 
Neutropenia 
Severe and life threatening neutropenia, including febrile neutropenia, has been reported 
during treatment with obinutuzumab for hematologic malignancies. 
5.1.5 
Thrombocytopenia 
Severe and life threatening thrombocytopenia, including acute thrombocytopenia 
(occurring within 24 hours after the infusion), has been observed during treatment with 
obinutuzumab for hematologic malignancy.  Fatal hemorrhagic events have also been 
reported during Cycle 1 in patients treated with obinutuzumab for hematologic 
malignancy. 
5.1.6 
B-Cell Depletion and Recovery 
B-cell recovery has taken place whenever peripheral B cells are no longer depleted.  
B-cell peripheral blood depletion is defined as levels below the lower limit of 
quantification (LLOQ) of the HSFC assay (1 cell/L).  B-cell repopulation is defined as 
the return of peripheral blood B cells to a level of 10 cells/L.  B-cell recovery is defined 
as peripheral blood B cells at the patient’s pretreatment baseline or at the LLN for the 
population under study (25 cells/µL).  In the majority of cases, B-cell recovery has taken 
longer than 12 months in previous studies of obinutuzumab, with and without 
chemotherapy, for the treatment of hematologic malignancies. 


 
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5.1.6.1 
Obinutuzumab Monotherapy - NHL and CLL Patients 
In the Phase II part of study BO21003 (relapsed indolent NHL), 87 patients were 
included in the obinutuzumab arm and 86 in rituximab arm.  The median level of 
CD19 cells was 0.079  109 cells/L at baseline and decreased rapidly to zero by 
2.5 hours post-infusion on Cycle 1, Day 1.  At the end of the treatment phase, of those 
with a known B-cell status, 80 of the rituximab patients (95%) and 82 of the 
obinutuzumab patients (96%) had B-cell depletion.  At 18 months post-treatment, 
5 of 8 and 17 of 19 patients (who were tested) in the rituximab and obinutuzumab arms, 
respectively, remained B-cell depleted. 
The data from patients with NHL in Studies BO21003 and BO20999 were pooled and 
analyzed for B-cell depletion (a total of 205 patients).  In this population from the pooled 
analysis, 195 of 202 patients (97%) had B-cell depletion at the end of treatment.  At 
12 months, 10 of 56 patients (18%) with known B-cell status had recovered B cells. 
The data from patients with CLL in Studies BO21003 and BO20999 were pooled and 
analyzed for B-cell depletion (a total of 38 patients).  In this CLL population from the 
pooled analysis, 30 of 35 patients with available data (86%) had B-cell depletion at the 
end of treatment.  Twenty-seven of these patients had at least 6 months follow-up 
information (after the last study drug administration), and after 24 months, 
19 of 27 patients (70%) had recovered B cells.  Of note, there were no B-cell count data 
on the remaining 30% of patients as they had either progressed or died or were lost to 
follow-up before this timepoint. 
5.1.6.2 
Obinutuzumab in Combination with Chemotherapy - CLL 
Patients 
In the Phase III Study BO21004/CLL11, 40 of 44 patients (91%) in the 
obinutuzumab  chlorambucil arm with available data had B-cell depletion at the end of 
treatment.  Within 24 months after the end of follow-up, 18 of 40 patients (45%) had 
recovered B-cells, including 5 patients who also experienced disease progression at the 
time of recovery. 
5.1.7 
Immunoglobulin Depletion and Recovery 
When obinutuzumab has been used for treatment of hematologic malignancies, 
immunoglobulin depletion and recovery has varied.  In Study BO20999 Phase I, for 
patients with NHL, the levels of IgA, IgG, and IgM immunoglobulins were either low or 
normal for the duration of the treatment period.  For the patients with CLL, 
immunoglobulin levels were low during the course of treatment.  In Phase II, across 
indications (aggressive NHL, indolent NHL, and CLL), changes in baseline mean and 
median levels of IgA, IgG, and IgM were observed during the treatment period, but 
baseline levels had been achieved by the end of the treatment period. 
In Study BO21003, in Phase II, in the obinutuzumab arm, mean and median values for 
IgA, IgG, and IgM concentrations were all within the standard reference ranges. 


 
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In Study BO21000, the serum levels of IgA, IgG, and IgM decreased from baseline to 
Cycle 4 and follow-up (Day 28), but the median levels remained within the corresponding 
normal ranges.  No differences between treatment population or dose groups were 
observed in either treatment arm. 
5.1.8 
Gastrointestinal Perforations 
In the pivotal study in NHL, cases of GI perforation have been reported in patients 
treated with obinutuzumab in association with bendamustine.  Patients with NHL may 
have a tumor involvement of the GI tract (very rare in CLL patients), which may shrink 
rapidly and lead to an opening in the GI wall. 
5.1.9 
Management of Specific Adverse Events 
Guidelines for management of specific adverse events are outlined in Table 6.  
Additional guidelines are provided in the subsections below. 
 
 


 
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Table 6 
Guidelines for Management of Specific Adverse Events 
Event 
Action to Be Taken 
General IRR 
 
Patients who have pre-existing cardiac or pulmonary conditions 
should be monitored carefully throughout the infusion and the 
post-infusion period. 
 
Withholding of antihypertensive treatments should be considered 
for 12 hours prior to and throughout each obinutuzumab infusion 
and for the first hour after administration. 
 
Patients at acute risk of hypertensive crisis should be evaluated 
for the benefits and risks of withholding their anti-hypertensive 
medication. 
 
Hypersensitivity may be difficult to distinguish from IRRs.  If a 
hypersensitivity reaction is suspected during infusion (e.g., 
symptoms typically occurring after previous exposure and very 
rarely with the first infusion), the infusion should be stopped and 
treatment permanently discontinued.  
 
Patients with known IgE mediated hypersensitivity to 
obinutuzumab must not be treated. 
 
For additional guidance see Table 3. 
Infections:  General 
 
No patient will be enrolled with an active infection or history of 
chronic or recurring infections. 
 
Patients who develop an active infection during the study will have 
study drug withheld until the event has resolved. 
 
Patients who require vaccination should be pre-vaccinated 
6 weeks prior to receiving study drug. 
 
Vaccination with live vaccine during study is contra-indicated (see 
Section 4.4.3). 
Infections:  Hepatitis B 
 
Hepatitis B screening is required prior to initiation of study drug. 
 
Patients with active or chronic hepatitis B (surface Ag) will be 
excluded from the study. 
 
Patients who are HBcAb with no detectable DNA will be allowed 
into the study but will require regular monitoring of HBV DNA.  If 
reactivation is seen, study drug treatment must be withheld. 
 
Patients will be monitored regularly for transaminitis. 
 
Patients with transaminitis will be promptly referred to a 
hepatologist for evaluation and treatment.  
 
Patients with Hepatitis B reactivation, despite the use of 
appropriate antivirals, will be discontinued from treatment as 
outlined in Section 4.6.2. 
CSF = cerebrospinal fluid; GI = gastrointestinal; HBcAb = hepatitis B core antibody; 
HBV = hepatitis B virus; IRR = infusion-related reaction; IVIG = intravenous 
immunoglobulin; JC = John Cunningham; MRI = magnetic resonance imaging; 
PML = progressive multifocal leukoencephalopathy. 


 
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Table 6 
Guidelines for Management of Specific Adverse Events (cont.) 
Event 
Action to Be Taken 
Infections:  suspected 
PML 
 
Stop study drug. 
 
Obtain neurological consult. 
 
In consultation with a neurologist, we recommend obtaining an 
MRI and performing a lumbar puncture to assess for CSF JC viral 
DNA. 
 
Notify monitors immediately. 
 
Study treatment will be withheld for all participants while patient is 
unblinded and investigated for suspected PML. 
Neutropenia 
 
Patients who experience neutropenia should be closely monitored 
with regular laboratory tests until resolution.  
 
If treatment is necessary, it should be administered in accordance 
with local guidelines and administration of granulocyte 
colony stimulating factors should be considered.  
 
Any signs of concomitant infection should be treated as 
appropriate. 
 
Grade 3 or 4 neutropenia that does not resolve to Grade  2 within 
8 weeks is a treatment-discontinuation criterion. 
 
Cases of late onset neutropenia (occurring 28 days after the end 
of treatment) or prolonged neutropenia (lasting more than 28 days 
after treatment has been completed/stopped) have also been 
reported in studies of obinutuzumab for hematologic malignancy. 
Thrombocytopenia 
 
Patients should be closely monitored for thrombocytopenia,  
 
If thrombocytopenia occurs, regular laboratory tests should be 
performed until the event resolves, and dose delays should be 
considered in case of severe or life-threatening thrombocytopenia.  
 
Transfusion of blood products (i.e., platelet transfusion) according 
to institutional practice is at the discretion of the treating physician.  
 
Thrombocytopenia that does not resolve to Grade  2 within 
8 weeks is a treatment-discontinuation criterion. 
 
Use of all concomitant therapies, which could possibly worsen 
thrombocytopenia related events such as platelet inhibitors and 
anticoagulants, should also be taken into consideration 
Hypogammaglobulinemia  
Ig levels will be monitored throughout the study period. 
 
IVIG should be considered for patients with recurrent/severe 
infections despite appropriate treatment, with concomitant 
hypogammaglobulinemia. 
GI perforations 
 
Promptly evaluate patients presenting with new onset abdominal 
symptoms. 
CSF  cerebrospinal fluid; GI  gastrointestinal; HBcAb  hepatitis B core antibody; 
HBV  hepatitis B virus; IRR  infusion-related reaction; IVIG  intravenous 
immunoglobulin; JC  John Cunningham; MRI  magnetic resonance imaging; 
PML  progressive multifocal leukoencephalopathy. 
 


 
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5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guidelines for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation patient administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event 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 
Section 5.3.5.10. 
 
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., ECG, Xray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 
Is fatal (i.e., the adverse event actually causes or leads to death) 
 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death. 
 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.11) 


 
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 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
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 drug 
 
Is a significant medical event in the investigator'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 adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) criteria; 
see Section 5.3.3); 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 adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include the following: 
 
Cases of potential drug-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 Section 5.3.5.7) 
 
Suspected transmission of an infectious agent by the study drug, 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 applies only when a 
contamination of the study drug is suspected. 
 
IRRs (see Section 5.1.1) 
 
Grade 3 or higher infections (see Section 5.1.2) 
 
Any hepatitis B reactivation and PML (see Section 5.1.2) 
 
Drug-related neutropenia (see Section 5.1.4) 


 
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 
Drug-related thrombocytopenia (see Section 5.1.5) 
 
GI perforations (see Section 5.1.8) 
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1  
for definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections Sections 5.4  5.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4 ). 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported (see 
Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events, regardless of relationship to study 
drug, will be reported until the patient completes his or her last study visit at Week 104 or 
for a period of 76 weeks after the last dose of study drug (whichever is longer).  After this 
period, the investigator should report any serious adverse events that are believed to be 
related to prior study drug treatment (see Section 5.6). 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation time-points.  Examples of 
non-directive questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?" 
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 3 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 


 
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Table 7 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
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 adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v4.0), 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 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.4.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators 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 adverse event is considered to be related to the study drug, indicating "yes" or 
"no" accordingly.  The following guidance should be taken into consideration (see also 
Table 8): 
 
Temporal relationship of event onset to the initiation of study drug 
 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
 
Known association of the event with the study drug 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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Table 8 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Infusion-Related Reactions 
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to obinutuzumab infusion should be captured as a diagnosis 
(e.g., "infusion-related reaction") on the Adverse Event 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 study drug, each reaction should 
be recorded separately on the Adverse Event eCRF, with signs and symptoms also 
recorded separately on the dedicated Infusion-Related Reaction eCRF. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
For adverse events other than IRRs (see Section 5.3.5.1), a diagnosis (if known) should 
be recorded on the Adverse Event eCRF 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 on the Adverse Event eCRF.  If a diagnosis is 
subsequently established, all previously reported adverse events based on signs and 


 
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symptoms should be nullified and replaced by one adverse event report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events 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 adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
 
If a severe GI hemorrhage leads to renal failure, both events should be reported 
separately on the eCRF. 
 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation time points.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  Details regarding any increases (or decreases) in severity will be captured on the 
Adverse Event Intensity or Grade Changes eCRF.  If the event becomes serious, it 
should be reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning that the event became serious; see Section 5.4.2 for reporting instructions).  
The Adverse Event eCRF 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 serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation time points 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 


 
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5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event 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 investigator’s judgment  
 
It is the investigator’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 adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5  ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, 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 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.  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 on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event 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 investigator’s judgment  
 
It is the investigator’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 adverse event. 


 
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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 on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  ULN) in combination with either an elevated 
total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  ULN in combination with total 
bilirubin  2  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 on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2). 
5.3.5.8 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of SLE. 
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 Adverse Event eCRF.  Generally, only one such event should be 
reported. If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
If the death is attributed to progression of lupus/SLE, “systemic lupus erythematosus 
progression" should be recorded on the Adverse Event eCRF. 


 
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5.3.5.9 
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 eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.10 
Lack of Efficacy or Worsening of Systemic Lupus 
Erythematosus 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  If there is any uncertainty as to whether an 
event is due to disease progression, it should be reported as an adverse event. 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below. 
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Hospitalization for respite care 
 
Planned hospitalization required by the protocol, including initial kidney biopsy 
and/or study drug administration  
 
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 experienced an adverse event 
 
Hospitalization for routine or scheduled repeat surveillance kidney biopsy 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
 
Hospitalization for an adverse event that would ordinarily have been treated in an 
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5.3.5.12 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2). 
No safety data related to overdosing of obinutuzumab are available.  In clinical studies 
with obinutuzumab, doses ranging from 50 mg up to and including 2000 mg per infusion 
have been administered.  The incidence and intensity of adverse reactions reported in 
these studies did not appear to be dose dependent. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical study.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
 
Serious adverse events (see Section 5.4.2 for further details) 
 
Adverse events of special interest (see Section 5.4.2 for further details) 
 
Pregnancies (see Section 5.4.3  for further details) 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor 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 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 


 
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5.4.1 
Emergency Medical Contacts 
To ensure the safety of study participants, access to the Medical Monitors is available 
24 hours per day, 7 days per week.  Details will be provided separately.An Emergency 
Medical Call Center will also be available 24 hours per day, 7 days per week. The 
Emergency Medical Call Center will connect the investigator with an Emergency 
Medical Contact, provide medical translation service if necessary, and track all calls.  
Contact information, including toll-free numbers for the Emergency Medical Call 
Center, will be distributed to investigators. 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators. 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported for a period of 52 weeks after the last dose.  Investigators should 
record all case details that can be gathered immediately (i.e., within 24 hours after 
learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators. Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.   
Instructions for reporting post-study adverse events are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 18 months after the last 
dose of study drug.  A Clinical Trial Pregnancy Reporting Form should be completed by 
the investigator immediately (i.e., no more than 24 hours after learning of the pregnancy) 
and submitted either by faxing or by scanning and emailing the form using the fax 


 
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number or email address provided to investigators.  Pregnancy should not be recorded 
on the Adverse Event eCRF.  The investigator should discontinue study drug and 
counsel the patient, discussing the risks of the pregnancy and the possible effects on the 
fetus.  Monitoring of the patient should continue until conclusion of the pregnancy.  Any 
serious adverse events associated with the pregnancy (e.g., an event in the fetus, an 
event in the mother during or after the pregnancy, or a congenital anomaly/birth defect in 
the child) should be reported on the Adverse Event eCRF.  In addition, the investigator 
will submit a Clinical Trial Pregnancy Reporting Form when updated information on the 
course and outcome of the pregnancy becomes available. 
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
12 months after the last dose of study drug.  A Clinical Trial Pregnancy Reporting Form 
should be completed by the investigator immediately (i.e., no more than 24 hours after 
learning of the pregnancy) and submitted either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Attempts 
should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male patient exposed to study drug.  To allow the Sponsor 
to collect additional information, the Sponsor will request that the pregnant partner signs 
an Authorization for Use and Disclosure of Pregnancy Health Information to allow for 
follow-up on her pregnancy.  If the authorization has been signed, the investigator will 
update a Clinical Trial Pregnancy Reporting Form with additional information on the 
course and outcome of the pregnancy.  An investigator who is contacted by the male 
patient or his pregnant partner may provide information on the risks of the pregnancy 
and the possible effects on the fetus, to support an informed decision in cooperation with 
the treating physician and/or obstetrician. 
5.4.3.3 
Abortions 
Any abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2). 
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2). 


 
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5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or study-related 
procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case. 
5.6 
POST-STUDY ADVERSE EVENTS 
Post-study, the investigator is not required to actively monitor patients for adverse 
events; however, the investigator should notify the Sponsor of any death, other serious 
adverse event, or adverse event of special interest occurring after the end of the adverse 
event reporting period, believed to be related to treatment, if he or she becomes aware 
of them. 
The Sponsor should also be notified if the investigator becomes aware of the 
development of cancer or a congenital anomaly/birth defect in a subsequently conceived 
offspring of a patient who participated in this study. 
The investigator should report these events directly to the Sponsor or its designee, either 
by faxing or by scanning and emailing the Serious Adverse Event/Adverse Event of 
Special Interest Reporting Form using the fax number or email address provided to 
investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 


 
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communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities in accordance with applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document: 
 
Obinutuzumab Investigator's Brochure 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting decisions will also be based on the investigator's assessment of causality and 
seriousness, with allowance for upgrading by the Sponsor as needed. 
An iDMC will monitor the incidence of anticipated adverse events during the study.  An 
aggregate report of any clinically relevant imbalances that do not favor the test product 
will be submitted to health authorities. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
All efficacy outcomes will be analyzed according to the modified intent-to-treat principle 
and will include all randomized patients who have received any amount of study drug.  
Patients will be grouped according to randomized (assigned) treatment, rather than 
treatment received. 
Treatment period data will be locked after all patients have completed the Week 52 visit.  
The primary efficacy and safety analyses will be performed on data for all patients 
through the Week 52 assessments or early discontinuation. 
Safety assessments will be performed on patients who receive study medication.  In all 
safety analyses, patients will be grouped according to the treatment that patients actually 
received rather than the treatment assigned. 
6.1 
DETERMINATION OF SAMPLE SIZE 
This Phase II study is a proof-of-concept study that is designed to detect an 
improvement in CRR.  The primary efficacy endpoint of this study is the proportion of 
patients that achieve CRR. 
It is estimated that approximately 30% of patients with proliferative LN who are receiving 
MMF (or equivalent) will achieve a CRR at Week 52 and that the addition of 
obinutuzumab to MMF (or equivalent) will induce an overall CRR rate of 50% at 
Week 52.  On the basis of these assumptions, a total of 120 patients randomized to 
obinutuzumab- and placebo-treated groups in a 1:1 ratio (60 patients in each of the 
obinutuzumab- and placebo-treated groups) will yield approximately 83% power at the 


 
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two-sided   0.2 significance level using a Cochrane-Mantel-Haenzel (CMH) test, 
assuming the same CRR proportions across the strata. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
The numbers of patients, who enroll, discontinue, and complete the study, will be 
tabulated by treatment group and study period (treatment or BCFU).  Reasons for 
premature study discontinuation will be listed and summarized by treatment group and 
study period.  Eligibility criteria exceptions and other major protocol deviations will also 
be summarized by treatment group. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic and pretreatment characteristics such as age, sex, serum creatinine, 
proteinuria, MMF/MPA use, treatment, LN class, SLE and nephritis duration, 
race/ethnicity, weight, British Isles Lupus Assessment Group (BILAG) score, and 
background therapies for SLE will be summarized by treatment group. 
Continuous data (e.g., age, body weight, and height) will be summarized using 
descriptive statistics (mean, standard deviation, median, minimum, and maximum).  
For categorical data (e.g., race/ethnicity and sex), the number and percentage of 
participants in each category will be presented. 
6.4 
EFFICACY ANALYSES 
The primary and secondary efficacy analyses will include all randomized patients who 
received any study medication, with patients grouped according to the treatment 
assigned at randomization. 
6.4.1 
Primary Efficacy Endpoint 
The primary assessment of efficacy of obinutuzumab, to induce a clinically significant 
improvement in renal function in patients with ISN/RPS 2003 class III or IV LN, will be 
assessed by attainment of CRR. 
CRR is defined as achievement of all of the following: 
 
Normalization of serum creatinine as evidenced by the following: 
Serum creatinine  the ULN range of central laboratory values if the baseline 
(Day 1) serum creatinine is above the ULN 
Serum creatinine  15% above baseline and  the ULN range of central 
laboratory values if baseline (Day 1) serum creatinine is  the ULN range of 
central laboratory values 
 
Inactive urinary sediment (as evidenced by  10 RBCs/HPF and the absence of red 
cell casts) 
 
Urinary protein to creatinine ratio  0.5 
 


 
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Any patient who switches to rescue medication prior to Week 52 will be considered a 
non-responder.  Additional criteria for analyses of patients who are considered 
non-responders will be specified in the SAP. 
The proportions of patients achieving CRR across treatment groups will be compared 
using a CMH test with race (Afro-Caribbean/African American versus others) and region 
(United States versus non-United States) as stratification factors.  If the test result is in 
favor of the obinutuzumab group at   0.1-level (one-sided), it will be concluded that 
there is a shift toward better renal response associated with the obinutuzumab group. 
6.4.2 
Secondary Efficacy Endpoints 
The proportion of patients who achieve an overall response at Week 52 (CRR  PRR) 
will be analyzed using a CMH test, with race and region as strata. 
The proportion of patients achieving PRR at Week 52 as defined by achievement of all 
of the following: 
 
Serum creatinine  15% above baseline value 
 
No urinary red cell casts and either RBCs/HPF  50% above baseline 
or  10 RBCs/HPF 
 
50% improvement in the urine protein to creatinine ratio, with one of the following 
conditions met: 
If the baseline urine protein to creatinine ratio is  3.0, then a urine protein to 
creatinine ratio of  1.0 
If the baseline protein to creatinine ratio is  3.0, then a urine protein to creatinine 
ratio of  3.0 
 
Time to first overall response (CRR  PRR) over the course of 52 weeks will be 
presented using Kaplan-Meier methodology and compared between treatment groups 
using a stratified log-rank test with race and region as strata.  Time to CRR during this 
period will be analyzed similarly. 
The percent change from baseline and mean and median assessments of biomarkers of 
LN disease activity will be analyzed using appropriate statistical methodology. 
The proportions of patients who achieve a CRR at Week 24 will be analyzed using the 
same methodology as the primary analysis.  In addition, the modified definitions, 
mCRR1, mCRR2, and mCRR3, of CRR will be analyzed in this way to assess the 
sensitivity of CRR to its definition. 
Sensitivity analyses will be performed to assess the potential impact on the primary 
endpoint, and possibly also key secondary endpoints, of missing data and possibly also 
changes to background immunosuppressive medication.  


 
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The secondary, sensitivity, PRO, and exploratory analyses will be fully specified in the 
SAP. 
6.4.3 
Exploratory Efficacy Endpoints 
The exploratory outcome endpoints for this study are: 
 
Change in B-cell subsets over the course of the study 
 
Change in serum and urine biomarkers over the course of the study 
 
Proportion of patients experiencing an extrarenal flare over 52 weeks 
 
Proportion of patients experiencing a renal flare over 52 weeks and 104 weeks 
 
Proportion of patients achieving CRR, mCRR1, mCRR2, and mCRR3, at additional 
timepoints, including Week 12 and Week 36 
 
Change in Physician’s Global Assessment over 52 weeks 
 
Change in GTCI over 52 weeks 
 
Change in Renal biopsy histopathology over time 
 
6.5 
SAFETY ANALYSES 
The safety analyses will include all randomized patients who received any study drug, 
with patients grouped according to the treatment actually received. 
6.5.1 
Adverse Events 
Adverse events will be coded according to a standardized thesaurus.  The severity of 
adverse events will be classified using the NCI CTCAE, Version 4.0. 
The number and percentage of patients who experience an adverse event will be 
summarized by mapped term, appropriate thesaurus level, and toxicity grade for each 
treatment group.  Separate summaries will be provided for serious adverse events, 
treatment-related adverse events (defined as any adverse event occurring during or 
within 24 hours following the completion of a study drug infusion), infusion-related 
adverse events and adverse events leading to study discontinuation. 
6.5.2 
Deaths 
Patient deaths, including the primary cause of death, will be summarized. 
6.5.3 
Laboratory Tests 
Descriptive statistics of laboratory values and the change from baseline (Day 1) will be 
presented for each treatment group.  The number and percentage of patients with 
treatment-emergent laboratory abnormalities will be presented for each treatment group.  
Laboratory measurements will include serum chemistries; urinalysis; hematology; 
plasma immunoglobulins; and circulating B-cells, T-cells, neutrophils, and other cell 
populations. 


 
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The number and percentage of patients with positive serum antibodies to obinutuzumab 
at baseline and during the treatment period will be tabulated. 
6.5.4 
Vital Signs 
The change from pretreatment (measured just before initiation of the infusion) in vital 
signs recorded during infusion and post-infusion will be summarized.  Vital signs that are 
obtained during screening and the follow-up period will also be summarized. 
6.6 
PHARMACODYNAMIC ANALYSES 
The primary PD marker will be CD19 B-cell counts.  Exploratory PD markers from 
blood samples will be summarized graphically and descriptively over time by cohort; 
these markers include B-cell subsets, and quantitative Ig levels (total, IgG, IgM, and 
IgA).  In addition, the percent change from baseline for each marker will be computed at 
each sampling timepoint using the Day 1 pre-dose value as the baseline point. 
Potential PD markers specific to SLE/LN will be summarized graphically and 
descriptively as appropriate and may include but are not limited to the following: 
 
Markers of inflammation or B-cell activation:  BAFF, proteinuria, and 
C3 and C4 complement 
 
Autoantibodies:  ANA, anti-dsDNA, Sm, Ro, La, RNP, and others 
 
Exploratory analyses will be performed to assess the possible relationship between 
obinutuzumab dosing, PD markers, PK measures, and clinical response.  The key 
exploratory analyses will be specified in the SAP. 
6.7 
PHARMACOKINETIC ANALYSES 
PK parameters derived from serum concentrations of obinutuzumab will be computed by 
the following: 
 
Maximum serum concentration 
During the entire study (Cmax) 
After the first course of study drug (Cmax1) 
After the second course of study drug (Cmax2) 
 
AUC from 
Time 0 to infinity (AUC0) based on all four infusions 
Time 0 to 336 days (AUC0–336) based on all four infusions 
Time 0 to 168 days (AUC0–168) based on the first two infusions 
Time 168 to 336 days (AUC168–336) based on the third and fourth infusions 
 
Systemic clearance 
 
Volume of distribution under steady-state conditions (Vss) 


 
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 
Half-life (t1/2) for the terminal portion of the serum concentration–time curve after 
both courses of treatment 
 
PK parameters will be determined for all patients with serum concentration data by the 
method that best describes the data.  This may be non-compartmental analysis, 
compartmental analysis for each individual patient, or population PK analysis.  PK 
parameters will be computed for all patients with serum concentration data except for 
patients who are noncompliant to dosing and/or sampling schedule or whose samples 
have interference by ADAs (which precludes data inclusion); these patients will be 
excluded from the analysis. 
PK analysis will include an exploratory analysis to identify baseline covariates that affect 
the pharmacokinetics of obinutuzumab in this patient population.  Baseline covariates 
that will be examined include demographics, other patient characteristics (such as 
disease severity), and selected laboratory measures. 
No hypothesis testing will be performed using the PK parameters.  PK data will be 
summarized using descriptive statistics, including mean, standard deviation, geometric 
mean, coefficient of variation, median, and range. 
Additional PK analyses will be conducted as appropriate. 
6.8 
PATIENT- AND PHYSICIAN-REPORTED OUTCOME ANALYSES 
The Subject’s Global Assessment of disease activity VAS and the Physician’s Global 
Assessment of disease activity VAS are recorded at baseline and at Weeks 4, 12, 24, 
36, and 52/Early Termination.  This assessment will be presented separately from 
adverse event data.  Details will be provided in the SAP. 
6.9 
EXPLORATORY ANALYSES 
The exploratory analyses include the following: 
 
Change from baseline in proteinuria at Week 52 
 
Change from baseline in albumin level 
 
Proportion of subjects that experience a doubling of serum creatinine at Week 52 
 
Change from baseline in estimated GFR at Week 52  
 
Change from baseline in the SLICC/ACR damage index at Week 52 
 
Change from baseline in SLE-associated autoantibodies at Week 52 
 
Assessment of local versus centralized expert panel assessment of renal biopsies 
 
Histopathologic assessment of renal biopsies for the presence of CD19 B cells and 
other immune cells 
 
Change in SLEDAI-2K from baseline to Week 52. 
 
Additional exploratory analyses will be pre-specified in the SAP. 


 
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6.10 
INTERIM ANALYSES 
6.10.1 
Planned Interim Analyses 
6.10.1.1 
Pharmacodynamic Futility Interim Analysis: 
Given the rationale for this study, including the results from the LUNAR 
(Rovin et al. 2012) and BELONG studies (Mysler et al. 2013), an interim analysis for 
futility is planned on the basis of CD19 B-cell counts after 30 patients have been 
assigned to the obinutuzumab arm and have had their Day 28 blood CD19 B-cell counts 
assessed by HSFC. 
The effect of rituximab on CD19 B-cell counts has been measured by HSFC in an 
investigator-sponsored study in which peripheral B-cell depletion below the LLOQ of the 
assay occurred in 46% of patients (Vital et al. 2011).  Slightly less than half of these 
rituximab-treated patients with full peripheral B-cell depletion achieved a major clinical 
response, with the remainder of the patients having partial clinical responses.  
Therefore, it is hypothesized that an improved outcome over rituximab is achievable for 
a LN patient population with full peripheral B-cell depletion, with the assumption that 
improved tissue depletion with treatment will parallel the peripheral depletion.  To test 
the hypothesis in this study, we will require at least 50% of the obinutuzumab-treated 
patients to have peripheral B-cell depletion below the LLOQ of the HSFC assay in order 
to have a realistic chance of a positive primary endpoint analysis for the treatment arm.  
Quantification of the link between this biomarker and the study’s primary analysis has 
not been established; therefore predictive probabilities for study statistical significance 
cannot be provided.  Consequently, the study will be terminated if the 5% one-sided 
Clopper-Pearson upper confidence limit for the proportion of patients who achieve B-cell 
depletion is not greater than 0.5.  Assuming that there are 30 patients at the time of the 
interim analysis, this will effectively require that  11 obinutuzumab patients have 
complete B-cell depletion below the LLOQ of the HSFC assay at the time of the interim 
analysis. 
The interim analysis will be performed by the iDMC, which may recommend that the 
study be stopped for futility if the futility criterion is satisfied.  Additional criteria for 
recommending that the study be stopped for futility may be added to the iDMC Charter. 
As this interim analysis will only result in termination of the study due to futility, and not 
for efficacy, an adjustment to the -level is not required.  Although the outcome of the 
interim analysis may reduce the power of this study to below the estimated 83%, a 
sample size adjustment has not been made. 
6.10.1.2 
Renal Response Interim Analysis: 
The iDMC will conduct an interim efficacy analysis to evaluate renal response when the 
last patient has achieved the 6-month visit.  The interim analysis will be performed and 
interpreted by members of the iDMC, who may recommend to the Sponsor the initiation 
of future study planning, according to rules outlined in the iDMC Charter.  If the iDMC 
does recommend that future study planning can begin, then the summary of renal 


 
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response data at Week 24 will be shared with appropriate Sponsor senior management 
personnel who will be unblinded at the treatment group level. 
This interim analysis is for planning purposes only and will have no impact on the 
progression of this study.  Consequently, an adjustment to the -level is not required. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and other 
electronic data will be sent directly to the Sponsor, using the Sponsor’s standard 
procedures to handle and process the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
7.2 
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 


 
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clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical study. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for study-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic PRO data (if applicable), Informed Consent Forms, 
laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for 15 years after completion or discontinuation of the study, or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations. 
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 


 
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The Sponsor will retain study data for 25 years after the final Clinical Study Report 
has been completed or for the length of time required by relevant national or local health 
authorities, whichever is longer. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.   
Studies conducted in the European Union or European Economic Area will comply with 
the E.U. Clinical Trials Directive (2001/20/EC) or Clinical Trials Regulation 
(536/2014) and applicable local, regional, and national laws. 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Home Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee 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 IRB/EC-approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 


 
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The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally 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 study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
8.3 
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 Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.  


 
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8.4 
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 data sets that are transmitted to any Sponsor 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. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. Food and Drug Administration and other national and local 
health authorities, Sponsor monitors, representatives, and collaborators, and the IRB/EC 
for each study site, as appropriate. 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access.  In the event of a data security breach, appropriate mitigation measures will be 
implemented. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., last patient last 
visit). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
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9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
During the conduct of this protocol, an IxRS will be implemented to enable appropriate 
randomization and stratification, and a central laboratory will be employed through a 
central laboratory vendor.  The protocol oversight will include an iDMC, which will meet 
on a regular predefined basis.  Additionally, a centralized renal histopathology reading 
process will be employed to collect renal biopsy data and enable exploratory analyses of 
the pathology findings. 
9.5 
DISSEMINATION 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.  Study data may be shared with others who 
are not participating in this study (see Section 8.4 for details), and redacted Clinical 
Study Reports and/or other summaries of clinical study results may be available in 
health authority databases for public access, as required by local regulation, and will be 
made available upon request.  For more information, refer to the Roche Global Policy on 
Sharing of Clinical Study Informations at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/  
 
The results of this study may be published or presented at scientific congresses.  For all 
clinical studies in patients involving an IMP for which a marketing authorization 
application has been filed or approved in any country, the Sponsor aims to submit a 
journal manuscript reporting primary clinical study results within 6 months after the 
availability of the respective clinical study report.  In addition, for all clinical studies in 


 
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98/Protocol WA29748, Version 4 
patients involving an IMP for which a marketing authorization application has been filed 
or approved in any country, the Sponsor aims to publish results from analyses of 
additional endpoints and exploratory data that are clinically meaningful and statistically 
sound. 
The investigator 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 investigator. 
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 investigator will be designated by mutual 
agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/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 necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


 
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10. 
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Ward MM. Prevalence of physician-diagnosed systemic lupus erythematosus in the 
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Appendix 1  
Schedule of Assessments 
Week 
 
Treatment Period 
 4 to 0 
1 
2 
4 
12 
24 
26 
36 
52/ET 
Day 
 28 to  1 
1 a 
15 
28 
84 
168 
182 
252 
364 
Informed consent 
x 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
x 
 
 
 
 
 
 
 
Medical history 
x 
x 
 
 
 
 
 
 
 
IxRS assignment b 
x 
x 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
Subject’s Global Assessment c 
 
x 
 
x 
x 
x 
 
x 
x 
Physical exam (limited) 
x 
x 
 
 
 
x 
 
 
x 
Height 
x 
 
 
 
 
 
 
 
 
Vital signs and weight d 
x 
x 
x 
x 
x 
x 
x 
x 
x 
12-Lead ECG 
x 
 
 
 
 
 
 
 
x 
Chest X-ray e 
x 
 
 
 
 
 
 
 
 
Physician’s Global Assessment 
 
x 
 
x 
x 
x 
 
x 
x 
SLICC/ACR assessment 
x 
 
 
 
 
x 
 
 
x 
SLEDAI-2K 
x 
x 
 
x 
x 
x 
 
x 
x 
Glucocorticoid Toxicity Change Index 
 
x 
 
 
x 
x 
 
 
x 
Hematology f 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum chemistries g 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinalysis h 
x 
x 
 
x 
x 
x 
 
x 
x 
 


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
105/Protocol WA29748, Version 4 
Appendix 1  
Schedule of Assessments (cont.) 
Week 
 
Treatment Period 
 4 to 0 
1 
2 
4 
12 
24 
26 
36 
52/ET 
Day 
 28 to  1 
1 a 
15 
28 
84 
168 
182 
252 
364 
24-hour urine collection i 
x 
x 
 
 
x 
x 
 
x 
x 
Pregnancy test j 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HBsAg k, HBcAb, Hepatitis C antibody 
x 
 
 
 
 
 
 
 
 
Autoantibody profile l 
x 
x 
 
x 
x 
x 
 
x 
x 
Antibody titers m 
x 
 
 
 
 
x 
 
 
x 
Serum PK sampling n 
 
x n 
x n 
x 
x 
x n 
x n 
x 
x 
Blood sample for flow cytometry o 
 
x 
x 
x 
x 
x o 
 
 
x 
Serum ADAs 
 
x o 
 
 
 
x o 
 
 
x  
Quantitative serum Ig levels (total, IgG, IgM, 
and IgA) 
x 
x 
 
 
x 
x 
 
 
x 
C3, C4, CH50 complement 
x 
x 
x 
x 
x 
x 
 
x 
x 
Serum for biomarkers o 
x 
x o 
x 
x 
x 
x o 
 
x 
x 
Plasma for biomarkers o 
x 
x o 
x 
x 
x 
x o 
 
x 
x 
Urine for biomarkers p, o 
x 
x 
x 
x 
x 
x 
 
x 
x 
PAXgene RNA o 
x 
x o 
x 
x 
x 
x o 
 
x 
x 
Blood DNA q (optional) 
x 
 
 
 
 
 
 
 
 
Record of menses 
x 
x 
x 
X 
x 
x 
x 
x 
x 
Adverse events r 
 
x r 
x r 
X 
x 
x r 
x r 
x 
x 
 
 


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
106/Protocol WA29748, Version 4 
Appendix 1  
Schedule of Assessments (cont.) 
Week 
 
Treatment Period 
 4 to 0 
1 
2 
4 
12 
24 
26 
36 
52/ET 
Day 
 28 to  1 
1 a 
15 
28 
84 
168 
182 
252 
364 
Concomitant medications 
x 
x 
x 
X 
x 
x 
x 
x 
x 
Study drug infusion 
 
x s 
x s 
 
 
x s 
x s 
 
 
Corticosteroid dose/taper t 
 
x 
x 
X 
x 
 
 
 
 
Renal biopsy (optional) u 
 
 
 
 
 
 
 
 
(x) 
ADA  anti-drug antibody; ET  Early Termination Visit; HBcAb  hepatitis B core antibody; HBsAg  hepatitis B surface antigen; HBV  hepatitis B 
virus; IV  intravenous; IxRS  interactive voice/Web response system; PK  pharmacokinetic; PO  by mouth; SLEDAI-2K  Systemic Lupus 
Erythematosus Disease Activity Index; SLICC/ACR  Systemic Lupus International Collaborating Clinics/American College of Rheumatology. 
Notes:  All assessments will be performed pre-infusion unless otherwise specified.  Infusion visits (Days 15, 168, and 182) except for Day 1, should 
be performed within  3 days of the scheduled visit.  Non-infusion visits should be performed within  3 days of the scheduled visit. 
a Day 1, unless otherwise notified. 
b At screening, IxRS will be contacted to obtain assignment of patient screening number.  At Day 1, IxRS will be contacted to obtain patient 
randomization number and drug assignment. 
c Subject’s Global Assessment will be performed prior to other assessments. 
d Blood pressure and pulse rate while patient is seated for 5 minutes, and respiratory rate and body temperature.  Vital signs should be taken 
pre-infusion, then every 15 minutes for 1 hour, then every 30 minutes until the end of the infusion, and within 30 minutes post-infusion.  Additional 
readings may be obtained at the discretion of the investigator in the event of an infusion-related reaction (e.g., hypotension and/or fever). 
e If a chest X-ray has been obtained within the past 3 months and no clinically significant abnormality was observed and no new pulmonary signs 
or symptoms are exhibited, no chest X-ray is required. 
f Hematology:  CBC, RBC count, WBC count and differential, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, 
and quantitative platelet count. 
g Serum chemistries include AST/SGOT, ALT/SGPT, alkaline phosphatase, total protein, albumin, cholesterol, total bilirubin, BUN, uric acid, 
creatinine, random glucose, lactate dehydrogenase, potassium, sodium, chloride, calcium, phosphorus, CPK, and triglycerides.  At screening and 
at unscheduled visits, amylase and lipase will be also included. 
 


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
107/Protocol WA29748, Version 4 
Appendix 1  
Schedule of Assessments (cont.) 
h All urinalyses must include microscopic examination, macroscopic urinalysis, and spot urine protein to creatinine ratio (preferably done on the 
first morning urine).  The spot urine protein to creatinine ratio on Days 1, 84, 168, 252, and 364 must be done from first-morning urine. 
i To be analyzed for total protein, total creatinine, creatinine clearance, and protein to creatinine ratio. 
j For women of childbearing potential, including those who have had a tubal ligationPositive test results will be confirmed with a serum pregnancy 
test.  Study drug infusion must not be administered unless the pregnancy test result is negative. 
k Patients who are HBsAg negative and HBcAb positive with no detectable DNA will be allowed into the study but will require regular monitoring of 
HBV DNA (see the Laboratory Manual for further details). 
l Autoantibodies include anti-nuclear antibody, anti-dsDNA, Sm, Ro, La, RNP, and anti-C1q. 
m Antibody titers include mumps, rubella, Varicella, tetanus, influenza, and S. pneumoniae. 
n Obtain pre-infusion (within 30 minutes prior to the start of infusion) and at the end of infusion (or within 30 minutes after the end of infusion). 
o Samples will be drawn before administration of study drug on dosing days. 
p Urine for biomarkers will be processed at the study site.  Instructions will be provided in the laboratory manual. 
q The DNA samples are optional and should only be obtained from patients who sign the separate Roche Clinical Repository Informed Consent 
Form.  Preferably, samples will be obtained at screening visit, but they may be obtained at subsequent study visits. 
r On Day 1, adverse events will be recorded during infusion and post-infusion.  For Days 15, 168, and 182, adverse events will be recorded 
pre-infusion, during infusion, and post-infusion.  For all serious infectious adverse events reported, CBC with differentials, quantitative Ig, and 
CD19 B-cell counts should be determined within 1 week of onset. 
s On Days 1, 15, 168, and 182, administer 80 mg methylprednisolone IV (or placebo), 6501000 mg acetaminophen PO, and 50 mg 
diphenhydramine PO (or other antihistamine) 3060 minutes prior to the study-drug infusion. 
t Patients may initiate 0.5 mg/kg/day oral prednisone in screening or at Day 2.  Oral corticosteroid taper will begin on Day 16.  The maximum 
allowable daily dose of prednisone will be 60 mg. 
u All patients will be asked to undergo an optional repeat renal biopsy after completion of the treatment portion of the study (after Week 52).  If a 
patient agrees to a repeat renal biopsy, one should be performed within 4 weeks of completion of the treatment portion of the study.  Biopsies 
performed at other times, for clinical reasons, will also be submitted for central review.  Because examination of the biopsy sample may 
potentially unblind the study treatment, investigators and study site personnel should not examine the biopsy sample for immunohistochemistry of 
B cells or be informed of its results.  
 
 


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
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Appendix 2  
Follow-Up and B-Cell Follow-Up Assessments 
Evaluation/Procedure 
Follow-Up 
B-Cell Follow-Up 
Week 
76 
104 
Every 6 Months 
Study Day ( 7 days) 
532 
728 
 
SLICC/ACR 
 
x 
 
Serum chemistries a 
x 
x 
x 
Urinalysis b 
x 
x 
x 
Urine chemistries:  P/C b 
x 
x 
x 
Pregnancy test c 
x 
x 
x 
Autoantibody profile d 
x 
x 
x 
Blood sample for flow cytometry 
 
x 
x 
Serum ADAs  
x 
x 
x 
Serum pharmacokinetics 
x 
x 
x 
Quantitative serum Ig levels (total, IgG, IgM, and IgA) 
x 
x 
x 
PAXgene RNA  
x 
x 
x 
Urine for biomarkers e 
x 
x 
x 
Serum for biomarkers 
x 
x 
x 
Plasma for biomarkers 
x 
x 
x 
Adverse events f 
x 
x 
x 
Glucocorticoid Toxicity Change Index 
x 
x 
 
Concomitant medications 
x 
x 
x 
ADA  anti-drug antibody; P/C  protein to creatinine ratio; SLICC/ACR  Systemic Lupus International 
Collaborating Clinics/American College of Rheumatology. 
Note:  All urine tests should be performed on first-morning urine. 
a Serum chemistries include AST/SGOT, ALT/SGPT, alkaline phosphatase, total protein, albumin, 
cholesterol, total bilirubin, BUN, uric acid, creatinine, random glucose, lactate dehydrogenase, 
potassium, sodium, chloride, calcium, phosphorus, CPK, and triglycerides. 
b Microscopic and macroscopic. 
c For women of childbearing potential, including those who have had a tubal ligation.  Urine pregnancy 
test on Weeks 76 and 104.  If result of urine pregnancy test is positive, confirm with a central 
laboratory serum pregnancy test. 
d Autoantibodies include:  ANA, dsDNA, Sm, Ro, La, RNP, anti-c1q 
e Urine for biomarkers will be processed at the study site.  Instructions will be provided in the 
laboratory manual. 
f For all serious infectious adverse events reported, CBC with differentials, quantitative Ig, and CD19 
B-cell counts should be determined within 1 week of onset. 
 


 
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Appendix 3 International Society of Nephrology/Renal 
Pathology Society (ISN/RPS)  
2003 Classification of Lupus Nephritis 
Table 1 
Classifications 
Class 
Description 
Class I 
Minimal mesangial LN 
Normal glomeruli by light microscopy, but mesangial immune deposits by 
immunofluorescence 
Class II 
Mesangial proliferative LN 
Purely mesangial hypercellularity of any degree or mesangial matrix 
expansion by light microscopy, with mesangial immune deposits 
A few isolated subepithelial or subendothelial deposits may be visible by 
immunofluorescence or electron microscopy, but not by light microscopy 
Class III 
Focal LN 
Active or inactive focal, segmental or global endo- or extracapillary 
glomerulonephritis involving  50% of all glomeruli, typically with focal 
subendothelial immune deposits, with or without mesangial alterations 
Class III (A) 
Active lesions:  focal proliferative LN 
Class III (A/C) 
Active and chronic lesions:  focal proliferative and sclerosing LN 
Class III (C) 
Chronic inactive lesions with glomerular scars: focal sclerosing LN 
Class IV 
Diffuse LN 
Active or inactive diffuse, segmental or global endo- or extracapillary 
glomerulonephritis involving  50% of all glomeruli, typically with diffuse 
subendothelial immune deposits, with or without mesangial alterations.  
This class is divided into diffuse segmental (IV-S) LN when  50% of the 
involved glomeruli have segmental lesions, and diffuse global (IV-G) LN 
when  50% of the involved glomeruli have global lesions.  Segmental is 
defined as a glomerular lesion that involves less than half of the 
glomerular tuft.  This class includes cases with diffuse wire loop deposits 
but with little or no glomerular proliferation. 
Class IV-S (A) 
Active lesions:  diffuse segmental proliferative LN 
Class IV-G (A) 
Active lesions:  diffuse global proliferative LN 
Class IV-S (A/C) 
Active and chronic lesions:  diffuse segmental proliferative and 
sclerosing LN 
Class IV-G (A/C) 
Active and chronic lesions:  diffuse global proliferative and sclerosing LN 
Class IV-S (C) 
Chronic inactive lesions with scars:  diffuse segmental sclerosing LN 
Class IV-G (C) 
Chronic inactive lesions with scars:  diffuse global sclerosing LN 


 
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Appendix 3 International Society of Nephrology/Renal 
Pathology Society (ISN/RPS)  
2003 Classification of Lupus Nephritis (cont.) 
Table 1 
Classifications (cont.) 
Class 
Description 
Class V 
Membranous LN 
Global or segmental subepithelial immune deposits or their morphologic 
sequelae by light microscopy and by immunofluorescence or electron 
microscopy, with or without mesangial alterations 
Class V LN may occur in combination with class III or IV in which case 
both will be diagnosed. 
Class V LN may show advanced sclerosis 
Class VI 
Advanced sclerotic LN 
 90% of glomeruli globally sclerosed without residual activity 
A  active; C  chronic; G  global; LN  lupus nephritis; S  segmental. 
 
 
 


 
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Table 2 
Definitions 
Term 
Definition 
Diffuse 
A lesion involving most ( 50%) glomeruli 
Focal 
A lesion involving  50% of glomeruli 
Global 
A lesion involving more than half of the glomerular tuft 
Segmental 
A lesion involving less than half of the glomerular tuft (i.e., at least half of 
the glomerular tuft is spared) 
Mesangial 
hypercellularity 
At least three mesangial cells per mesangial region in a 3 micron thick 
section 
Endocapillary 
proliferation 
Endocapillary hypercellularity due to increased number of mesangial 
cells, endothelial cells, and infiltrating monocytes, and causing narrowing 
of the glomerular capillary lumina 
Extracapillary 
proliferation or 
cellular crescent 
Extracapillary cell proliferation of more than two cell layers occupying one 
fourth or more of the glomerular capsular circumference 
Karyorrhexis 
Presence of apoptotic, pyknotic, and fragmented nuclei 
Necrosis 
A lesion characterized by fragmentation of nuclei or disruption of the 
glomerular basement membrane, often associated with the presence of 
fibrin-rich material 
Hyaline thrombi 
Intracapillary eosinophilic material of a homogeneous consistency by 
which immunofluorescence has been shown to consist of immune 
deposits 
Proportion of 
involved glomeruli 
Intended to indicate the percentage of total glomeruli affected by LN, 
including the glomeruli that are sclerosed due to LN, but excluding 
ischemic glomeruli with inadequate perfusion due to vascular pathology 
separate from LN 
LN  lupus nephritis. 
Source:  Weening JJ, D’Agati VD, Schwartz MM, et al. The classification of glomerulonephritis 
in systemic lupus erythematosus revisited. J Am Soc Nephrol 2004;15:24150. 
 


 
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Appendix 3 International Society of Nephrology/Renal 
Pathology Society (ISN/RPS)  
2003 Classification of Lupus Nephritis (cont.) 
DEFINITION OF ACTIVE AND CHRONIC LESIONS 
Active Lesions 
 
Endocapillary hypercellularity with or without leukocyte infiltration and with 
substantial luminal reduction 
 
Karyorrhexis 
 
Fibrinoid necrosis 
 
Rupture of glomerular basement membrane 
 
Crescents, cellular or fibrocellular subendothelial deposits identifiable by light 
microscopy (wireloops) 
 
Intraluminal immune aggregates (hyaline thrombi) 
 
Chronic Lesions 
 
Glomerular sclerosis (segmental, global) 
 
Fibrous adhesions 
 
Fibrous crescents 
 


 
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Appendix 4  
Guidelines for Mycophenolate Mofetil (or Equivalent) Dosing 
INITIAL DOSING 
Patients may use either mycophenolate mofetil (MMF) or mycophenolic acid (MPA) as 
standard of care background therapy in this study.  Dosing guidelines are based on use 
of MMF but an equivalent dose of MPA may be used (MMF 500 mg is equivalent to MPA 
360 mg).  Patients should be initiated on MMF at a dosage of 1500 mg/day (or 
equivalent) in divided doses.  The target MMF dosage for the protocol is 
2000 to 2500 mg/day (or equivalent). 
If patients are already receiving MMF (or equivalent) upon entry into the study, their 
current dosage should be  1500 mg/day (or equivalent); if the dosage is 
not  1500 mg/day (or equivalent), then it should be increased to that level.  The patient’s 
dose should also be divided into two or three times-a-day dosing.   
ESCALATION OF DOSE 
The dosage of MMF (or equivalent) should be increased, as tolerated, by 500 mg/week 
(or equivalent) with the goal of reaching 20002500 mg/day (or equivalent), given in  
divided doses, by Week 4 at the latest.  
ADJUSTMENTS TO MMF (OR EQUIVALENT) DOSE 
Investigators will be allowed to adjust the dosage because of tolerance and adverse 
effects, but the dosage should not be increased to greater than 2500 mg/day (or 
equivalent).  The most common adverse effects requiring titration of MMF (or equivalent) 
are gastrointestinal (GI) intolerance, neutropenia, and infectious complications 
(CellCept U.S. Package Insert [USPI], Myfortic USPI).  To maintain consistency in 
dose adjustments, recommended reductions are listed in Table 1. 
If a patient develops GI toxicity due to MMF (or equivalent), it is recommended to reduce 
the dose according to “step 1,” as listed in Table 1 if other methods/evaluations, as 
outlined below, are not helpful.  If symptoms persist for 2 weeks after the change, the 
investigator may reduce the dose according to “step 2,” as listed in Table 1.  After the 
symptoms resolve, an attempt should be made to increase MMF (or equivalent) to a goal 
of 2000 mg/day (or equivalent) per the previous dosing algorithm.  If GI symptoms 
return, then the patient should be continued on the highest tolerable dose. 
GI toxicity may not necessarily require dose reduction of MMF (or equivalent).  If 
diarrhea occurs, infectious causes (e.g., C. difficile and enteropathogens) should be 
ruled out and treated if necessary.  If, in the investigator’s opinion, the diarrhea is non-
infectious, agents such as Lomotil or tincture of opium may be used to decrease 
diarrhea. 


 
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Appendix 4  
Guidelines for Mycophenolate Mofetil (or Equivalent)  Dosing 
(cont.) 
If a patient develops an absolute neutrophil count (ANC) between 1000 and 1200, the 
dose should be reduced according to “step 1,” as listed in Table 1 and the neutrophil 
count should be checked again at the next scheduled visit.  If the ANC continues to be 
between 1000 and 1200, the dose should be reduced according to “step 2,” as listed in 
Table 1.  After the ANC increases to  1200, the dose should be titrated towards goal, 
but at a rate of 500 mg per month. 
If the patient’s ANC is  1000, MMF (or equivalent) must be stopped immediately.  The 
patient must return within 1421 days for repeat measurement of ANC.  If ANC 
is  1500, then MMF (or equivalent) may be restarted at the “step 1” dose according to 
what the patient’s previous MMF (or equivalent) dose was.  For example, if the patient’s 
dosage of MMF was 2500 mg/day at the time of interruption of MMF, then MMF should 
be restarted at 2000 mg/day. 
If a patient experiences an infectious complication, MMF (or equivalent) should be 
stopped until the episode has resolved.  MMF (or equivalent) can then be reinstituted at 
the previous dose. 
Regardless of dose reduction, every attempt must be made to bring the patient’s dosage 
of MMF (or equivalent) to  1500 mg/day (or equivalent). 
Table 1 
Protocol-Specified MMF (or Equivalent) Dose Reduction 
MMF dosage 
(mg/day) 
Step 1 Reduction 
(mg) 
Step 2 Reduction 
(mg) 
2500 
2000 
1500 
2250 
1750 
1250 
2000 
1500 
1000 
1500 
1000 
750 
 
REFERENCE 
Hogg RJ, Wyatt RJ, Scientific Planning Committee of the North American IgA 
Nephropathy Study. A randomized controlled trial of mycophenolate mofetil in 
patients with IgA nephropathy. BMC Nephrol 2004;5:3. 
 
 


 
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Appendix 5  
Initial Prednisone/Prednisolone Tapering Schedule 
Patients will receive both intravenous (IV) and oral corticosteroids as part of their initial 
course of therapy.  IV methylprednisolone will be dosed at 1000 mg to treat active lupus 
nephritis (LN) according to standard clinical practice, which typically recommends one to 
three infusions of methylprednisolone at this dose.  Between one and three infusions of 
1000 mg methylprednisolone will be allowed for the inclusion of patients into this 
protocol and can occur at any time before or during the screening interval.  For instance, 
a patient with LN may have been identified in the community prior to referral to the 
investigator’s site and received 1000 mg of methylprednisolone.  This dose and all doses 
of steroids must be accounted for in the steroid concomitant medications section of the 
case report form.  The target protocol methylprednisolone dose is a single 1000 mg 
infusion, but up to three infusions will be acceptable for study entry. 
The initial oral prednisone dose will be 0.50 mg/kg/day, not to exceed 60 mg, and will be 
given on Days 216, excluding concomitant dosing of IV methylprednisolone.  
Investigators are instructed to round the calculated dose to the nearest 10-mg increment 
listed in Table 1.  The investigator should instruct the patient to initiate a corticosteroid 
taper beginning on Day 16.  The patient’s initial study prednisone dose (or equivalent) is 
listed on the top line of Table 1, and the subsequent doses, changing every 2 weeks, are 
noted in the column below the selected initial dose.  Patients whose calculated 
prednisone dose would be  60mg/day should use 60 mg/day as their starting dose. 
Table 1 
Prednisone Tapering Schedule 
Starting Prednisone Dose 
(mg/day) 
30 
40 
50 
60 
Day 16 
25 
35 
40 
50 
Day 28 
25 
30 
30 
40 
Day 42 
20 
25 
20 
30 
Day 56 
15 
20 
15 
20 
Day 70 
10 
15 
10 
10 
Day 84 
7.5 
7.5 
7.5 
7.5 
 
CORTICOSTEROID DOSING FOR EXTRARENAL FLARES 
To maintain consistency in the use of corticosteroids for extrarenal flares, patients will 
not be allowed to increase their prednisone dose during their participation in the study 
unless it is judged clinically appropriate by the investigator.  A flare is defined as an 
increase in Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)-2K that is 
not accounted for by either hypocomplementemia or an increase in anti-dsDNA antibody 
level or the initiation of new immunosuppressive therapy or an increase of corticosteroid 


 
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Appendix 5  
Initial Prednisone/Prednisolone Tapering Schedule (cont.) 
dose.  On the basis of the severity of the disease, patients may be retreated with 
prednisone up to 1.0 mg/kg.  IV corticosteroids in equivalent doses may be allowed if 
gastrointestinal involvement temporarily precludes oral corticosteroid use. 
Because it is important to maintain a consistent corticosteroid taper to interpret the 
results of this clinical study, it is suggested that investigators round the calculated 
corticosteroid dose (based on the patient’s weight in kilograms) to the nearest 10-mg 
increment listed in Table 2 (not to exceed 60 mg/day) and follow the recommended 
tapering schedule.  The investigator should instruct the patient to initiate a corticosteroid 
taper 14 days after starting the increased corticosteroid dose.  The patient’s increased 
study prednisone dosage (or equivalent) is listed on the top line of Table 2, and the 
subsequent dosages, changing every 2 weeks, are noted in the column below the 
selected initial dose.  If the investigator determines that a higher dose or longer 
treatment period is necessary, he or she should first contact the Medical Monitor to 
discuss this.  Patients who do not show improvement in their symptoms after 2 weeks of 
increased corticosteroid treatment are considered to be nonresponsive to 
corticosteroids. 
Patients who initiate a new immunosuppressive or any other new systemic lupus 
erythematosus medication will return for all protocol-scheduled visits and will not receive 
further study drug. 
Table 2 
Prednisone Dosing Recommendations for Extrarenal Flares 
Starting Prednisone 
Dose (mg/day) 
20 
30 
40 
50 
60 
Day 16 
15 
25 
30 
40 
50 
Day 30 
10 
20 
25 
30 
40 
Day 44 
10 
10 
15 
20 
30 
Day 58 
7.5 
10 
10 
10 
20 
Day 72 
7.5 
7.5 
10 
10 
10 
Day 86 
7.5 
7.5 
7.5 
7.5 
7.5 
 
CORTICOSTEROID DOSING FOR RENAL FLARES 
To maintain consistency in the treatment of renal flares, retreatment with higher doses of 
corticosteroids is permitted if judged clinically appropriate by the investigator and if 
patients meet the criteria for a renal flare as defined by all of the following: 
 
Stable or increased creatinine 


 
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Appendix 5  
Initial Prednisone/Prednisolone Tapering Schedule (cont.) 
 
Worsening active urinary sediment from baseline, as defined by a  50% increase in 
RBCs/high-power field or the appearance of new RBC casts when none were 
previously present 
 
Increase in proteinuria, as evidenced by an increase in the urine protein to 
creatinine ratio to  2, if the most recent urine protein to creatinine ratio was  2.  
 
Patients may be treated with prednisone (up to 0.5 mg/kg; not to exceed 60 mg/day) for 
2 weeks.  Prednisone will then be tapered to achieve  10 mg/day 6 weeks after the 
initial corticosteroid increase (see Table 3).  Patients who do not exhibit a response to 
the initial 2 week course of increased corticosteroids, as evidenced by an improvement 
in urinary sediment and/or a reduction in the urine protein to creatinine ratio, or who 
initiate a new immunosuppressive therapy will be deemed treatment failures and 
continue scheduled protocol visits of the study and will not receive additional study drug. 
Table 3 
Prednisone Dosing Recommendations for Renal Flares 
Days after Initial 
Corticosteroid Increase 
Prednisone Dose 
(mg/day) 
20 
30 
40 
50 
60 
14 
15 
25 
30 
40 
50 
21 
15 
20 
25 
30 
40 
28 
10 
20 
20 
20 
30 
35 
10 
15 
15 
15 
20 
42 
10 
10 
10 
10 
10 
 
 


 
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Appendix 6  
Criteria for Classification of Systemic Lupus Erythematosus 
There are 11 criteria for the classification of systemic lupus erythematosus (SLE).  On 
the basis of this classification, a patient would be considered to have “definite” SLE if 
any 4 or more of the 11 criteria are present, serially or simultaneously, during any 
interval of observation. 
In this study, a patient will be considered to have SLE if he or she has at least four 
criteria present, one of which must be a positive anti-nuclear antibody (Criterion 11). 
Criterion 
Definition 
1.  Malar rash 
Fixed erythema, flat or raised, over the malar eminences, tending to spare 
the nasolabial folds 
2.  Discoid rash 
Erythematous raised patches with adherent keratotic scaling and follicular 
plugging; atrophic scarring may occur in older lesions 
3.  Photosensitivity 
Skin rash as a result of unusual reaction to sunlight, by patient history or 
physician observation 
4.  Oral ulcers 
Oral or nasopharyngeal ulceration, usually painless, observed by 
physician  
5.  Arthritis 
Nonerosive arthritis involving  2 peripheral joints, characterized by 
tenderness, swelling, or effusion 
6.  Serositis 
a) 
Pleuritis--convincing history of pleuritic pain or rubbing heard by a 
physician or evidence of pleural effusion 
 
 
OR  
b) 
Pericarditis--documented by ECG or rub or evidence of pericardial 
effusion  
7.  Renal disorder 
a) 
Persistent proteinuria  0.5 g/day or  3 if quantitation not performed  
 
 
OR  
b) 
Cellular casts--may be red cell, hemoglobin, granular, tubular, or 
mixed  
8.  Neurologic disorder 
a) 
Seizures--in the absence of offending drugs or known metabolic 
derangements (e.g., uremia, ketoacidosis, or electrolyte imbalance) 
 
 
OR  
b) 
Psychosis--in the absence of offending drugs or known metabolic 
derangements (e.g., uremia, ketoacidosis, or electrolyte imbalance) 
 
 
 
 
 
 
 
 
 
 


 
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Appendix 6  
Criteria for Classification of Systemic Lupus Erythematosus 
(cont.) 
Criterion 
Definition 
9.  Hematologic 
disorder 
a) 
Hemolytic anemia--with reticulocytosis  
 
 
OR 
b) 
Leukopenia:   4,000/mm3 total on 2 or more occasions  
 
OR  
c) 
Lymphopenia:   1,500/mm3 on 2 or more occasions  
 
 
OR 
d) 
Thrombocytopenia:   100,000/mm3 in the absence of offending drugs 
10.  Immunologic 
disorder a 
a) 
Anti-DNA:  antibody to native DNA in abnormal titer 
 
OR 
b) 
Anti-SM:  presence of antibody to SM nuclear antigen  
 
OR 
c) 
Positive finding of antiphospholipid antibodies based on (1) an 
abnormal serum level of IgG or IgM anti-cardiolipin antibodies, (2) a positive 
test result for lupus anticoagulant using a standard method, or (3) a false 
positive serologic test for syphilis known to be positive for  6 months and 
confirmed by Treponema pallidum immobilization or fluorescent treponemal 
antibody absorption test 
11.  Anti-nuclear 
antibody 
An abnormal titer of anti-nuclear antibody by immunofluorescence or an 
equivalent assay at any point in time and in the absence of drugs known to 
be associated with "drug-induced lupus" syndrome  
a The modifications to criterion number 10 were made in 1997 (Hochberg 1997). 
Source:  Tan et al. 1982. 
 
REFERENCE 
Hochberg MC. Updating the American College of Rheumatology revised criteria for the 
classificiation of systemic lupus erythematosus. Arthritis Rheum 1997;40(9):1725. 
Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of 
systemic lupus erythematosus. Arthritis Rheum 1982;25(11):12717. 
 


 
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Appendix 7  
Study Drug Administration 
ADMINISTRATION OF STUDY DRUG 
Study drug (obinutuzumab or placebo) should be given as a slow intravenous (IV) 
infusion.  It should not be administered as an IV push or bolus. 
Although obinutuzumab may be administered on an outpatient basis, patients may be 
hospitalized for observation at the discretion of the investigator.  Irrespective, 
obinutuzumab must be administered in a hospital or clinic environment where full 
resuscitation facilities are immediately available and under close supervision of the 
investigator or designee.  The guidelines below may be slowed at the discretion of the 
investigator based on a patient’s clinical presentation. 
FIRST INFUSION (DAY 1) 
Patients should receive prophylactic treatment of acetaminophen (6501000 mg) and 
diphenhydramine hydrochloride (HCl) (50 mg; or equivalent dose of a similar agent) by 
mouth 3060 minutes prior to the start of an infusion.  Prior to the Day 1 infusion, 
patients must receive 80 mg IV methylprednisolone or placebo 3060 minutes prior to 
the start of the study drug infusion. 
NOTE:  Patients should be cautioned not to operate vehicles or hazardous machinery 
until their response to diphenhydramine (or similar antihistamine) has been determined. 
Study drug infusions should be made through a dedicated line and commence at a rate 
of 50 mg/hr.  This may be escalated at a rate of 50 mg/hr every 30 minutes to a 
maximum of 400 mg/hr.  Table 1 presents the schedule for the first infusion. 
Table 1 
Schedule for First Infusion 
Time 
(min) 
Infusion Rate 
Dose in 30 minutes 
(mg) 
Cumulative Dose 
(mg) 
(mg/hr) 
(mL/hr) 
030 
50 
12.5 
25 
25 
3160 
100 
25 
50 
75 
6190 
150 
37.5 
75 
150 
91120 
200 
50 
100 
250 
121150 
250 
62.5 
125 
375 
151180 
300 
75 
150 
525 
181210 
350 
87.5 
175 
700 
212240 
400 
100 
200 
900 
241255 a 
400 
100 
200 
1000 
a Should complete at 255 minutes (4 hours, 15 minutes) to complete total dose of 1000 mg. 
 


 
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Appendix 7  
Study Drug Administration (cont.) 
If a patient experiences a mild infusion-related reaction (IRR) that is deemed by the 
investigator to be clinically significant, the infusion rate should be reduced to half the 
infusion rate that was used at the time of the reaction (e.g., from 100 mg/hr to 50 mg/hr).  
After the reaction has resolved, the infusion should be kept at the reduced rate for an 
additional 30 minutes.  If the reduced rate is tolerated, then the infusion rate may be 
increased to the next closest rate on the infusion schedule.  Patients who experience a 
moderate-to-severe IRR should have their infusion interrupted immediately and should 
receive aggressive symptomatic treatment.  The infusion should not be restarted before 
all the symptoms have disappeared; after all symptoms have disappeared, the infusion 
may be restarted at half the rate.  If the reduced rate is tolerated for 30 minutes, then the 
infusion rate may be increased to the next closest rate on the infusion table. 
After the end of the first infusion, the IV line should remain in situ for at least 2 hours to 
be able to administer drugs intravenously if necessary.  At the end of the remaining 
infusions, the IV line should remain in place for at least 30 minutes.  If no adverse events 
occur during this period of time, the IV line may be removed. 
SUBSEQUENT INFUSIONS (DAYS 15, 168, AND 182) 
Patients should receive prophylactic treatment of acetaminophen (6501000 mg) and 
diphenhydramine HCl (50 mg; or equivalent dose of similar agent) by mouth 
3060 minutes prior to the start of an infusion.  Patients must receive 80 mg IV 
methylprednisolone or placebo 3060 minutes prior to the start of the study drug 
infusion. 
Patients who tolerated the first infusion of study drug well may receive the second 
infusion as detailed in Table 2.  Patients who experienced an IRR to the first infusion, 
deemed by the investigator to be clinically significant, should receive study drug as per 
the initial infusion schedule, with the starting rate of infusion not exceeding half that 
associated with the prior reactions.  If the infusion reaction during the first infusion 
occurred at a rate  200 mg/hr, then the second infusion rate should start at 100 mg/hr. 
Study drug infusions should be made through a dedicated line and commence at a rate 
of 100 mg/hr.  This may be escalated at a rate of 100 mg/hr every 30 minutes to a 
maximum of 400 mg/hr.  Table 2 presents the schedule for the second and subsequent 
infusions. 
In the event that the patient experiences an IRR, the infusion rate should be reduced to 
half that rate (e.g., from 100 mg/hr to 50 mg/hr).  Patients who experience a 
moderate-to-severe IRR should have their infusion interrupted immediately and should 
receive aggressive symptomatic treatment.  The infusion should not be restarted before 
all the symptoms have disappeared (see above). 


 
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Appendix 7  
Study Drug Administration (cont.) 
Note:  These recommendations do not address life-threatening events, including 
anaphylaxis, for which all appropriate standard measures (including full resuscitation 
medications and equipment) must be available and should be used as clinically 
indicated. 
Table 2 
Schedule for Second and Subsequent Infusions 
Time 
(min) 
Infusion Rate 
Dose in 30 minutes 
(mg) 
Cumulative Dose 
(mg) 
(mg/hr) 
(mL/hr) 
030 
100 
25 
50 
50 
3160 
200 
50 
100 
150 
6190 
300 
75 
150 
300 
91120 
400 
100 
200 
500 
121150 
400 
100 
200 
700 
151180 
400 
100 
200 
900 
181195a 
400 
100 
200 
1000 
a Should complete at 195 minutes (3 hours, 15 minutes) to complete total dose of 
1000 mg. 
 


 
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Appendix 8  
Corticosteroid Equivalence Chart 
 
Equivalent Dose 
(mg) 
Hydrocortisone 
20 
Cortisone acetate 
25 
Prednisone 
5 
Prednisolone 
5 
Methylprednisolone 
4 
Dexamethasone 
0.75 
Betamethasone 
0.75 
Triamcinolone 
4 
Beclometasone 
0.75 
Note:  Cortisol (hydrocortisone) is the standard of 
comparison for glucocorticoid potency.  
Hydrocortisone is the name used for pharmaceutical 
preparations of cortisol. 
 


 
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Appendix 9  
Instructions for Collecting and Analyzing Urine Samples 
BASED ON THE EUROPEAN URINALYSIS GUIDELINES [2000] 
URINE COLLECTION 
Urine collected at Screening; Day 1; and Weeks 12, 24, 36, and 52 should be collected 
in the following manner: 
 
A 24-hour urine sample must be initiated prior to the visit, at which point it is to be 
collected and include only one first-morning urine. 
 
A separate first-morning urine on the day of the visit should be collected.  
 
The investigator will take a 30-mL aliquot of urine from the first-morning urine 
sample for urine sediment analysis (as outlined below), macroscopic analysis, and a 
spot urine protein to creatinine ratio.  The recommended volume of urine collected 
should be 30 mL, but a minimum of 18 mL should be collected.  Please refer to the 
Central Laboratory Manual for details. 
 
It is preferable that all of the urine for the 24-hour urine collection is collected separately 
from the first morning sample used for urine sediment analysis, macroscopic analysis, 
and a spot urine protein to creatinine ratio.  If the first morning urine on the day of the 
visit is the final urine collected for the 24-hour urine collection, then aliquots, as 
described above, should be taken for urine sediment analysis, macroscopic analysis, 
and a spot urine protein to creatinine ratio; the leftover urine should be combined with 
the rest of the 24-hour urine collection, and an aliquot should be taken and sent for 
creatinine, protein, and protein to creatinine measurement. 
For all other visits requiring a urine specimen, every effort should be made to collect a 
first-morning urine sample.  If a first-morning urine sample cannot be collected, then a 
second-morning urine sample should be collected.  If a second-morning urine sample 
cannot be collected, the patient should be asked to come back within the window period 
for that visit to give a first- or second-morning urine sample (first-morning urine is 
preferable).  Aliquots as described above should be taken for these samples as well (i.e., 
one sample for macroscopic analysis, one for urine sediment analysis, and one for a 
spot protein to creatinine ratio). 
Written instructions should be given to the patient about how to collect a morning urine 
sample.  In addition, it is encouraged to remind the patient that strenuous physical 
exercise should be avoided for the 72 hours preceding a urine collection. 
In females, urine collection should be avoided during menstruation. 


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
125/Protocol WA29748, Version 4 
Appendix 9  
Instructions for Collecting and Analyzing Urine Samples (cont.) 
URINE EXAMINATION 
Four hours is the maximum recommended time between urine collection and local 
microscopic analysis.  
The recommended volume of urine collected should be 30 mL, but a minimum of 18 mL 
should be collected. 
The sample should be split into three equal aliquots.  One aliquot will be used for central 
laboratory macroscopic and microscopic urinalyses, one aliquot will be used for 
measurement of spot urine protein to creatinine ratio, and the remaining aliquot will be 
used for local microscopic analysis.  Please refer to the Central Laboratory manual for 
details. 
Local urine microscopic analysis should be performed by manual evaluation.  If this 
cannot be done, validated automated analysis is acceptable, but the Principal 
Investigator should first discuss the use of the method with the Medical Monitor.  The 
procedure below outlines the recommended process for manual evaluation. 
Preparation for microscopic analysis is as follows: 
 
The aliquot for microscopic analysis should be centrifuged between 400 and 
1500  g for approximately 5 minutes (1000  g for 5 minutes is preferred). 
 
The supernatant should be decanted. 
 
After decanting, if supravital staining will be used to aid in particulate analysis, 
10% volume of the supravital stain to be used should be added and the solution 
mixed gently.  
 
The sediment should be gently resuspended and then placed onto a microscope 
slide. 
 
A coverslip should be added horizontally to maximize even distribution. 
 
 
 


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
126/Protocol WA29748, Version 4 
Appendix 9  
Instructions for Collecting and Analyzing Urine Samples (cont.) 
VISUAL MICROSCOPIC ANALYSIS 
 
Equipment/staining:  If available, it is recommended that phase-contrast microscopy 
be used if supravital stain is not added for particulate analysis. 
 
Examination 
The sample should first be viewed under low-power magnification to note the 
presence of casts (red cell casts and white cell casts). 
The sample should then be viewed under high-power magnification, and the 
number of different particles per high-power objective field should be counted.  
The number of specific particles, (specifically RBCs and WBCs) should be 
reported as an average observed in at least 10 fields selected from all areas of 
the coverslip and reported as number of specific particle (either RBC or WBC) 
per high-power field (HPF).  Automated quantification of RBCs and WBCs is 
acceptable. 
In terms of casts, the number and type of casts should be reported as an 
absolute number as seen in the whole sample and not as an average per HPF.  
If the absolute number of casts cannot be reported, then it is important to note 
whether casts are present or absent and, if casts are present, the type of casts.  
If casts are present, reporting a range is allowed (as long as that range does 
not include “0”). 
 
 


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
127/Protocol WA29748, Version 4 
Appendix 10  
Systemic Lupus International Collaborating Clinics/ 
American College of Rheumatology (SLICC/ACR) 
(Sample Case Report Form; Not to Be Used to Enter Subject Data) 
 
NOTE: Damage (nonreversible change, not related to active inflammation) 
occurring since onset of lupus, ascertained by clinical assessment and present 
for at least 6 months unless otherwise stated.  Repeat episodes must occur 
6 months apart to score 2. The same lesion cannot be scored twice. 
 
Score 
Item 
Not Present 
Present 
Ocular (either 
eye, by clinical 
assessment) 
Any cataract ever 
 0 
 1 
Retinal change or optic atrophy 
 0 
 1 
Neuropsychiatric Cognitive impairment (e.g., 
memory deficit, difficulty with 
calculation, poor concentration, 
difficulty in spoken or written 
language, impaired 
performance levels) or major 
psychosis 
 0 
 1 
Seizures requiring therapy for 
6 months 
 0 
 1 
Cerebrovascular accident 
(CVA) ever (score 2 > 1 CVA) 
 0 
 1          
 2 
Cranial or peripheral 
neuropathy (excluding optic) 
 0 
 1 
Transverse myelitis 
 0 
 1 
Renal 
Estimated or measured 
glomerular filtration 
rate < 50 mL/min 
 0 
 1 
Proteinuria ≥ 3.5 gm/24 hours 
 0 
 1 
OR 
End-stage renal disease 
(regardless of dialysis or 
transplantation) 
 0 
 3 
Pulmonary 
Pulmonary hypertension (right 
ventricular prominence, or loud 
P2) 
 0 
 1 
Pulmonary fibrosis (physical 
and radiograph) 
 0 
 1 
Shrinking lung (radiograph) 
 0 
 1 
Pleural fibrosis (radiograph) 
 0 
 1 
Pulmonary infarction 
(radiograph) 
 0 
 1 


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
128/Protocol WA29748, Version 4 
Appendix 10  
Systemic Lupus International Collaborating Clinics/ 
American College of Rheumatology (SLICC/ACR) (cont.) 
 
 
Score 
Item 
Not Present 
Present 
Cardiovascular 
Angina or coronary artery 
bypass 
 0 
 1 
Myocardial infarction (MI) ever 
(score 2 if > 1 MI) 
 0 
 1          
 2 
Cardiomyopathy (ventricular 
dysfunction) 
 0 
 1 
Valvular disease (diastolic 
murmur, systolic murmur > 3/6) 
 0 
 1 
Pericarditis for 6 months, or 
pericardiectomy 
 0 
 1 
Peripheral 
vascular 
Claudication for 6 months 
 0 
 1 
Minor tissue loss (pulp space) 
 0 
 1 
Significant tissue loss ever (e.g., 
loss of digit or limb) (score 2 if > 
1 site) 
 0 
 1          
 2 
Venous thrombosis with 
swelling, ulceration, or venous 
stasis 
 0 
 1 
Gastrointestinal Infarction or resection of bowel 
below duodenum spleen, liver, 
or gall bladder ever, for cause 
any (score 2 if > 1 site) 
 0 
 1          
 2 
Mesenteric insufficiency 
 0 
 1 
Chronic peritonitis 
 0 
 1 
Stricture or upper 
gastrointestinal tract surgery 
ever 
 0 
 1 
Musculoskeletal Muscle atrophy or weakness 
 0 
 1 
Deforming or erosive arthritis 
(including reducible deformities, 
excluding avascular necrosis) 
 0 
 1 
Osteoporosis with fracture or 
vertebral collapse (excluding 
avascular necrosis) 
 0 
 1 
Avascular necrosis (score 2 if > 
1) 
 0 
 1          
 2 
Osteomyelitis 
 0 
 1 
 


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
129/Protocol WA29748, Version 4 
Appendix 10  
Systemic Lupus International Collaborating Clinics/ 
American College of Rheumatology (SLICC/ACR) (cont.) 
 
Score 
Item 
Not Present 
Present 
Skin 
Scarring chronic alopecia 
 0 
 1 
Extensive scarring or panniculum 
other than scalp and pulp space 
 0 
 1 
Skin ulceration (excluding 
thrombosis) for > 6 months 
 0 
 1 
Premature gonadal failure 
 0 
 1 
Diabetes (regardless of 
treatment) 
 0 
 1 
Malignancy (exclude dysplasia) 
(score 2 if > 1 site) 
 0 
 1          
 2 
 
REFERENCE 
Gladman D, Ginzler E, Goldsmith C, et al. The development and initial validation of the 
systemic lupus international collaborating clinics/American College of Rhumatology 
Damage Index for systemic lupus erythematosus. Arthritis Rheum 1996;39:3639. 
 


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
130/Protocol WA29748, Version 4 
Appendix 11  
Subject’s Global Assessment 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in this study. 
(Sample Case Report Form; Not to Be Used to Enter Subject Data)
 
 


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
131/Protocol WA29748, Version 4 
Appendix 12  
Physician’s Global Assessment 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in this study. 
(Sample Case Report Form; Not to Be Used to Enter Subject Data)
 
 


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
132/Protocol WA29748, Version 4 
Appendix 13  
Systemic Lupus Erythematosus Disease Activity Index-2K 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in this study. 
 
 


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
133/Protocol WA29748, Version 4 
Appendix 14  
Glucocorticoid Toxicity Change Index 
COMPOSITE GLUCOCORTICOID TOXICITY CHANGE INDEX 
1. Body mass index (BMI) (compared to baseline) 
a) Improvement (in either direction) by more than 2 BMI units toward normal BMI 
(normal range  18.524.9 kg/m2) 
b) No significant change (BMI remains within  2 BMI units compared with 
baseline) or BMI remains within the normal range 
c) 
Moderate increase in BMI (increase by more than 2 but less than 5 BMI units to 
above the upper limit of normal BMI [24.9 kg/m2]) 
d) Major increase in BMI (increase by more than 5 BMI units to above normal 
BMI [24.9 kg/m2]) 
2. Glucose tolerance (compared to baseline) 
a) Improvement in glucose tolerance:  
 
HbA1c (glycosylated hemoglobin) declined  10% from baseline without 
medication increase 
or 
 
Decrease in diabetic medication without an increase in HbA1c of  10% or 
HbA1c  5.7% 
b) No significant change in glucose tolerance: 
 
HbA1c within 10% of baseline or HbA1c  5.7% and no change in 
medication  
or  
 
HbA1c increased to  10% of baseline due to a decrease in medication  
or  
 
Improvement in glucose tolerance  10% due to an increase in medication 
c) 
Worsening of glucose tolerance or medication status:  
 
HbA1c increased to  10% and HbA1c  5.7% without a change in 
medication  
or  
 
Increase in diabetic medication with  10% increase in HbA1c 
d) Worsening of glucose tolerance despite treatment: 
 
HbA1c  5.7% and increased to  10% of baseline and an increase in 
diabetic medication 
3. 
Blood pressure (BP) (compared to baseline) 
a) Improvement in BP:  


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
134/Protocol WA29748, Version 4 
Appendix 14  
Glucocorticoid Toxicity Change Index (cont.)  
 
Decrease in BP of  10% of baseline without medication increase 
or 
 
 
Decrease in medication without an increase in BP of  10% or systolic 
BP  120 and diastolic BP  85 
b) No significant change in BP: 
 
BP within 10% of baseline or systolic BP  120 and diastolic BP  85 and no 
change in medication  
or  
 
Deterioration in either systolic or diastolic BP  10% due to a decrease in 
medication 
or  
 
An improvement in either systolic or diastolic BP of  10% due to an 
increase in medication 
c) 
Worsening of hypertension:  
 
Increase in BP of  10% such that the systolic BP exceeds 120 mmHg or 
the diastolic BP exceeds 85 mmHg without a change in medication  
or  
 
Increase in anti-hypertensive medication without an improvement in 
BP  10% 
d) Worsening of hypertension despite treatment: 
 
Increase in BP of  10% such that the systolic BP exceeds 120 mmHg or 
the diastolic BP exceeds 85 mmHg and an increase in medication 
4. 
Hyperlipidemia (compared to baseline) 
a) Improvement in lipids:  
 
Decrease in low-density lipoprotein (LDL) concentration  10% of baseline 
without medication increase toward the target range  
or 
 
Decrease in medication without an increase in LDL of  10% or LDL 
remains within target range 
b) No significant change in LDL: 
 
LDL within 10% of baseline or within the target range for patient and no 
change in medication  
or  


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
135/Protocol WA29748, Version 4 
Appendix 14  
Glucocorticoid Toxicity Change Index (cont.) 
 
Increase in LDL  10% due to a decrease in medication 
or  
 
Improvement in LDL of  10% due to an increase in medication 
 
c) 
Worsening of LDL or medication status:  
 
Increase in LDL of  10% to above target range without increase in 
medication 
or  
 
Increase in medication without  10% change in LDL 
d) Worsening of LDL despite treatment: 
 
Increase in LDL of  10% and an increase in medication 
5. 
Steroid myopathy 
a) No steroid myopathy 
b) Mild steroid myopathy (weakness without functional limitation) 
c) 
Moderate steroid myopathy (weakness with functional limitation) 
See steroid myopathy definitions below. 
6. 
Skin  
a) No skin toxicity 
b) Mild  
c) 
Moderate  
See skin definitions below. 
7. 
Neuropsychiatric  
a) No neuropsychiatric symptoms 
b) Mild 
c) 
Moderate  
See neuropsychiatry definitions below. 
8. 
Infection (since last assessment)  
a) No significant infection 
b) Specific infections  Grade 3 (oral or vaginal candidiasis, uncomplicated zoster) 
c) 
Grade 3  
See infection notes below. 


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
136/Protocol WA29748, Version 4 
Appendix 14  
Glucocorticoid Toxicity Change Index (cont.)  
9. 
Bone mineral density (BMD) (compared to baseline) 
a) Improvement  increase in BMD by  3% 
b) No significant change (BMD between  3% and  3%) 
c) 
Deterioation   decrease by   3%  
Percentage (%) refers to total BMD in gms/cm2. 
If BMD not evaluated, then option “b” should be selected. 
GLUCOCORTICOID-INDUCED MYOPATHY DEFINITIONS 
 
Glucocorticoid-induced myopathy is defined as mild symmetrical weakness of the 
proximal muscles and/or neck flexors associated with steroid therapy and not due to 
any other apparent cause.  Muscle enzymes are typically within normal limits. 
 
Mild and moderate myopathy are defined by muscle strength of 4 on the standard 
Medical Research Council strength testing scale.  A 4 means weaker than normal 
but greater than anti-gravity strength.  
 
“Mild” is Grade 4 weakness that does not functionally limit the patient.  
 
”Moderate” is Grade 4 weakness that does impose functional limitations on the 
patient, interfering with normal daily activities. 
 
Note that inability to rise from a chair without assistance constitutes severe 
glucocorticoid-induced myopathy (Specific Domain) 
 
SEVERITY OF GLUCOCORTICOID TOXICITY IN THE SKIN 
Manifestations to be considered: 
 
Acneiform rash 
 
Easy bruising 
 
Hirsutism 
 
Atrophy/striae 
 
Erosions/tears/ulcerations 
 
Skin 6b. Mild 
Skin 6c. Moderate 
Severe (Specific Domain) 
Acneiform rash (Grades 12) 
Acneiform rash (Grade 3) 
Acneiform rash (Grade 4) 
Easy bruising (Grade 1) 
Easy bruising (Grade 2) 
 
Hirsutism (Grade 1) 
Hirsutism (Grade 2) 
 
Atrophy/striae (Grade 1) 
Atrophy/striae (Grade 2) 
Atrophy/striae (Grade 3) 
Erosions/tears/ulcerations 
(Grade 1) 
Erosions/tears/ulcerations 
(Grade 2) 
Erosions/tears/ulcerations 
(Grade 3) 
 


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
137/Protocol WA29748, Version 4 
Appendix 14  
Glucocorticoid Toxicity Change Index (cont.)  
Acneiform rash 
– 
Grade 1:  Papules and/or pustules covering  10% body surface area (BSA), which 
may or may not be associated with symptoms of pruritus or tenderness 
– 
Grade 2:  Papules and/or pustules covering 10%30% BSA, which may or may not 
be associated with symptoms of pruritus or tenderness; associated with 
psychosocial impact; limiting instrumental activities of daily living (ADL) 
– 
Grade 3:  Papules and/or pustules covering  30% BSA, which may or may not be 
associated with symptoms of pruritus or tenderness; limiting self care ADL; 
associated with local superinfection with oral antibiotics indicated 
– 
Grade 4:  Papules and/or pustules covering any % BSA, which may or may not be 
associated with symptoms of pruritus or tenderness and are associated with 
extensive superinfection with intravenous (IV) antibiotics indicated; life-threatening 
consequences 
 
Easy bruising 
– 
Grade 1:  Localized or in a dependent area 
– 
Grade 2:  Generalized 
 
Hirsutism:  In women, increase in length, thickness, or density of hair in a male 
distribution 
– 
Grade 1:  Hirsutism that the patient is able to camouflage by periodic shaving, 
bleaching, or removal of hair 
– 
Grade 2:  Hirsutism that requires daily shaving or consistent destructive means of 
hair removal to camouflage; associated with psychosocial impact 
Atrophy/striae 
– 
Grade 1:  Covering  10% BSA; associated with telangiectasias or changes in skin 
color 
– 
Grade 2:  Covering 10%30% BSA; associated with striae or adnexal structure loss 
– 
Grade 3:  Covering  30% BSA; associated with ulceration 
 
Erosions/tears/ulcerations 
– 
Grade 1:  Combined area of ulcers  1 cm; non-blanchable erythema of intact skin 
associated with warmth or erythema 
– 
Grade 2:  Combined area of ulcers 12 cm; partial thickness skin loss involving skin 
or subcutaneous fat 
– 
Grade 3:  Combined area of ulcers  2 cm; full-thickness skin loss involving damage 
to or necrosis of subcutaneous tissue that may extend down to fascia 
 


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
138/Protocol WA29748, Version 4 
Appendix 14  
Glucocorticoid Toxicity Change Index (cont.)  
SEVERITY OF NEUROPSYCHIATRIC GLUCOCORTICOID TOXICITY 
Manifestations to be considered:  
 
Insomnia 
 
Mania 
 
Cognitive impairment 
 
Depression 
 
7b. MildNo Functional 
Impairment 
7c. ModerateFunctional 
Impairment 
Severe (Specific Domain) 
Insomnia 
Insomnia 
 
Mania (Grade 1) 
Mania (Grade 2) 
Mania (Grade 3) 
Cognitive impairment 
(Grade 1) 
Cognitive impairment (Grade 
2) 
Cognitive impairment 
(Grade 3) 
Depression (Grade 1) 
Depression (Grade 2) 
Depression (Grade 3) 
  
DEFINITIONS OF SEVERITY WITHIN THE NEUROPSYCHIATRIC DOMAIN 
Insomnia:  Dissatisfaction with sleep quality and difficulty initiating or maintaining 
sleep or early morning awakening 
– 
Grade 1:  Not associated with functional impairment 
– 
Grade 2:  Associated with functional impairment; recorded as moderate toxicity 
 
Mania 
– 
Grade 1:  Slightly or occasionally elevated or irritable mood and 01 mild or 
occasional additional symptoms of inflated self-esteem, decreased need for sleep, 
increased talkativeness, feeling that thoughts are faster than usual, distractibility, 
increased activity or agitation, and impulsive actions 
– 
Grade 2:  Frequent or moderately elevated or irritable mood and 23 mild additional 
symptoms of inflated self-esteem, decreased need for sleep, increased 
talkativeness, feeling that thoughts are faster than usual, distractibility, increased 
activity or agitation, and impulsive actions 
– 
Grade 3:  Severe or constantly elevated or irritable mood and 4 or more additional 
symptoms of inflated self-esteem, decreased need for sleep, increased 
talkativeness, feeling that thoughts are faster than usual, distractibility, increased 
activity or agitation, and impulsive actions 
 


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
139/Protocol WA29748, Version 4 
Appendix 14  
Glucocorticoid Toxicity Change Index (cont.)  
Cognitive impairment 
– 
Grade 1:  Minor cognitive complaints, no objective findings on mental status 
examination (i.e., not apparent to the examiner) that were not present before 
initiating steroids 
– 
Grade 2:  New moderate cognitive deficits that were not present before initiating 
steroids 
– 
Grade 3:  Frank delirium  
 
Depression 
– 
Grade 1:  Feeling slightly down or depressed and 02 mild or occasional additional 
symptoms of loss of interest, low energy, guilt, poor concentration, insomnia, 
restlessness, or change in appetite 
– 
Grade 2:  Frequent or moderate feelings of being down or depressed and/or 
34 symptoms of loss of interest, low energy, guilt, poor concentration, insomnia, 
restlessness, or change in appetite 
– 
Grade 3: Severe constant feeling of being down or depressed and/or 5 or more 
symptoms of loss of interest, low energy, guilt, poor concentration, insomnia, 
restlessness, or change in appetite and/or suicidal thoughts 
 
INFECTION NOTES 
 
No significant infection:  No specific infections or serious infections Grade 3 or 
greater 
 
Specific isnfections:  Oral or vaginal candidiasis or zoster infections without 
postherpetic neuralgia or eye involvement 
Grade 3:  IV antibiotic, anti-fungal, or anti-viral intervention or hospitalization 
indicated or radiologic or operative intervention indicated or herpes zoster 
complicated by postherpetic neuralgia or eye involvement 
Grade 4 or 5:  Life-threatening consequences; urgent intervention indicated or death 
from infection (Specific Domain) 


Signature Page for Protocol - WA29748 - GAZYVA - v4 - Global/Core - Published
System identifier: RIM-CLIN-483560
Approval Task
Company Signatory
18-Apr-2023 14:24:31 GMT+0000

SAP_005.pdf: 
Official Title: 
A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study 
to Evaluate the Safety and Efficacy of Obinutuzumab in Patients With 
ISN/RPS 2003 Class III or IV Lupus Nephritis 
NCT Number: 
NCT02550652 
Document Date: 
SAP Version 2: 25-October-2023 


STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL 
CONFIDENTIAL 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WA29748 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, MULTI-CENTER 
STUDY TO EVALUATE THE SAFETY AND 
EFFICACY OF OBINUTUZUMAB IN PATIENTS 
WITH ISN/RPS 2003 CLASS III OR IV LUPUS 
NEPHRITIS 
PROTOCOL NUMBER: 
WA29748 
STUDY DRUG: 
Obinutuzumab (GA101; RO5072759) 
VERSION NUMBER: 
2 
IND NUMBER: 
125,054 
EUDRACT NUMBER: 
2015-002022-39 
SPONSOR: 
F. Hoffmann-La Roche Ltd.
PLAN PREPARED BY: 
, MSc 
DATE FINAL: 
See electronic date stamp below 
DATE AMENDED: 
See electronic date stamp below 
Version 1: 17 August 2018 


Obinutuzumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan 
WA29748 
2
 
 
STATISTICAL ANALYSIS PLAN AMENDMENT 
RATIONALE 
• 
The list of exploratory endpoints has been streamlined based on the data 
availability (Section 2.2.3). 
• 
Data cut and analysis timing have been updated to include all data up to the final 
database lock (Section 2.4 & 4.4). 
• 
Per protocol population has been removed since the handling method for major 
protocol deviations that has an impact on the analyses has been discussed in 
Section 4.6 (Section 4.1). 
• 
Subgroup analyses on the primary endpoint have been updated to include 
clinically relevant subgroups (Section 4.6.1.7). 
Additional minor changes have been made to improve clarity and consistency.   
 


Obinutuzumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan 
WA29748 
3
 
 
 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE ............................. 2 
1. 
BACKGROUND .............................................................................. 6 
2. 
STUDY DESIGN ............................................................................. 6 
2.1 
Protocol Synopsis ...................................................................... 6 
2.2 
Outcome Measures ................................................................... 6 
2.2.1 
Primary Efficacy Outcome Measures ......................................... 6 
2.2.2 
Secondary Efficacy Outcome Measures .................................... 7 
2.2.3 
Exploratory Efficacy Outcome Measures ................................... 7 
2.2.4 
Safety Outcome Measures ........................................................ 7 
2.3 
Determination of Sample Size ................................................... 8 
2.4 
Analysis Timing .......................................................................... 8 
3. 
STUDY CONDUCT ......................................................................... 8 
3.1 
Randomization ........................................................................... 8 
3.2 
Data Monitoring ......................................................................... 9 
4. 
STATISTICAL METHODS .............................................................. 9 
4.1 
Analysis Populations .................................................................. 9 
4.1.1 
Randomized Population ............................................................. 9 
4.1.2 
Pharmacokinetic-Evaluable Population ..................................... 9 
4.1.3 
Safety Population ..................................................................... 10 
4.1.4 
Modified Intent-To-Treat Population ........................................ 10 
4.2 
Analysis of Study Conduct ....................................................... 10 
4.3 
Analysis of Treatment Group Comparability ............................ 11 
4.3.1 
Demographics .......................................................................... 11 
4.3.2 
Disease Characteristics ........................................................... 11 
4.4 
Data-Cut for Analyses .............................................................. 12 
4.5 
Visit Windows .......................................................................... 12 
4.6 
Efficacy Analysis ...................................................................... 13 
4.6.1 
Primary Efficacy Endpoint ........................................................ 14 
4.6.1.1 
Complete Renal Response at Week 52 ................................... 14 


Obinutuzumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan 
WA29748 
4
 
 
4.6.1.2 
Serum Creatinine ..................................................................... 15 
4.6.1.3 
Inactive Urinary Sediment ........................................................ 15 
4.6.1.4 
Urinary Protein to Creatinine Ratio .......................................... 16 
4.6.1.5 
Treatment Failure .................................................................... 16 
4.6.1.6 
Sensitivity analyses ................................................................. 17 
4.6.1.7 
Subgroup analyses .................................................................. 17 
4.6.2 
Secondary Efficacy Endpoints ................................................. 18 
4.6.2.1 
Overall Renal Response .......................................................... 18 
4.6.2.2 
Biomarkers of Lupus Nephritis ................................................. 18 
4.6.2.3 
Complete Renal Response at Week 24 ................................... 18 
4.6.2.4 
Modified Complete Renal Response ....................................... 19 
4.6.3 
Exploratory Efficacy Endpoints ................................................ 20 
4.6.3.1 
Urine protein creatinine ratio (UPCR) ...................................... 20 
4.6.3.2 
Renal Flares ............................................................................ 20 
4.6.3.3 
Physician’s Global Assessment (PGA) .................................... 20 
4.6.3.4 
Subject’s Global Assessment (SGA) ....................................... 20 
4.6.3.5 
Components of CRR ................................................................ 20 
4.7 
Pharmacokinetic and Pharmacodynamic Analyses ................. 20 
4.8 
Safety Analyses ....................................................................... 21 
4.8.1 
Exposure to Study Medication ................................................. 21 
4.8.2 
Adverse Events ........................................................................ 22 
4.8.3 
Deaths ..................................................................................... 23 
4.8.4 
Laboratory Data ....................................................................... 23 
4.8.4.1 
Safety Laboratory Parameters ................................................. 23 
4.8.4.2 
Immunoglobulins ...................................................................... 23 
4.8.5 
Vital Signs ................................................................................ 24 
4.9 
Data Handling Methods ........................................................... 24 
4.9.1 
Presentation of Data ................................................................ 24 
4.9.2 
Definitions ................................................................................ 24 
4.9.3 
Multiple Values ........................................................................ 25 
4.10 
Missing Data ............................................................................ 25 
4.11 
Interim Analyses ...................................................................... 25 


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4.11.1 
Pharmacodynamic Futility Interim Analysis ............................. 25 
4.11.2 
Renal Response Interim Analysis ............................................ 26 
5.
REFERENCES.............................................................................. 26
LIST OF TABLES 
Table 1 
Time Windows of Study Days to Assign Study Visit for 
Urinalysis .................................................................................... 12 
LIST OF APPENDICES 
Appendix 1 
Protocol Synopsis ....................................................................... 27 
Appendix 2 
Schedule of Assessments ........................................................... 37 
Appendix 3 
Imputation Rules for Partial or Missing Dates ............................. 41 


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1.
BACKGROUND
Study WA29748 (NOBILITY) is a Phase II, parallel-group, double-blind, randomized, 
placebo-controlled study that aims to evaluate the efficacy and safety of obinutuzumab 
plus mycophenolate mofetil (MMF) vs. placebo plus MMF in patients with Class III 
or IV lupus nephritis (LN).  The study consists of three periods:  a screening period, a 
104-week, double-blinded, treatment period followed by an additional B-cell follow-up
(BCFU) period extending until the study completion criteria specified in the protocol are
met.
To date, two study Clinical Study Reports (CSRs) have been reported for NOBILITY: 
•
Week 52 CSR (Report No. 1094412)
•
Week 104 CSR (Report No. 1102050)
This Statistical Analysis Plan (SAP) describes the statistical methodology and data 
handling rules to be used for the final CSR reporting, where all available study data in 
the final locked database will be reported. 
The final CSR reporting event and study database lock will occur after end of the study 
(when all patients have completed or discontinued from the study). 
2.
STUDY DESIGN
2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is provided in Appendix 1.  Additional details including the study 
flowchart and schedule of assessments (Appendix 2) can be found in the study protocol 
(version (v) 4.0; 18 April 2023). 
2.2 
OUTCOME MEASURES 
2.2.1 
Primary Efficacy Outcome Measures 
The proportion of patients who achieve complete renal response (CRR) will be evaluated 
at 52 weeks.  CRR is defined as meeting all of the following: 
•
Normalization of serum creatinine as evidenced by the following:
–
Serum creatinine ≤ the upper limit of normal (ULN) range of central
laboratory values if baseline (Day 1) serum creatinine is above the ULN
–
Serum creatinine ≤ 15% above baseline and ≤ the ULN range of central
laboratory values if baseline (Day 1) serum creatinine is ≤  the ULN range of
central laboratory values
•
Inactive urinary sediment as evidenced by:
–
<10 RBCs/high-power field (HPF);and
–
the absence of red cell casts


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•
Urinary protein to creatinine ratio <0.5
2.2.2 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures are as follows: 
•
Proportion of patients who achieve an overall response at Week 52 (CRR + partial
renal response [PRR])
•
Proportion of patients that achieve a modified CRR (mCRR1) at Week 52 as defined
in Section 4.6.2
•
Proportion of patients that achieve a second modified CRR (mCRR2) at Week 52 as
defined in Section 4.6.2
•
Time to CRR, over the course of 52 weeks.
•
Time to overall response (CRR + PRR) over the course of 52 weeks
•
Change in anti-double stranded deoxyribonucleic acid (dsDNA) titre, C3 and
C4 from baseline at Week 52
•
Proportion of patients that achieve a PRR at Week 52
•
Proportion of patients who achieve a CRR at Week 24
•
Proportion of patients that achieve a third modified CRR (mCRR3) at Week 52 as
defined in Section 4.6.2
2.2.3 
Exploratory Efficacy Outcome Measures 
The protocol presents the complete list of exploratory outcomes.  The list below includes 
exploratory outcomes that are planned to be presented in the final CSR: 
•
Change in urine protein creatinine ratio (UPCR) from baseline to Week 52
•
Proportion of patients experiencing a renal flare over 52 weeks and 104 weeks
•
Physician’s Global Assessment of disease activity
•
Subject’s Global Assessment of disease activity
•
Proportion of patients who achieve each of the components of the primary endpoint
2.2.4 
Safety Outcome Measures 
The safety outcome measures are as follows: 
•
Incidence, type, and severity of adverse events (AEs) and adverse events of special
interest (AESI), including infusion reactions, infections, thrombocytopenia, and
neutropenia
•
Proportion of patients with abnormal vital signs
•
Proportion of patients with abnormal laboratory values
Safety will be monitored through regular physical examinations, vital signs, hematologic 
and chemistry laboratory tests, urinalyses, and incidence and severity of AEs. 


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In addition, the following will be examined: 
• 
Circulating B cells, T cells, neutrophils, and other cell populations 
• 
Plasma immunoglobulins (total immunoglobulin [Ig], immunoglobulin G [IgG], 
immunoglobulin M [IgM], and immunoglobulin A [IgA]) 
• 
Pregnancy 
• 
Antibody titers for mumps, rubella, varicella, tetanus, influenza, and Streptococcus 
pneumoniae 
  
2.3 
DETERMINATION OF SAMPLE SIZE 
The primary efficacy endpoint of this study is the proportion of patients that achieve CRR 
at Week 52.  It is estimated that approximately 30% of patients with proliferative LN who 
are receiving MMF (or equivalent) will achieve a CRR at Week 52 and that the addition 
of obinutuzumab to MMF (or equivalent) will induce an overall CRR rate of 50% at 
Week 52.  On the basis of these assumptions, a total of 120 patients randomized to 
obinutuzumab- and placebo-treated groups in a 1:1 ratio (60 patients in each of the 
obinutuzumab- and placebo-treated groups) will yield approximately 83% power at the 
two-sided α = 0.2 significance level using a Cochrane-Mantel-Haenzel (CMH) test, 
assuming the same CRR proportions across the strata. 
No adjustment will be made for dropouts.  Patients withdrawing early from the study or 
meeting the criteria for treatment failure (including rescue therapy) will not receive any 
additional study drug, but will be monitored for safety for at least 52 weeks after their last 
dose of study drug, unless they have withdrawn consent.  Patients with missing or 
incomplete data where a status cannot be determined after applying relevant imputation 
rules (as defined in Section 4.6.1 ), will be set to non-responders. 
2.4 
ANALYSIS TIMING 
The study database will be locked and the analysis will be after the end of the study (all 
patients complete or discontinue from the study).  All data will be thoroughly cleaned and 
will form part of the final CSR.  
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION 
After completing the informed consent form, eligible patients will be enrolled into the 
study and randomized using a central Interactive Voice/Web Response System (IxRS).  
Patients will be randomly allocated to receive obinutuzumab or placebo in a 1:1 ratio.  
Randomization will be performed according to a stratified permuted block 
designstratified by race (Afro-Caribbean/African American vs. others) and 
geographical region (US vs. non-US). 


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3.2 
DATA MONITORING 
Safety data and data pertaining to trial conduct will be reviewed by an independent Data 
Monitoring Committee (iDMC). 
In accordance with the study protocol, the iDMC will meet on a regular basis for formal 
safety data reviews.  The first meeting will occur approximately three months after the 
first study drug infusion in the first enrolled patient.  The iDMC will then meet formally, 
approximately every three to six months, to review current safety data. 
In addition to the regularly scheduled safety reviews, an unscheduled review of the data 
may be performed at the request of the iDMC or study team, on the basis of a perceived 
concern for patient safety. 
The iDMC will review the results of a planned futility analysis based on the expected 
pharmacodynamic (PD) effects of obinutuzumab (i.e., CD19 +  B-cell depletion as 
measured by a high sensitivity flow cytometry assay), which is scheduled to be 
undertaken after 30 subjects have been assigned obinutuzumab and have had their 
Day 28 CD19 +  B-cell count performed. 
In addition, an interim efficacy analysis to evaluate CRR will be conducted when the last 
patient has attended the Week 24 visit.  This interim analysis is for Phase III planning 
purposes only and will have no impact on the progression of this study.  The interim 
analysis will be performed by the independent Data Coordinating Center (iDCC) and 
interpreted by members of the iDMC. 
The Sponsor’s study team will have no direct contact with the iDMC during the trial 
conduct except for the scheduled open sessions of the iDMC. 
Further details can be found in the iDMC charter. 
4. 
STATISTICAL METHODS 
All analyses, summaries, and listings will be performed using SAS software (v 9.4 or 
later). 
4.1 
ANALYSIS POPULATIONS 
4.1.1 
Randomized Population 
The randomized population will include all patients randomized into the study. 
4.1.2 
Pharmacokinetic-Evaluable Population 
The pharmacokinetic-evaluable population (PK population) will include all patients 
randomized to  and received any dose of  obinutuzumab given as study medication, 


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have at least one post-dose pharmacokinetic (PK) sample that is evaluable, and have no 
major protocol deviations that would impact the PK results. 
4.1.3 
Safety Population 
The safety population will include all randomized patients who received any part of an 
infusion of study drug.  Patients who received the incorrect therapy throughout the study 
from that assigned at randomization will be reported under the therapy actually received.  
Patients who were not randomized but who received study drug will be included in the 
safety population and reported under the therapy actually received. 
Patients receiving at least one dose of both active study treatments during the study 
(e.g., in error, or in the unlikely event of crossing over) will be reported under the original 
treatment received.  Patients who received obinutuzumab as rescue therapy will be 
reported under the original treatment received before the rescue. 
All safety analyses will be performed using the safety population. 
4.1.4 
Modified Intent-To-Treat Population 
The modified intent-to-treat (mITT) population will include all randomized patients who 
received any part of an infusion of study drug.  Patients who received an incorrect 
therapy will be reported under the treatment arm to which they were randomized. 
Patients who were not randomized but still received study treatment will be excluded 
from the mITT population. 
All efficacy analyses will be performed using the mITT population. 
4.2 
ANALYSIS OF STUDY CONDUCT 
Analyses of study conduct will be carried out on the safety population or all randomized 
patients, as appropriate. 
A summary of enrollment by investigator site will be produced. 
The number of patients who completed or discontinued from the study including the 
reason for discontinuation, will be summarized by treatment group.  A listing of early 
discontinuations will be produced. 
Major protocol deviations will be listed.  Any study conduct that is impacted by COVID-
19 or Ukraine-Russia conflict will be summarized in the final CSR.  
Patient duration in the entire study will be summarized.  Duration will be calculated as: 
date of last visit − date of the first dose + 1 
 


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Previous and concomitant medications will be summarized descriptively by mapped term 
and treatment group.  A summary of rescue medications will also be produced. 
A summary of the number of patients who experience treatment failure along with the 
reason(s) for treatment failure will be produced.  The number of patients receiving 
rescue will also be listed and summarised. 
A summary of exposure to study treatment will be produced using the dose recorded on 
the electronic case report form (eCRF).  The number of obinutuzumab/placebo infusions 
and dose received at each infusion and overall will be summarised by treatment group.  
The total cumulative dose of obinutuzumab/placebo over the 52-week treatment period 
will be summarised.  Note that these summaries highlight adherence to the blinded study 
treatment and not exposure to the active treatments (which will be described separately).  
Proportion of patients received rescue medication will be summarized by treatment 
group. 
4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
Demographic and baseline disease characteristics will be summarized as described in 
the following sections. 
4.3.1 
Demographics 
Demographics will be summarized, including: 
• 
Sex 
• 
Age (years) 
• 
Height (cm) 
• 
Weight (kg) 
• 
Body mass index (kg/m2) 
• 
Race 
• 
Ethnicity 
• 
Region 
• 
Smoking status 
• 
Female reproductive status 
 
4.3.2 
Disease Characteristics 
Baseline values will be summarized, including: 
• 
Duration of LN (months) 
• 
Duration of systemic lupus erythematous (SLE) (months) 
• 
Estimated glomerular filtration rate (eGFR) calculated using the CKD-epi formula 
• 
Urine red blood cells (RBCs), white blood cells (WBCs) and RBC casts 


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• 
Serum creatinine 
• 
Urinary Protein to Creatinine Ratio 
– 
24-hour urine sample and from random sample 
• 
LN biopsy class: 
– 
Proportion of patients with Class III 
– 
Proportion of patients with Class IV 
– 
Proportion of patients with concomitant Class V 
– 
NIH activity and chronicity scores 
 
Medical history data, including surgery and procedures, MMF/mycophenolic acid (MPA) 
(including dose) and cyclophosphamide use, and baseline conditions will be summarized 
descriptively by treatment group using the safety population.  A glossary showing the 
mapping of investigator verbatim terms to diseases will be produced for the medical 
history data. 
4.4 
DATA-CUT FOR ANALYSES 
All data in the final database will be reported, unless otherwise specified in the relevant 
sections of the SAP. 
4.5 
VISIT WINDOWS 
In general, data for assessments that are collected by scheduled visits will be mapped to 
visits that appear in the schedule of assessments (Appendix 2) per the protocol using 
the actual study day of assessment.  Data mapped to scheduled visits will include all 
data collected up to the final database lock, and may include withdrawal visits and 
unscheduled visits.  Data will never be mapped to visits for which the assessment was 
not scheduled in the protocol (i.e., results for an assessment conducted at an 
unscheduled visit will be mapped to the appropriate visit at which the assessment was 
scheduled).  Visit windows will be continuous from the midpoint between two 
consecutive study visits, and will be dependent on the schedule of assessments for each 
variable independently.  An example of the urinalysis visit window is given in Table 1.  
Visit windows for each variable will be constructed in the same manner. 
Table 1 
Time Windows of Study Days to Assign Study Visit for Urinalysis  
Study Visit 
Scheduled Study Day  
Actual Study Day Time Window 
Baseline 
1 
 ≤ 1  
Week 4 
28 
2 ≤ day < 57 
Week 12 
84 
57 ≤ day < 127 
Week 24 
168 
127 ≤ day < 211 
Week 36 
252 
211 ≤ day < 309 


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Week 52 
364 
309 ≤ day < 425 
Week 76 
532 
425 ≤ day < 631 
Week 104 
728 
631 ≤ day < 789 
BCFU 
 ≥ 789 
 
BCFU =B-cell follow up  
Derived variables that are collected on an ongoing basis will be presented using 
appropriate time intervals.  For primary analysis at Week 52, the upper limit of the visit 
window will be Day 364 + 60 days.  For Week 104, the upper limit of the visit window will 
be 728 + 60 days. For BFU, the visit is scheduled every 6 months.  
Data displays that are presented by visit will only include visits at which the assessment 
was scheduled to be collected.  The methods for handling multiple values within a visit 
window are described in Section 4.9.3.  
4.6 
EFFICACY ANALYSIS 
The primary and secondary efficacy analyses will include all randomized patients who 
received any study medication, with patients grouped according to the treatment 
assigned at randomization. 
The primary and secondary endpoints will be tested at an overall 20% significance level 
using two-sided hypothesis tests. 
The primary and secondary efficacy endpoints are listed below: 
1. 
Proportion of patients that achieve a CRR at Week 52 
2. 
Proportion of patients who achieve an overall response at 
Week 52 (CRR+PRR) 
3. 
Proportion of patients that achieve a modified CRR (mCRR1) at 
Week 52 employing the primary−efficacy measure definition and removing the 
urinary sediment analysis criteria  
4. 
Proportion of patients that achieve a second modified CRR (mCRR2) at 
Week 52 
5. 
Change in anti-dsDNA titers 
6. 
Change in C3 levels 
7. 
Change in C4 levels 
8. 
Time to overall response (CRR+PRR) over the course of 52 weeks 
9. 
Proportion of patients that achieve a PRR at Week 52 
10. Time to CRR, over the course of 52 weeks 
11. Proportion of patients that achieve a third modified CRR (mCRR3) at Week 52 
12. Proportion of patients who achieve a CRR at Week 24 


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If at any step in the testing procedure, the p-value associated with a test is not < 0.20, the 
remaining endpoints below the sequence will not be considered statistically significant. 
The final CSR will include all the primary and secondary endpoints in order of testing for 
completeness. 
4.6.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of patients achieving CRR at Week 52. 
The following two-sided hypothesis will be tested at the 20% significance level 
(double-sided): 
H0: ρMMF + OBZ − ρMMF+PBO = 0  
H1: ρMMF + OBZ − ρMMF+PBO≠0  
where ρdenotes the proportion of patients achieving complete renal response; 
PBO = Placebo; and OBZ = Obinutuzumab.  The clinical meaningful difference is 15%. 
The primary method for comparing the proportion of patients achieving sustained 
complete remission will be the CMH test.  The analysis will be stratified by the 
stratification factors applied at randomization.  The proportion of patients achieving 
sustained complete remission in each treatment group will be presented along with the 
adjusted difference, 95% confidence interval for the difference, and p-value. 
4.6.1.1 
Complete Renal Response at Week 52 
A patient will be considered a responder for complete renal response if all of the 
following conditions are met at the Week 52 visit: 
• 
Normalization of serum creatinine as evidenced by the following: 
– 
Serum creatinine ≤ the upper limit of normal (ULN) range of central 
laboratory values if baseline (Day 1) serum creatinine is above the ULN 
– 
Serum creatinine ≤ 15% above baseline and ≤ the ULN range of central 
laboratory values if baseline (Day 1) serum creatinine is ≤ the ULN range of 
central laboratory values 
• 
Inactive urinary sediment as evidenced by: 
– 
 < 10 RBCs/high-power field (HPF) and  
– 
the absence of red cell casts 
• 
Urinary protein to creatinine ratio < 0.5 
 
Any patient who switches to rescue medication will be considered a non-responder. 


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Patients who discontinue early from the study or meet the criteria for treatment failure 
will be evaluated using data up to the point of withdrawal or treatment failure only, 
whichever occurs first.  They will be deemed non-responders. 
Complete renal response is a composite endpoint derived using several sources of 
information.  Methods for data handling and dealing with missing data for the 
components of the primary endpoint are provided below.  Any missing or ambiguous 
data will be queried and all efforts will be made to resolve data issues prior to database 
lock. 
If any of the conditions for complete renal response are still missing after the below 
imputation rules are applied, then the patient will be set to non-responder. 
4.6.1.2 
Serum Creatinine 
Only creatinine data obtained from the central laboratory will be used for efficacy 
analysis. 
Missing Data:  If Day 1 serum creatinine data is missing, then the screening value will be 
used.  Missing post-baseline serum creatinine will be imputed using the value from the 
previous visit.  If the previous visit is still missing, no imputation will be made, unless 
otherwise specified. 
4.6.1.3 
Inactive Urinary Sediment 
Urine sediment data from the local laboratory will be prioritized in the efficacy analysis 
given the time-sensitive nature of this analysis and the delay between local specimen 
collection and central laboratory analysis.  The central laboratory data will be used when 
local laboratory data are missing using the strategy highlighted below. 
Missing Data 
Missing urine sediment data at Day 1 will be imputed in the following order: 
• 
Urine sediment data at Day 1 (central lab) 
• 
Urine sediment data from screening (local lab) 
• 
Urine sediment data from screening (central lab) 
 
Missing post-baseline RBC counts will be imputed in the following order: 
• 
RBC counts at the same visit (central lab) 
• 
RBC counts from the previous visit (local lab) 
• 
RBC counts from the previous visit (central lab) 
 
If the value is still missing, then no imputation will be made. 


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Missing post-baseline RBC casts will be imputed in the following order: 
• 
RBC casts at the same visit (central lab) 
• 
RBC casts from the previous visit (local lab) 
• 
RBC casts from the previous visit (central lab) 
 
If the central laboratory value from previous visit is still missing, then “casts absent” will 
be imputed.  
4.6.1.4 
Urinary Protein to Creatinine Ratio 
Only Urinary Protein to Creatinine Ratio (UPCR) (mg/mg) data obtained from the central 
laboratory will be used for efficacy analysis with the exception of the first 4 patients 
enrolled into the study.  Through a laboratory error, baseline UPCR was not calculated 
for these subjects.  In this case, local values for UPCR will be used, if available. 
Missing Data 
Missing 24-hour UPCR at Day 1 will be imputed in the following order: 
• 
24-hour UPCR from the screening visit (central laboratory) 
• 
Spot UPCR from the Day 1 visit (central laboratory) 
• 
Spot UPCR from the screening visit (central laboratory) 
 
Missing post-baseline 24-hour UPCR will be imputed in the following order: 
• 
Spot UPCR from the same visit (central laboratory) 
• 
24-hour UPCR from the previous visit (central laboratory) 
• 
Spot UPCR from the previous visit (central laboratory) 
 
4.6.1.5 
Treatment Failure 
Treatment failure occurs in the following scenarios: 
• 
Patients who do not exhibit a response to the initial 2-week course of increased 
corticosteroids for treatment of renal flares and who initiate a new 
immunosuppressive therapy. 
• 
If patients require a new immunosuppressive drug (other than corticosteroids) for 
treatment of their extrarenal SLE flare, those patients will be counted as treatment 
failures and will not receive further study drug but will continue their protocol 
mandated study visits. 
• 
Any patient who switches to rescue medication will be considered a non-responder. 
 
The clinical definitions of treatment failure above are aligned with “non-responder” 
classification for the primary analysis.  Patients experiencing treatment failure will be 
categorized as non-responders in the primary analysis but will continue to be followed in 
the study per the schedule of assessments.  Patients who achieve complete renal 


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response without experiencing an event constituting treatment failure beforehand will not 
be categorized as non-responders, regardless of whether they subsequently meet the 
criteria. 
Patients who experience treatment failure are eligible to receive rescue therapy during 
the treatment period as per the investigator’s best medical judgment.  Patients who 
receive rescue therapy will continue to be followed in the study per the schedule of 
assessments. 
Patients who receive rescue therapy for LN will be evaluated up to the point of rescue 
only for all main efficacy analyses.  Methods for data handling and/or imputing 
post-rescue data are described throughout Section 4.6.1.  Additional exploratory 
summaries on key efficacy assessments will be produced that will include rescue data.  
Safety analyses will include data up to the point of rescue.  Cumulative safety analyses 
will be presented for safety summaries separately.  
Listings will be provided for all data, including post rescue safety data. 
4.6.1.6 
Sensitivity analyses 
A sensitivity analysis of the primary endpoint data will be conducted excluding the 
patients whose treatment arm information were potentially unblinded at 24 sites during 
the course of the study. This issue has been documented in a corrective action and 
preventive action (CAPA) dated 21 December 2017. While there were reasons to believe 
that unblinding did not occur, this sensitivity analysis will assess the robustness of 
efficacy results if affected patients are excluded from the dataset.  
4.6.1.7 
Subgroup analyses 
Summary tables for CRR will be described in the following sub-populations: 
• 
Race 
• 
Region 
• 
Baseline UPCR ≥ 3 versus < 3 
• 
Serum creatinine ≤ ULN versus > ULN 
• 
Baseline biopsy histology: Class III vs. Class IV 
• 
Baseline biopsy histology: concomitant Class V vs. no Class V 
• 
anti-dsDNA: ≥ 75 vs. < 75 
• 
C3: ≥ 90mg/dL vs. < 90mg/dL 
• 
C4: ≥ 10mg/dL vs. < 10mg/dL 
 


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4.6.2 
Secondary Efficacy Endpoints 
4.6.2.1 
Overall Renal Response 
The proportion of patients who achieve an overall response at Week 52 (CRR + PRR) will 
be analyzed using a CMH test, with race and region as strata. 
The proportion of patients achieving PRR at Week 52 as defined by achievement of all 
of the following: 
• 
Serum creatinine ≤ 15% above baseline value 
• 
No urinary red cell casts and either RBCs/HPF ≤ 50% above baseline 
or < 10 RBCs/HPF 
• 
50% improvement in the urine protein to creatinine ratio, with one of the following 
conditions met: 
– 
If the baseline urine protein to creatinine ratio is ≤ 3.0, then a urine protein 
to creatinine ratio of  < 1.0 
– 
If the baseline protein to creatinine ratio is > 3.0, then a urine protein to 
creatinine ratio of < 3.0 
 
Missing Data  
Missing data for each component of the endpoint will be imputed using the relevant 
approach discussed in Section 4.6.1. 
Time to First Overall Response 
Time to first overall response (CRR + PRR) over the course of 52 weeks will be 
presented using Kaplan-Meier methodology and compared between treatment groups 
using a stratified log-rank test with race and region as strata.  Time to CRR during this 
period will be analyzed similarly. 
4.6.2.2 
Biomarkers of Lupus Nephritis 
The change from baseline of biomarkers of LN disease activity will be summarized by 
treatment arm using tables and graphs.  These biomarkers may include changes in 
anti-dsDNA antibody levels and in C3, C4, levels. 
Missing Data 
Missing data will be imputed using last observation carried forward (LOCF). 
4.6.2.3 
Complete Renal Response at Week 24 
The proportions of patients who achieve a CRR will be analyzed using similar 
methodology as the primary analysis. 


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Missing Data for Serum Creatinine at Week 24 
Missing serum creatinine at Week 24 will be imputed using the value from Week 12 first, 
and if still missing, then take the value from Week 26.  If still missing then, no imputation 
will be made. 
Missing Data for Inactive Urinary Sediment at Week 24 
Missing data will be imputed using the same method specified in Section 4.6.1.3 .  
Missing Data for UPCR (24-Hour) at Week 24 
Missing data will be imputed using the same method specified in Section 4.6.1.4 .  
 
4.6.2.4 
Modified Complete Renal Response 
In addition, the modified definitions, mCRR1, mCRR2, and mCRR3 of CRR will be 
analyzed to assess the sensitivity of CRR to its definition. 
• 
Proportion of patients who achieve a modified CRR (mCRR1) at 
Week 52 employing the primary−efficacy measure definition and removing the 
urinary sediment analysis criteria. 
mCRR1 is defined by attainment of normalization of serum creatinine as 
evidenced by the following: 
– 
Serum creatinine ≤ the ULN range of central laboratory values if 
baseline (Day 1) serum creatinine is above the ULN 
– 
Serum creatinine ≤ 15% above baseline and ≤ the ULN range of central 
laboratory values if baseline (Day 1) serum creatinine ≤ the ULN range 
of central laboratory values 
– 
Urinary protein to creatinine ratio < 0.5 
• 
Proportion of patients that achieve a second modified CRR (mCRR2) at Week 52 as 
defined by attainment of the following: 
– 
Serum creatinine ≤ 15% above baseline if baseline (Day 1) serum 
creatinine is above the normal range of the central laboratory values 
– 
Serum creatinine ≤ the ULN range of central laboratory values if 
baseline (Day 1) serum creatinine is ≤ the ULN range of central 
laboratory values 
– 
Inactive urinary sediment (as evidenced by < 10 RBCs/HPF and the 
absence of red cell casts) 
– 
Urinary protein to creatinine ratio < 0.5 
• 
Proportion of patients that achieve a third modified CRR (mCRR3) at Week 52 as 
defined by attainment of the following: 
– 
Serum creatinine  ≤ the ULN range of central laboratory values 
– 
Urinary protein to creatinine ratio < 0.5 
 


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Missing Data 
Missing data for each component of the endpoint will be imputed using the relevant 
approach discussed in Section 4.6.1.1. 
4.6.3 
Exploratory Efficacy Endpoints 
The following endpoints will provide additional information to assess treatment efficacy. 
4.6.3.1 
Urine protein creatinine ratio (UPCR) 
Absolute value at each visit and change from baseline in UPCR over 104 weeks will be 
presented in each arm using summary statistics to evaluate the trends over time.  
4.6.3.2 
Renal Flares 
Proportion of patients experiencing a renal flare over 52 weeks and 104 weeks.  This will 
be summarized using frequency counts and percentages.  
4.6.3.3 
Physician’s Global Assessment (PGA) 
Absolute value at each visit and change from baseline in PGA over 52 weeks will be 
presented in each arm using summary statistics to show the trends over time. 
4.6.3.4 
Subject’s Global Assessment (SGA) 
Absolute value at each visit and change from baseline in SGA over 52 weeks will be 
presented in each arm using summary statistics to show the trends over time.  
4.6.3.5 
Components of CRR 
Proportion of patients achieving each of the components of the primary endpoint will be 
present by each visit over 104 weeks.  This will be summarized using frequency counts 
and percentages. 
4.7 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Pharmacokinetic (PK) parameters have been determined for all patients with serum 
concentration data in the previous CSRs.  A list of PK and ADA values will be presented 
in the final CSR.  
The primary pharmacodynamic (PD) marker will be CD19 +  B-cell counts.  Exploratory 
PD markers from blood samples may be summarized graphically and descriptively over 
time by treatment arm. 
In addition, the percent change from baseline for each marker will be computed at each 
sampling timepoint using the Day 1 pre-dose value as the baseline point. 
Exploratory analyses may be performed to assess the possible relationship between 
obinutuzumab dosing, PD markers, PK measures, and clinical response. 


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4.8 
SAFETY ANALYSES 
The safety analysis will be performed on the safety population as defined in 
Section 4.1.3.  Analyses of safety data will include patients up to the point of receipt of 
non-corticosteroid rescue only.  All safety data including the post-rescue data will be 
summarized separately for key safety outputs.  
All safety outputs will include cumulative data to the final database lock.  In addition, 
data collected after Week 104 will be summarized separately for key safety outputs to 
understand the Safety events occurring during the B-cell follow-up period only.  Safety 
data will be summarized by treatment groups.  
4.8.1 
Exposure to Study Medication 
The number and percentage of patients who received obinutuzumab will be summarized 
by treatment course, along with summary statistics for the dose of obinutuzumab 
received at each infusion and overall, and the duration of exposure.  Duration of 
exposure will be calculated as: 
exposure date (as defined in Section 4.2) − date of first infusion + 1. 
Obinutuzumab exposure data will be determined using the dosing information as 
recorded on the obinutuzumab administration log on the eCRF and the actual treatment 
received as per IxRS.  Exposure to obinutuzumab will not include obinutuzumab given 
as rescue, which will be analyzed separately. 
Exposure to MMF will be summarized using the average daily dose, total cumulative 
dose, and treatment duration.  Treatment duration will be calculated as: 
date of last dose  −  date of first dose  +  1 
The total cumulative dose will be calculated by summing the total daily dose over the 
treatment duration.  Average daily dose will be calculated as: 
total cumulative dose  ÷  treatment duration 
MMF exposure data will be determined using the dosing information as recorded on the 
MMF administration log on the eCRF and the actual treatment received as per IxRS.  
Exposure to MMF will not include MMF given as rescue, which will be analyzed 
separately. 
Exposure to corticosteroids will be summarized using the average daily dose, total 
cumulative dose, and treatment duration.  Treatment duration will be calculated as: 
date of last dose  −  date of first dose  +  1 
The total cumulative dose will be calculated by summing the total daily dose over the 
treatment duration.  Average daily dose will be calculated as: 
total cumulative dose  ÷  treatment duration 


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Corticosteroid exposure data will be determined using the dosing information as 
recorded on the concomitant medication administration log on the eCRF and the actual 
treatment received as per IxRS.  Exposure to corticosteroid will not include corticosteroid 
given as rescue, which will be analyzed separately. 
4.8.2 
Adverse Events 
Adverse events will be mapped and reported using the Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus using the most current version at the time of analysis 
(Version 20.1 or later).  Glossaries showing the mapping of investigator verbatim terms 
to coded events will be produced. 
Treatment-emergent adverse events (TEAEs) will be summarized.  All AEs referenced in 
the section below will be TEAEs.  TEAEs are defined as those AEs with observed or 
imputed onset date on or after the start date of trial treatment.  Only where the most 
extreme intensity is greater than the initial intensity (or if most extreme intensity is not 
missing and initial intensity is missing) will events with an onset date prior to the start of 
trial treatment be considered treatment-emergent.  An AE with a completely missing start 
date will be assumed to be treatment-emergent unless the AE has a complete 
non-imputed end date that is prior to study Day 1. 
Listings will show all AEs reported, including AEs occurring after rescue therapy, and 
any AEs that may have occurred during the oral corticosteroid dose adjustments in the 
screening period. 
AEs will be summarized by system organ class (SOC) and preferred term (PT), and will 
be presented in order of descending frequency summed across the treatment arms 
within each SOC and PT. 
The following will be summarized, and/or listings produced where required: 
• 
All AEs 
• 
Serious Adverse Events (SAEs) 
• 
AEs by relationship to obinutuzumab/placebo 
• 
AEs by relationship to MMF/MPA 
• 
Corticosteroid-related adverse events 
• 
AEs leading to study drug dose modification or interruption 
• 
AEs by common terminology criteria grade 
• 
Infections 
• 
Serious Infections 
• 
Infusion related reactions (IRRs) 
• 
Serious IRRs 


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• 
AEs leading to withdrawal 
• 
AEs leading to death 
 
AEs to monitor will be listed, including: 
• 
Opportunistic infections (Roche Standard AE Grouped Term [AEGT] Basket) 
 
AE rates per 100 patient-years exposure will be produced for key safety events.  Rates 
will be based on all occurrences of AE.  AE rate per 100 patient-years is defined as: 
(number of events ÷ total exposure) × 100 
The 95% confidence intervals (CIs) will be calculated based on exact poisson 
distribution. 
Positive pregnancy results will be listed, as identified using the serum test results. 
4.8.3 
Deaths 
Details of any deaths will be presented in the form of an individual patient listing. 
4.8.4 
Laboratory Data 
4.8.4.1 
Safety Laboratory Parameters 
All laboratory data will be converted to SI units.  The International Standard for the 
Handling and Reporting of Laboratory Data COG 3007 will be used to implement 
reference ranges and marked abnormalities for laboratory data where possible.  
Additionally, serum creatinine, hemoglobin, albumin and hematocrit will be presented in 
conventional units. 
Summary statistics for the absolute and change from baseline values will be produced 
by visit for laboratory parameters. 
Marked abnormalities will be summarized for laboratory parameters.  Summaries by 
National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) grade will also be produced for certain lab assessments, including shift 
tables from baseline to highest grade post-baseline. 
Shift tables from baseline to highest NCI CTCAE grade post-baseline will be produced 
for liver function laboratory tests. 
4.8.4.2 
Immunoglobulins 
The absolute values and change from baseline will be summarized by treatment group 
and visit for total Ig, IgA, IgG, and IgM. 
The proportion of patients with a value of total Ig, IgA, IgG, and IgM which is less than 
the lower of limit of normal per visit will be produced. 


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A plot of the mean value over time will be produced for total Ig, IgA, IgG, and IgM.  The 
plots will display error bars (mean±standard deviation) around the mean. 
4.8.5 
Vital Signs 
Vital signs are measured at each scheduled visit in accordance with the schedule of 
assessments (see protocol).  At infusion visits, vital signs should be taken pre-infusion, 
then every 15 minutes for 1 hour, then every 30 minutes until the end of the infusion, and 
within 30 minutes post-infusion.  Additional readings may be obtained at the discretion of 
the investigator in the event of an infusion-related reaction. 
Summary tables for the absolute value and change from baseline in vital sign 
assessments will be presented by visit.  Vital sign assessments include respiratory rate, 
pulse rate, temperature, systolic and diastolic blood pressure.  Body mass index will be 
calculated for these time points that body weight is measured. 
4.9 
DATA HANDLING METHODS 
4.9.1 
Presentation of Data 
Data displays include listings, tables, and plots.  All data displays will be presented by 
treatment group. 
Data presented in summary tables will be displayed using summary statistics.  
Continuous data will include number of patients, mean, standard deviation, median, 
minimum, and maximum.  Categorical data will include the number and percentage of 
patients. 
4.9.2 
Definitions 
Baseline 
Baseline is defined as the last non-missing value prior to receipt of study treatment.  
Typically, baseline will be the pre-dose Day 1 assessment, but may include screening 
results if the pre-dose Day 1 result is not available or missing.  If the Day 1 or screening 
result is missing, then no imputation will be made and the baseline result will be set to 
missing.  
Study Day 
For each patient, the first day of study treatment will be designated study Day 1.  Each 
subsequent assessment will be assigned a study day calculated as: 
date of assessment − date of first dose  + 1 
 


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4.9.3 
Multiple Values 
For summaries displayed by visit, multiple values for a given assessment within a time 
window will be handled as follows: 
Efficacy 
The nearest non-missing assessment to the nominal timepoint will be assigned to the 
visit.  If two or more values are equidistant from the nominal timepoint, then the latest 
assessment will be selected. 
Safety 
The assessment with the worst result will be assigned to the visit. 
4.10 
MISSING DATA 
Methods for handling missing data for efficacy analyses are described in detail 
throughout Section 4.6.1.  Missing or partial dates for AEs, concomitant medications 
(except oral corticosteroids), laboratory assessments, and medical history will be 
imputed as detailed in Appendix 3. 
4.11 
INTERIM ANALYSES 
4.11.1 
Pharmacodynamic Futility Interim Analysis 
An interim analysis for futility is planned on the basis of CD19 B-cell counts after 
30 patients have been assigned to the obinutuzumab arm and have had their 
Day 28 blood CD19 +  B-cell counts assessed by high-sensitivity flow cytometry (HSFC).  
The effect of rituximab on CD19 +  B-cell counts has been measured by HSFC in an 
investigator sponsored study in which peripheral B-cell depletion below the lower limit of 
quantification (LLOQ) of the assay occurred in 46% of patients.  Slightly less than half of 
these rituximab treated patients with full peripheral B-cell depletion achieved a major 
clinical response, with the remainder of the patients having partial clinical responses.  
Therefore, it is hypothesized that an improved outcome over rituximab is achievable for 
a LN patient population with full peripheral B-cell depletion, with the assumption that 
improved tissue depletion with treatment will parallel the peripheral depletion.  To test 
the hypothesis in this study, we will require at least 50% of the obinutuzumab-treated 
patients to have peripheral B-cell depletion below the LLOQ of the HSFC assay in order 
to have a realistic chance of a positive primary endpoint analysis for the treatment arm.  
Quantification of the link between this biomarker and the study’s primary analysis has 
not been established; therefore, predictive probabilities for study statistical significance 
cannot be provided.  Consequently, the study will be terminated if the 5% one-sided 
Clopper-Pearson upper confidence limit for the proportion of patients who achieve B-cell 
depletion is not greater than 0.5.  Assuming that there are 30 patients at the time of the 
interim analysis, this will effectively require that ≥ 11 obinutuzumab patients have 
complete B-cell depletion below the LLOQ of the HSFC assay at the time of the interim 
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The interim analysis will be performed by the iDMC, which may recommend that the 
study be stopped for futility if the futility criterion is satisfied.  Additional criteria for 
recommending that the study be stopped for futility may be added to the iDMC Charter.  
As this interim analysis will only result in termination of the study due to futility and not 
for efficacy, an adjustment to the α−level is not required.  Although the outcome of the 
interim analysis may reduce the power of this study to below the estimated 83%, a 
sample size adjustment has not been made. 
4.11.2 
Renal Response Interim Analysis 
The iDMC will also conduct an interim efficacy analysis to evaluate renal response when 
the last patient has achieved the 6-month visit.  The interim analysis will be performed by 
the iDCC and interpreted by members of the iDMC.  The iDMC may recommend to the 
Sponsor to consider the planning of Phase III if the treatment difference (obinutuzumab 
minus placebo) in complete renal response at Week 24 is ≥ 10%.  In addition, the iDMC 
will inform the Sponsor if the treatment difference (obinutuzumab minus placebo) in 
complete renal response at Week 24 is ≥ 20%. 
5. 
REFERENCES 
Not applicable.


 
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Appendix 1 Protocol Synopsis 
 
TITLE: 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
MULTI-CENTER STUDY TO EVALUATE THE SAFETY AND 
EFFICACY OF OBINUTUZUMAB IN PATIENTS WITH ISN/RPS 
2003 CLASS III OR IV LUPUS NEPHRITIS 
PROTOCOL NUMBER: 
WA29748 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2015-002022-39 
IND NUMBER: 
125,054 
NCT NUMBER: 
NCT02550652 
TEST PRODUCT: 
Obinutuzumab (GA101; RO5072759) 
PHASE: 
II 
INDICATION: 
ISN/RPS Class III or IV Lupus Nephritis 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
OBJECTIVES 
EFFICACY OBJECTIVES 
The primary efficacy objective for this study is as follows: 
• 
To evaluate the efficacy of obinutuzumab compared with placebo in patients with 
International Society of Nephrology (ISN)/Renal Pathology Society (RPS) Class III or IV 
lupus nephritis (LN) as measured by complete renal response (CRR) at 52 weeks 
 
The secondary efficacy objectives for this study are as follows: 
• 
To assess overall renal response (defined as CRR plus partial renal response [PRR]) 
• 
To evaluate the ability of obinutuzumab to improve time-to-response (CRR plus PRR) over 
the course of 52 weeks 
 
SAFETY OBJECTIVES 
The safety objectives for this study are as follows: 
• 
To evaluate the safety of obinutuzumab compared with placebo in patients with Class III or 
IV LN, focusing on the nature, frequency, and severity of serious and non-serious adverse 
events, as well as effects on laboratory values, vital signs, or other safety biomarkers 
• 
To characterize the immunogenic potential of obinutuzumab by measuring human anti-drug 
antibodies and assessing their relationship with other outcome measures 
• 
To fully characterize adverse events of special interest, including infusion reactions, 
infections, thrombocytopenia, and neutropenia 
 
PHARMACODYNAMIC OBJECTIVE 
The pharmacodynamic (PD) objective for this study is as follows: 


 
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• 
To compare changes in CD19+ B cells in the peripheral blood following treatment with 
obinutuzumab versus placebo 
 
PHARMACOKINETIC OBJECTIVES 
The pharmacokinetic (PK) objectives for this study are as follows: 
• 
To characterize the pharmacokinetics of obinutuzumab in the LN population 
• 
To assess potential PK interactions between obinutuzumab and concomitant medications, 
including mycophenolate mofetil (MMF) 
 
PATIENT-REPORTED OUTCOME OBJECTIVES 
The patient-reported outcome (PRO) objective for this study is as follows: 
• 
To assess the change from baseline of the patient’s general health over the course of the 
study by use of the Subject’s Global Assessment 
 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are as follows: 
• 
To evaluate pre-dose levels of exploratory biomarkers (which may include but are not 
limited to B-cell subsets and levels of protein and mRNA in serum, plasma, blood, and 
urine) and potential associations with outcome 
• 
To evaluate changes in exploratory biomarkers (which may include but are not limited to 
B-cell subsets and levels of protein and mRNA in serum, plasma, blood, and urine) over 
time in patients dosed with obinutuzumab versus patients dosed with placebo 
• 
To evaluate the occurrence of extrarenal flares 
• 
To evaluate the impact of therapy on patient and physician-reported outcomes 
• 
To assess damage through the Glucocorticoid Toxicity Change Index (GTCI) 
• 
To assess renal biopsy histopathology (for the presence and depletion of B cells at the 
screening biopsy and from subsequent biopsies) 
 
Additional exploratory objectives and outcome measures will be included in a final Statistical 
Analysis Plan (SAP). 
STUDY DESIGN 
DESCRIPTION OF STUDY 
This Phase II study is a parallel-group, double-blind, randomized, placebo-controlled study 
comparing the efficacy and safety of obinutuzumab plus MMF with placebo plus MMF in Class 
III and IV patients with proliferative LN.  The Sponsor intends to enroll approximately 120 
patients diagnosed with ISN/RPS Class III or IV LN, with a diagnosis of systemic lupus 
erythematosus (SLE) based on current American College of Rheumatology (ACR) criteria (at 
least 4 criteria must be present, one of which must be a positive anti-nuclear antibody [ANA]), in 
centers throughout the world.  In addition to study treatment, patients will receive 
standard-of-care therapy with angiotensin-converting enzyme 
(ACE) inhibitors/angiotensin-II−receptor blockers, MMF (dosed at 2.0−2.5 g/day) or 
mycophenolic acid (MPA) (dosed 1440−1800 mg/day), and a prednisone taper.  Patients must 
be 18−75 years of age and have ISN/RPS 2003 Class III or IV proliferative LN as evidenced by 
renal biopsy performed within 6 months prior to or during screening and may have concomitant 
Class V disease (e.g., Class III/V or Class IV/V).  Patients with Class III (C) or Class IV (C) 
disease will be excluded because of the lower likelihood of response within these categories.  
Patients must exhibit significant proteinuria (urine protein to creatinine ratio > 1.0 based on a 
24-hour urine collection).  Key exclusions will be evidence of severe renal impairment 
(estimated glomerular filtration rate [GFR] < 30 mL/minute per 1.73 m2 of body surface area), 
end-stage renal disease requiring dialysis or transplantation, evidence of active infections, and 
other safety-related exclusions.  Patients will receive an initial 1000 mg of methylprednisolone 
intravenous (IV) prior to or during screening, and may receive up to a total of 3000 mg 


 
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methylprednisolone IV prior to randomization for severe clinical activity according to guidelines 
of routine care for these patients.  Patients will receive 80 mg methylprednisolone (or 
methylprednisolone placebo) on the day of the obinutuzumab/placebo infusion to reduce 
infusion-related reactions.  Oral corticosteroids will be initiated at a dose of 0.5 mg/kg 
(maximum 60 mg/day) and will be reduced over 10 weeks.  This modified taper, from the 
LUNAR study, will be initiated at a lower dose in recognition that prednisone doses above 
10 mg/day are associated with significant adverse events, including increased risk of 
cardiovascular events.  Prior experience with rituximab suggests that it can potentially enable 
complete and PRRs in the absence of oral prednisone or a prednisone taper, thus allowing the 
use of lower doses of corticosteroids as proposed in this Phase II protocol. 
Patients will be followed until at least Week 104, with the primary endpoint evaluation at Week 
52.  An interim analysis at 6 months will be performed to evaluate early differences in CRR.  All 
patients will have central reading of the renal biopsy histopathology and will also receive repeat 
renal biopsy as available on the basis of clinical status and local practice.  All patients will be 
evaluated by high-sensitivity flow cytometry (HSFC) to evaluate the ability of obinutuzumab to 
deplete circulating peripheral B cells, and an interim PD analysis will be performed to assess 
whether patients do not fully deplete peripheral CD19 B cells as anticipated.  These mechanistic 
studies and more intensive histopathologic reviews are intended to test the hypothesis that 
greater B-cell depletion in the target organ (kidney) and associated secondary lymphoid 
structures will translate into greater CRR rates. 
NUMBER OF PATIENTS 
The study will enroll approximately 120 patients with active ISN/RPS 2003 Class III or IV LN at 
approximately sixty centers in North America, South America, Europe, and selected other 
countries. 
TARGET POPULATION 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form 
• 
Age 18−75 years 
• 
Ability to comply with the study protocol, in the investigator’s judgment 
• 
Diagnosis of SLE, according to current ACR criteria (at least four criteria must be present, 
one of which must be a positive ANA) 
• 
Diagnosis of ISN/RPS 2003 Class III or IV LN as evidenced by renal biopsy performed 
within 6 months prior to or during screening.  Patients may co-exhibit Class V disease in 
addition to either Class III or Class IV disease. 
• 
Proteinuria (urine protein to creatinine ratio) > 1.0, based on a 24-hour urine collection 
• 
For women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) 
or surgically sterile (absence of ovaries and/or uterus):  agreement to remain abstinent or 
use two adequate methods of contraception, including at least one method with a failure 
rate of < 1% per year, during the treatment period and for at least 18 months after the last 
dose of study drug 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
Barrier methods must always be supplemented with the use of a spermicide. 
Examples of contraceptive methods with a failure rate of < 1% per year include tubal 
ligation, male sterilization, hormonal implants, established, proper use of combined oral 
or injected hormonal contraceptives, and certain intrauterine devices. 
• 
For men:  agreement to remain abstinent or use a condom plus an additional contraceptive 
method that together result in a failure rate of < 1% per year during the treatment period and 
for at least 12 months after the last dose of study drug and agreement to refrain from 
donating sperm during this same period 


 
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Men with a pregnant partner must agree to remain abstinent or use a condom for the 
duration of the pregnancy. 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
Patients must be willing to practice this method of contraception while taking MMF and 
for 90 days after stopping MMF. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Retinitis, poorly controlled seizure disorder, acute confusional state, myelitis, stroke or 
stroke syndrome, cerebellar ataxia, or dementia that is currently active and resulting from 
SLE 
• 
Presence of rapidly progressive glomerulonephritis defined by 
The presence of crescent formation in ≥ 50% of glomeruli assessed on renal biopsy or 
Sustained doubling of serum creatinine within 12 weeks of screening or 
The investigator’s opinion that the patient has rapidly progressive glomerulonephritis. 
• 
Severe renal impairment as defined by estimated GFR < 30 mL/min or the need for dialysis 
or renal transplant 
• 
Greater than 50% of glomeruli with sclerosis on renal biopsy 
• 
Treatment with cyclophosphamide or calcineurin inhibitors within the 3 months prior to 
randomization 
• 
Unstable disease with thrombocytopenia or at high risk for developing clinically significant 
bleeding or organ dysfunction requiring therapies such as plasmapheresis or acute blood or 
platelet transfusions 
• 
Lack of peripheral venous access 
• 
Pregnancy or lactation 
• 
History of severe allergic or anaphylactic reactions to monoclonal antibodies or known 
hypersensitivity to any component of the obinutuzumab infusion 
• 
Significant or uncontrolled medical disease in any organ system not related to SLE or LN, 
which, in the investigator’s opinion, would preclude patient participation 
• 
Concomitant chronic conditions, excluding SLE, (e.g., asthma, Crohn’s disease) that 
required oral or systemic steroid use in the 52 weeks prior to screening 
• 
Known HIV infection 
• 
Known active infection of any kind (excluding fungal infection of nail beds) or any major 
episode of infection requiring hospitalization or treatment with IV anti-infectives within 
8 weeks of the screening visit or oral anti-infectives within 2 weeks prior to the screening 
visit 
• 
History of serious recurrent or chronic infection 
• 
History of cancer, including solid tumors, hematological malignancies, and carcinoma in situ 
(except basal cell carcinomas of the skin that have been treated or excised and have 
resolved) 
• 
Currently active alcohol or drug abuse or history of alcohol or drug abuse within 52 weeks 
prior to screening 
• 
Major surgery requiring hospitalization within 4 weeks of randomization (excluding 
diagnostic surgery) 
• 
Previous treatment with an anti-CD20−targeted therapy within 12 months of randomization 
• 
Previous treatment with a biologic B-cell−targeted therapy (other than anti-CD20) within 
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• 
Treatment with any investigational agent within 28 days of randomization or five half-lives of 
the investigational drug (whichever is longer) 
• 
Receipt of a live vaccine within 28 days prior to screening 
• 
Intolerance or contraindication to oral or IV corticosteroids 
• 
Aspartate aminotransferase or alanine aminotransferase > 2.5 × upper limit of normal (ULN) 
• 
Amylase or lipase > 2 × ULN 
• 
Neutrophils < 1.5 × 103/µL 
• 
Positive hepatitis B surface antigen (HbSAg) or hepatitis C serology.  Patients who are 
HBsAg negative and hepatitis B core antibody positive with no detectable DNA will be 
allowed into the study but will require regular monitoring of hepatitis B virus DNA. 
• 
Hemoglobin < 7 g/dL, unless caused by autoimmune hemolytic anemia resulting from SLE 
• 
Platelet count < 10,000/µL 
• 
Positive serum human chorionic gonadotropin measured prior to the first obinutuzumab 
infusion 
• 
Known intolerance to MMF and MPA 
 
LENGTH OF STUDY 
The study will follow all patients for a minimum of 78 weeks after the last infusion of 
obinutuzumab at Day 182.  In consideration of recruitment and follow-up (independent of B-Cell 
follow-up [BCFU]), the length of study is estimated to be greater than 36 months.  Patients may 
enter BCFU and continue to be evaluated for safety on a limited basis. 
END OF STUDY 
The end of this study is defined as the last patient’s last visit at Week 104.  This has been 
selected to enable 78 weeks (~18 months) of safety follow-up after the last dose of study drug 
to assess the occurrence of adverse events and to enable an assessment of peripheral blood 
CD19+ B cell return. 
Additional B-cell follow-up (BCFU) visits will occur until patients have achieved their baseline 
CD19+ count or achieved 25 cells/μL CD19+ count (the lower limit of normal (LLN) of CD19+ B 
cells for this lupus population), whichever occurs first.  B-cell follow-up (BCFU) visits for all 
patients will end when the last patient has completed ~18 months of safety follow-up from the 
last dose of blinded obinutuzumab infusion. 
Patients who receive additional therapies that reduce peripheral B-cell counts will not be 
included in BCFU. 
OUTCOME MEASURES 
PRIMARY EFFICACY OUTCOME MEASURE 
The primary efficacy outcome measure is the proportion of patients who achieve a CRR, 
evaluated at 52 weeks. 
CRR is defined by attainment of all of the following: 
• 
Normalization of serum creatinine as evidenced by the following: 
Serum creatinine ≤ the ULN range of central laboratory values if baseline (Day 1) serum 
creatinine is above the ULN 
Serum creatinine ≤ 15% above baseline and ≤ the ULN range of central laboratory 
values if baseline (Day 1) serum creatinine is ≤ the ULN range of central laboratory 
values 
• 
Inactive urinary sediment (as evidenced by < 10 RBCs/high-power field (HPF) and the 
absence of red cell casts) 
• 
Urinary protein to creatinine ratio < 0.5 
 


 
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SECONDARY EFFICACY OUTCOME MEASURES  
The secondary efficacy outcome measures are the following: 
• 
Proportional analysis of patients who achieve an overall response at Week 52 (CRR + PRR) 
• 
Time to overall response (CRR + PRR) over the course of 52 weeks 
• 
Percent reduction or increase from baseline and mean andmedian assessments of 
biomarkers of LN disease activity (e.g., reduction in anti-dsDNA antibody levels, increase 
C3 and C4 levels) 
• 
Proportion of patients that achieve a PRR at Week 52 as defined by attainment of all of the 
following: 
Serum creatinine ≤ 15% above baseline value 
No urinary red cell casts and either RBCs/HPF ≤ 50% above baseline or < 10 RBCs/HPF 
50% improvement in the urine protein to creatinine ratio, with one of the following 
conditions met: 
If the baseline urine protein to creatinine ratio is ≤ 3.0, then a urine protein to 
creatinine ratio of < 1.0 
If the baseline protein to creatinine ratio is > 3.0, then a urine protein to creatinine 
ratio of < 3.0 
• 
Proportion of patients who achieve a CRR at Week 24 
• 
Time to CRR, over the course of 52 weeks. 
• 
Proportion of patients that achieve a modified CRR (mCRR1) at Week 52 employing the 
primary−efficacy measure definition and removing the urinary sediment analysis criteria 
mCRR1 is defined by attainment of normalization of serum creatinine as evidenced by 
the following: 
Serum creatinine ≤ the ULN range of central laboratory values if baseline (Day 1) 
serum creatinine is above the ULN 
Serum creatinine ≤ 15% above baseline and ≤ the ULN range of central laboratory 
values if baseline (Day 1) serum creatinine ≤ the ULN range of central laboratory 
values 
Urinary protein to creatinine ratio < 0.5 
• 
Proportion of patients that achieve a second modified CRR (mCRR2) at Week 52 as 
defined by attainment of the following: 
Normalization of serum creatinine as evidenced by the following: 
Serum creatinine ≤ 15% above baseline if baseline (Day 1) serum creatinine is 
above the normal range of the central laboratory values or ≤ the ULN range of 
central laboratory values if baseline (Day 1) serum creatinine is ≤ the ULN range of 
central laboratory values 
Inactive urinary sediment (as evidenced by < 10 RBCs/HPF and the absence of red cell 
casts) 
Urinary protein to creatinine ratio < 0.5 
• 
Proportion of patients that achieve a third modified CRR (mCRR3) at Week 52 as defined 
by attainment of the following: 
Normalization of serum creatine as evidenced by serum creatinine ≤ the ULN range of 
central laboratory values 
Urinary protein to creatinine ratio < 0.5 
 
The hierarchical ordering of the secondary endpoints will be pre-specified in the SAP. 
SAFETY OUTCOME MEASURES 
The safety outcome measures for this study are as follows: 
• 
Incidence, type, and severity of adverse events 


 
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• 
Abnormal vital signs 
• 
Abnormal laboratory values 
 
Safety will be monitored through regular physical examinations, vital signs, hematologic and 
chemistry laboratory tests, urinalyses, and incidence and severity of adverse events.  In 
addition, the following will be examined: 
• 
Circulating B cells, T cells, neutrophils and other cell populations 
• 
Plasma immunoglobulins (total Ig, IgG, IgM, and IgA) 
• 
Record of menses 
• 
Pregnancy 
• 
Antibody titers for mumps, rubella, Varicella, tetanus, influenza, and Streptococcus 
pneumoniae 
 
PHARMACODYNAMIC OUTCOME MEASURE 
The primary PD outcome measure for this study is as follows: 
• 
Changes in levels of circulating CD19+ B-cells relative to baseline 
 
PHARMACOKINETIC OUTCOME MEASURES 
The obinutuzumab PK outcome measures for this study are as follows: 
Non-linear mixed-effects modeling (with software NONMEM) will be used to analyze the dose-
concentration−time data of obinutuzumab.  The PK profile data will be used to further develop a 
PK model, including the effect of major covariates (e.g., sex, race/ethnicity, weight, biochemical 
and hematological parameters at baseline, degree of underlying disease), on the main 
parameters (e.g., clearance).  The derivation of individual measures of exposure, such as area 
under the concentration-time curve and maximum concentration observed will depend on the 
final PK model used for this analysis.  Results of this analysis may be reported separately.  
Serum obinutuzumab will be summarized (mean, minimum, maximum, SD, and geometric 
mean) and reported within this study.  
Exploratory graphical analyses will be performed to assess whether the occurrences of serious 
adverse events and abnormalities in the safety laboratory parameters in patients treated with 
obinutuzumab can be attributed to obinutuzumab exposure.  Also, exploratory 
graphical analyses will be performed to assess whether the variability in response can be 
attributed to the variability in obinutuzumab exposure.  Relevant observed relationships 
between exposure and safety parameters may be further characterized using different 
approaches such as logistic regression analysis and indirect response modeling.  
Additional PK and PD analyses may be conducted as appropriate. 
PATIENT-REPORTED OUTCOME MEASURE 
The PRO measure for this study is as follows: 
• 
Subject’s Global Assessment 
This visual analog scale (VAS) will be captured in screening, at the baseline visit, and at 
several timepoints during study conduct. 
 
EXPLORATORY OUTCOME MEASURES 
The exploratory outcome measures for this study are as follows: 
• 
Changes in levels of circulating B-cell subsets relative to baseline  
• 
Changes in levels of exploratory biomarkers, which may include but are not limited to levels 
of protein and mRNA in serum, plasma, blood, and urine, relative to baseline  
• 
Proportion of patients experiencing a Systemic Lupus Erythematosus Disease Activity 
Index-2K flare 
• 
Proportion of patients experiencing a renal flare over 52 weeks and 104 weeks 


 
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• 
Proportion of patients achieving CRR, mCRR1, mCRR2, and mCRR3 at additional 
timepoints, including Week 12 and Week 36 
• 
Physician’s Global Assessment 
This VAS will be captured in screening, at the baseline visit, and at several timepoints 
during study conduct. 
• 
GTCI 
• 
Renal biopsy evaluations 
 
INVESTIGATIONAL MEDICINAL PRODUCTS 
TEST PRODUCT (INVESTIGATIONAL DRUG) 
The test product for this study is obinutuzumab and will be administered by IV infusion at a dose 
of 1000 mg on Days 1, 15, 168, and 182.  The study drug will be administered in a hospital or 
clinic environment where full resuscitation facilities are immediately available and under close 
supervision of the investigator or designee.  After the end of the first infusion, the IV line will 
remain in place for at least 2 hours to enable administration of IV drugs if necessary.  If no 
adverse events occur during this period of time, the IV line may be removed.  For subsequent 
infusions, access through an IV line should remain in place for at least 30 minutes from the end 
of the infusion, and if no adverse events occur after 30 minutes, the IV access may be removed. 
COMPARATOR (PLACEBO) 
The obinutuzumab placebo (corresponding to the obinutuzumab1000-mg dose) will be 
administered by IV infusion on Days 1, 15, 168, and 182.  The placebo will be administered in a 
hospital or clinic environment where full resuscitation facilities are immediately available and 
under close supervision of the investigator or designee.  After the end of the first infusion, the IV 
line will remain in place for at least 2 hours to enable administration of IV drugs if necessary.  If 
no adverse events occur during this period of time, the IV line may be removed.  For 
subsequent infusions, access through an IV line should remain in place for at least 30 minutes 
from the end of the infusion, and if no adverse events occur after 30 minutes, the IV access may 
be removed. 
NON-INVESTIGATIONAL MEDICINAL PRODUCTS 
After screening, patients who were not already receiving MMF or MPA will receive 1500 mg/day 
(or equivalent) in divided doses (2−3 times/day), and all patient doses will be titrated upward to 
a target dose of 2.0−2.5 g/day (or equivalent) in divided doses (2−3 times/day) by Week 4, as 
tolerated.  If reductions in dose are necessary, decreases will be allowed in 250−500 mg (or 
equivalent) decrements.  During screening or at randomization, if clinically indicated, patients 
may receive 750−1000 mg methylprednisolone IV once daily for up to 3 days to treat underlying 
LN clinical activity.  Patients will receive 0.5 mg/kg oral prednisone, tapering this prednisone 
dose, per protocol, starting on Day 16 and reducing the prednisone dosage to 7.5 mg/day by 
Week 12. 
Prior to each infusion of either study drug or placebo, patients should receive prophylactic 
treatment with acetaminophen (650−1000 mg) and diphenhydramine (50 mg; or equivalent dose 
of a similar agent) by mouth, given 30−60 minutes before the start of the infusion period.  The 
patients who are receiving obinutuzumab will receive 80 mg methylprednisolone IV and patients 
who are receiving placebo will receive placebo-methylprednisolone IV given 30−60 minutes 
before the start of the obinutuzumab/placebo infusion. 
CONCOMITANT THERAPY AND CLINICAL PRACTICE 
Patients who are not already taking vitamin D (800 IU/day) and calcium supplements 
(1200 mg/day of calcium citrate or 1500 mg/day of calcium carbonate) will begin taking these 
supplements at randomization.  All patients will take either an ACE inhibitor or an 
angiotensin-receptor blocker titrated to adequate blood pressure control as recommended by 
the National Kidney Foundation for chronic kidney disease. 
Other agents that affect proteinuria will not be allowed to be initiated during the study.  These 
include but are not limited to the following: 


 
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• 
Non-dihydropyridine calcium antagonists 
• 
Dihydropyridine calcium antagonists 
• 
Aldosterone antagonists 
• 
Direct renin antagonists 
 
STATISTICAL METHODS 
All efficacy outcomes will be analyzed according to the modified intent-to-treat principle and will 
include all randomized patients who have received any amount of study drug.  Patients will be 
grouped according to randomized (assigned) treatment, rather than treatment received. 
Treatment period data will be locked after all patients have completed the Week 52 visit.  The 
primary efficacy and safety analyses will be performed on data for all patients through the Week 
52 assessments or early discontinuation. 
Safety assessments will be performed on patients who receive study medication.  In all safety 
analyses, patients will be grouped according to the treatment that patients actually received 
rather than the treatment assigned. 
The primary and secondary efficacy analyses will include all randomized patients who received 
any study medication, with patients grouped according to the treatment assigned at 
randomization. 
PRIMARY ANALYSIS 
The primary assessment of efficacy of obinutuzumab, to induce a clinically significant 
improvement in renal function in patients with ISN/RPS 2003 class III or IV LN, will be assessed 
by attainment of CRR. 
CRR is defined as achievement of all of the following: 
• 
Normalization of serum creatinine as evidenced by the following: 
Serum creatinine ≤ the ULN range of central laboratory values if the baseline (Day 1) 
serum creatinine is above the ULN 
Serum creatinine ≤ 15% above baseline and ≤ the ULN range of central laboratory 
values if baseline (Day 1) serum creatinine is ≤ the ULN range of central laboratory 
values 
• 
Inactive urinary sediment (as evidenced by < 10 RBCs/HPF and the absence of red cell 
casts) 
• 
Urinary protein to creatinine ratio < 0.5 
 
Any patient who switches to rescue medication prior to Week 52 will be considered a 
non-responder. 
The proportions of patients achieving CRR across treatment groups will be compared using a 
Cochrane-Mantel-Haenzel (CMH) test with race (Afro-Caribbean/African American versus 
others) and region (United States versus non-United States) as stratification factors.  If the test 
result is in favor of the obinutuzumab group at α < 0.1-level (one-sided), it will be concluded that 
there is a shift toward better renal response associated with the obinutuzumab group. 
DETERMINATION OF SAMPLE SIZE   
This Phase II study is a proof-of-concept study that is designed to detect an improvement in 
CRR.  The primary efficacy endpoint of this study is the proportion of patients that achieve CRR. 
It is estimated that approximately 30% of patients with proliferative LN who are receiving MMF 
(or equivalent) will achieve a CRR at Week 52 and that the addition of obinutuzumab to MMF 
(or equivalent) will induce an overall CRR rate of 50% at Week 52.  On the basis of these 
assumptions, a total of 120 patients randomized to obinutuzumab- and placebo-treated groups 
in a 1:1 ratio (60 patients in each of the obinutuzumab- and placebo-treated groups) will yield 
approximately 83% power at the two-sided α = 0.2 significance level using a CMH test, 
assuming the same CRR proportions across the strata. 


 
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INTERIM ANALYSES 
Pharmacodynamic Futility Interim Analysis 
Given the rationale for this study, including the results from the LUNAR and BELONG studies, 
an interim analysis for futility is planned on the basis of CD19 B-cell counts after 30 patients 
have been assigned to the obinutuzumab arm and have had their Day 28 blood CD19 B-cell 
counts assessed by HSFC. 
The effect of rituximab on CD19 B-cell counts has been measured by HSFC in an investigator-
sponsored study in which peripheral B-cell depletion below the lower limit of quantification 
(LLOQ) of the assay occurred in 46% of patients.  Slightly less than half of these rituximab-
treated patients with full peripheral B-cell depletion achieved a major clinical response, with the 
remainder of the patients having partial clinical responses.  Therefore, it is hypothesized that an 
improved outcome over rituximab is achievable for a LN patient population with full peripheral B-
cell depletion, with the assumption that improved tissue depletion with treatment will parallel the 
peripheral depletion.  To test the hypothesis in this study, we will require at least 50% of the 
obinutuzumab-treated patients to have peripheral B-cell depletion below the LLOQ of the HSFC 
assay in order to have a realistic chance of a positive primary endpoint analysis for the 
treatment arm.  Quantification of the link between this biomarker and the study’s primary 
analysis has not been established; therefore predictive probabilities for study statistical 
significance cannot be provided.  Consequently, the study will be terminated if the 5% one-sided 
Clopper-Pearson upper confidence limit for the proportion of patients who achieve B-cell 
depletion is not greater than 0.5.  Assuming that there are 30 patients at the time of the interim 
analysis, this will effectively require that ≥ 11 obinutuzumab patients have complete B-cell 
depletion below the LLOQ of the HSFC assay at the time of the interim analysis. 
The interim analysis will be performed by the independent Data Monitoring Committee (iDMC), 
which may recommend that the study be stopped for futility if the futility criterion is satisfied.  
Additional criteria for recommending that the study be stopped for futility may be added to the 
iDMC Charter. 
As this interim analysis will only result in termination of the study due to futility, and not for 
efficacy, an adjustment to the α-level is not required.  Although the outcome of the interim 
analysis may reduce the power of this study to below the estimated 83%, a sample size 
adjustment has not been made. 
Renal Response Interim Analysis 
The iDMC will conduct an interim efficacy analysis to evaluate renal response when the last 
patient has achieved the 6-month visit.  The interim analysis will be performed and interpreted 
by members of the iDMC, who may recommend to the Sponsor the initiation of future study 
planning, according to rules outlined in the iDMC Charter.  If the iDMC does recommend that 
future study planning can begin, then the summary of renal response data at Week 24 will be 
shared with appropriate Sponsor senior management personnel who will be unblinded at the 
treatment group level. 
This interim analysis is for planning purposes only and will have no impact on the progression of 
this study.  Consequently, an adjustment to the α-level is not required. 
 


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WA29748 
 
 
 
 
 
 
 
 
37  
Appendix 2 Schedule of Assessments 
Week 
 
Treatment Period 
− 4 to 0 
1 
2 
4 
12 
24 
26 
36 
52/ET 
Day 
− 28 to − 1 
1 a 
15 
28 
84 
168 
182 
252 
364 
Informed consent 
x 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
x 
 
 
 
 
 
 
 
Medical history 
x 
x 
 
 
 
 
 
 
 
IxRS assignment b 
x 
x 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
Subject’s Global Assessment c 
 
x 
 
x 
x 
x 
 
x 
x 
Physical exam (limited) 
x 
x 
 
 
 
x 
 
 
x 
Height 
x 
 
 
 
 
 
 
 
 
Vital signs and weight d 
x 
x 
x 
x 
x 
x 
x 
x 
x 
12-Lead ECG 
x 
 
 
 
 
 
 
 
x 
Chest X-ray e 
x 
 
 
 
 
 
 
 
 
Physician’s Global Assessment 
 
x 
 
x 
x 
x 
 
x 
x 
SLICC/ACR assessment 
x 
 
 
 
 
x 
 
 
x 
SLEDAI-2K 
x 
x 
 
x 
x 
x 
 
x 
x 
Glucocorticoid Toxicity Change Index 
 
x 
 
 
x 
x 
 
 
x 
Hematology f 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum chemistries g 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinalysis h 
x 
x 
 
x 
x 
x 
 
x 
x 


 
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38  
Appendix 2 Schedule of Assessments (cont.) 
 
Week 
 
Treatment Period 
− 4 to 0 
1 
2 
4 
12 
24 
26 
36 
52/ET 
Day 
− 28 to − 1 
1 a 
15 
28 
84 
168 
182 
252 
364 
24-hour urine collection i 
x 
x 
 
 
x 
x 
 
x 
x 
Pregnancy test j 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HBsAg k, HBcAb, Hepatitis C antibody 
x 
 
 
 
 
 
 
 
 
Autoantibody profile l 
x 
x 
 
x 
x 
x 
 
x 
x 
Antibody titers m 
x 
 
 
 
 
x 
 
 
x 
Serum PK sampling n 
 
x n 
x n 
x 
x 
x n 
x n 
x 
x 
Blood sample for flow cytometry o 
 
x 
x 
x 
x 
x o 
 
 
x 
Serum ADAs 
 
x o 
 
 
 
x o 
 
 
x  
Quantitative serum Ig levels (total, IgG, IgM, 
and IgA) 
x 
x 
 
 
x 
x 
 
 
x 
C3, C4, CH50 complement 
x 
x 
x 
x 
x 
x 
 
x 
x 
Serum for biomarkers o 
x 
x o 
x 
x 
x 
x o 
 
x 
x 
Plasma for biomarkers o 
x 
x o 
x 
x 
x 
x o 
 
x 
x 
Urine for biomarkers p, o 
x 
x 
x 
x 
x 
x 
 
x 
x 
PAXgene RNA o 
x 
x o 
x 
x 
x 
x o 
 
x 
x 
Blood DNA q (optional) 
x 
 
 
 
 
 
 
 
 
Record of menses 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events r 
 
x r 
x r 
x 
x 
x r 
x r 
x 
x 


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
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39  
Appendix 2 Schedule of Assessments (cont.) 
 
Week 
 
Treatment Period 
− 4 to 0 
1 
2 
4 
12 
24 
26 
36 
52/ET 
Day 
− 28 to − 1 
1 a 
15 
28 
84 
168 
182 
252 
364 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study drug infusion 
 
x s 
x s 
 
 
x s 
x s 
 
 
Corticosteroid dose/taper t 
 
x 
x 
x 
x 
 
 
 
 
Renal biopsy (optional) u 
 
 
 
 
 
 
 
 
(x) 
ADA = anti-drug antibody; ET = Early Termination Visit; HBcAb = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B 
virus; IV = intravenous; IxRS = interactive voice/Web response system; PK = pharmacokinetic; PO = by mouth; SLEDAI-2K = Systemic Lupus 
Erythematosus Disease Activity Index; SLICC/ACR = Systemic Lupus International Collaborating Clinics/American College of Rheumatology. 
Notes:  All assessments will be performed pre-infusion unless otherwise specified.  Infusion visits (Days 15, 168, and 182) except for Day 1, should 
be performed within ± 3 days of the scheduled visit.  Non-infusion visits should be performed within ± 3 days of the scheduled visit. 
a Day 1, unless otherwise notified. 
b At screening, IxRS will be contacted to obtain assignment of patient screening number.  At Day 1, IxRS will be contacted to obtain patient 
randomization number and drug assignment. 
c Subject’s Global Assessment will be performed prior to other assessments. 
d Blood pressure and pulse rate while patient is seated for 5 minutes, and respiratory rate and body temperature.  Vital signs should be taken 
pre-infusion, then every 15 minutes for 1 hour, then every 30 minutes until the end of the infusion, and within 30 minutes post-infusion.  Additional 
readings may be obtained at the discretion of the investigator in the event of an infusion-related reaction (e.g., hypotension and/or fever). 
e If a chest X-ray has been obtained within the past 3 months and no clinically significant abnormality was observed and no new pulmonary signs 
or symptoms are exhibited, no chest X-ray is required. 
f Hematology:  CBC, RBC count, WBC count and differential, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, and 
quantitative platelet count. 
g Serum chemistries include AST/SGOT, ALT/SGPT, alkaline phosphatase, total protein, albumin, cholesterol, total bilirubin, BUN, uric acid, 
creatinine, random glucose, lactate dehydrogenase, potassium, sodium, chloride, calcium, phosphorus, CPK, and triglycerides.  At screening and 
at unscheduled visits, amylase and lipase will be also included. 


 
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40  
Appendix 2 Schedule of Assessments (cont.) 
 
h All urinalyses must include microscopic examination, macroscopic urinalysis, and spot urine protein to creatinine ratio (preferably done ion the 
first morning urine).  The spot urine protein to creatinine ratio on Days 1, 84, 168, 252, and 364 must be done from first-morning urine. 
i To be analyzed for total protein, total creatinine, creatinine clearance, and protein to creatinine ratio. 
j For women of childbearing potential, including those who have had a tubal ligationPositive test results will be confirmed with a serum pregnancy 
test.  Study drug infusion must not be administered unless the pregnancy test result is negative. 
k Patients who are HBsAg negative and HBcAb positive with no detectable DNA will be allowed into the study but will require regular monitoring of 
HBV DNA (see the Laboratory Manual for further details). 
l Autoantibodies include anti-nuclear antibody, anti-dsDNA, Sm, Ro, La, RNP, and anti-C1q. 
m Antibody titers include mumps, rubella, Varicella, tetanus, influenza, and S. pneumoniae. 
n Obtain pre-infusion (within 30 minutes prior to the start of infusion) and at the end of infusion (or within 30 minutes after the end of infusion). 
o Samples will be drawn before administration of study drug on dosing days. 
p Urine for biomarkers will be processed at the study site.  Instructions will be provided in the laboratory manual. 
q The DNA samples are optional and should only be obtained from patients who sign the separate Roche Clinical Repository Informed Consent 
Form.  Preferably, samples will be obtained at screening visit, but they may be obtained at subsequent study visits. 
r On Day 1, adverse events will be recorded during infusion and post-infusion.  For Days 15, 168, and 182, adverse events will be recorded 
pre-infusion, during infusion, and post-infusion.  For all serious infectious adverse events reported, CBC with differentials, quantitative Ig, and 
CD19 B-cell counts should be determined within 1 week of onset. 
s On Days 1, 15, 168, and 182, administer 80 mg methylprednisolone IV (or placebo), 650−1000 mg acetaminophen PO, and 50 mg 
diphenhydramine PO (or other antihistamine) 30−60 minutes prior to the study-drug infusion. 
t Patients may initiate 0.5 mg/kg/day oral prednisone in screening or at Day 2.  Oral corticosteroid taper will begin on Day 16.  The maximum 
allowable daily dose of prednisone will be 60 mg. 
u All patients will be asked to undergo an optional repeat renal biopsy after completion of the treatment portion of the study (after Week 52).  If a 
patient agrees to a repeat renal biopsy, one should be performed within 4 weeks of completion of the treatment portion of the study.  Biopsies 
performed at other times, for clinical reasons, will also be submitted for central review.  Because examination of the biopsy sample may 
potentially unblind the study treatment, investigators and study site personnel should not examine the biopsy sample for immunohistochemistry of 
B cells or be informed of its results.  


 
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Appendix 3 Imputation Rules for Partial or Missing Dates 
 
Start Date/Time 
End Date/Time 
Concomitant 
Medications 
Partially Missing 
Day: First day of the month (i.e., 01) 
Month: January 
Year: No imputation 
Seconds: 00 
Minutes: 00 
Hours: 00 
Completely Missing 
Date:  No imputation 
Time: 00:00:00 
Note:  if end time is available and start/end 
dates are equal and the imputed start time is 
after end time then impute start time with end 
time 
Partially Missing 
Day: Last day of the month 
Month: December 
Year: No imputation 
Seconds: 59 
Minutes: 59 
Hours: 23 
Completely Missing 
Date:  No imputation 
Time: 23:59:59 
 
Medical History 
Partially Missing 
Day: First day of the month (i.e., 01) 
Month: January 
Year: No imputation 
Seconds: 00 
Minutes: 00 
Hours: 00 
Completely Missing 
Date:  No imputation 
Time: 00:00:00 
Note:  if end time is available and start/end 
dates are equal and the imputed start time is 
after end time then impute start time with end 
time 
Partially Missing 
Day: Last day of the month 
Month: December 
Year: No imputation 
Seconds: 00 
Minutes: 00 
Hours: 00 
Completely Missing 
Date:  No imputation 
Time: 00:00:00 
 
 


 
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Appendix 3 Imputation Rules for Partial or Missing Dates (cont.) 
Laboratory 
Partially Missing 
Day: No imputation 
Month: No imputation 
Year: No imputation 
Seconds: 59 
Minutes: 59 
Hours: 23 
Completely Missing 
Date:  No imputation 
Time: 23:59:59 
Partially Missing 
Day: No imputation 
Month: No imputation 
Year: No imputation 
Seconds: 59 
Minutes: 59 
Hours: 23 
Completely Missing 
Date:  No imputation 
Time: 23:59:59 
Adverse 
Events 
Partially Missing 
Day: If the MM-YYYY of start date is not equal 
to the MM-YYYY of first treatment date then 
set to 01-MM-YYYY.  If the MM-YYYY of start 
date is equal to the MM-YYYY of first     
treatment date then if the end date is ≥ date of 
first treatment set to max(01-MM-YYYY, date 
of first treatment) , otherwise  if end date < 
date of first treatment set to 01-MM-YYYY.  
Month: Set to max(01-01-YYYY, date of first 
treatment).  
Year: Set to start date of first treatment.  
Seconds: 59 
Minutes: 59 
Hours: 23 
Completely Missing 
Set to start date of first treatment.   
 
Note:  For all imputations above, if the resulting 
imputed start date is after the end date then set 
start date to end date. 
Partially Missing 
Day: Set to last day of the month, unless 
the outcome is death in which case 
impute with min(last day of month, date of 
death) 
Month: December, unless the outcome is 
death in which case impute with min(DD-
12-YYYY, date of death) 
Year: If the outcome is death then impute 
with the date of death, otherwise no 
imputation. 
Seconds: 59 
Minutes: 59 
Hours: 23 
Completely Missing 
If the outcome is death then impute with 
the date of death, otherwise no 
imputation. 
 
 
 


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