Clinical trial NCT05376319
Conditions: Granulomatosis With Polyangiitis Microscopic Polyangiitis ANCA Associated Vasculitis
Keywords: Granulomatosis with Polyangiitis Microscopic Polyangiitis PR3-ANCA ANCA-associated Vasculitis
Sponsor: Mayo Clinic
Start date: 2023-06-30; Completion date: 2024-05-07
Enrollment: 6 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of obinutuzumab for the treatment of proteinase 3 Anti-Neutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis (PR3-AAV).

Detailed description:

Arms: arm 1: Subjects who have clinical diagnoses of either granulomatosis with polyangiitis or microscopic polyangiitis will receive two intravenous doses of obinutuzumab arm 2: Subjects who have clinical diagnoses of either granulomatosis with polyangiitis or microscopic polyangiitis will receive two intravenous doses of rituximab
Interventions: intervention 1: Obinutuzumab intervention 2: Rituximab
Intervention descriptions: intervention 1: 1000 mg per infusion given approximately two weeks apart, on day 1 and on day 15 intervention 2: 1000 mg per infusion given approximately two weeks apart, on day 1 and on day 15

Protocol documents:
Prot_SAP_000.pdf: 
 
 
A Randomized, Double-Blind, Active 
Comparator-Controlled Study to Evaluate the 
Effect of Obinutuzumab Versus Rituximab in 
PR3-Patients With Anti-Neutrophil Cytoplasmic 
Antibody (ANCA)-Associated Vasculitis 
 
NCT05376319 
 
17OCT2023 


 
 
Clinical Trial Protocol: PR3-AAV Resilient Remission or (PRRR)  
Study Title: 
A Randomized, Double-Blind, Active Comparator-Controlled Study to 
Evaluate the Effect of Obinutuzumab versus Rituximab in PR3-Patients 
with Anti-Neutrophil Cytoplasmic Antibody (ANCA)-Associated 
Vasculitis 
Brief Title: 
PR3-AAV Resilient Remission or PRRR 
Study Number: 
21-012197 
Study Phase: 
2 
Product Name: 
Obinutuzumab 
Indication: 
Treatment of PR3-ANCA-Associated Vasculitis 
Sponsor: 
Ulrich Specks, MD  
Genentech ID 
ML43834 
Protocol Co-Chair 
Ulrich Specks, MD 
Mayo Clinic 
200 First Street SW Rochester, MN 55905 
Phone: (507) 284-2301 
Fax: 
 
Email: specks.ulrich@mayo.edu 
Protocol Co-Chair 
, MD, MPH 
Massachusetts General Hospital 
55 Fruit Street/Yawkey 2 
Boston, MA., 02114 
Phone: 
 
Fax: 
 
Email: 
 
 
Sponsor Contact: 
  
Medical Monitor: 
Ulrich Specks, MD 
, MD, MPH 
Protocol Version: 
Protocol Effective 
Date: 
Version 3.0 
 17OCT2023 
 
 
Confidentiality Statement 
The information contained in this document is confidential property of the Mayo Clinic. 
Acceptance of this document constitutes agreement by the recipient that no information contained 
herein will be published or disclosed without prior written authorization from an official of Mayo 
Clinic. This document may be disclosed to appropriate Institutional Review Board and Ethics 
Committees or duly authorized representatives of a national regulatory authority under the 
condition that they are requested to keep it confidential.  


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Clinical Trial Protocol: PR3-AAV Resilient Remission or PRRR 
  
 
 
 
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REVISION LOG 
DATE 
CHANGES BY: 
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Version 1.0 
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Version 2.0 
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Version 2.1 
02-MAR-2023 
 
Version 3.0 
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TABLE OF CONTENTS 
SYNOPSIS ............................................................................................................................................ 8 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................. 15 
1 
INTRODUCTION ..................................................................................................................... 17 
2 
STUDY OBJECTIVES ............................................................................................................. 19 
2.1 
Primary Objective ............................................................................................................ 19 
2.2 
Secondary Objectives ...................................................................................................... 19 
2.3 
Exploratory Objectives .................................................................................................... 20 
2.4 
Safety Objectives ............................................................................................................. 21 
3 
INVESTIGATIONAL PLAN ................................................................................................... 22 
3.1 
Overall Study Design and Plan ....................................................................................... 22 
3.1.1 
Remission Induction Period ................................................................................. 22 
3.1.2 
Maintenance Phase ............................................................................................... 22 
3.1.3 
Endpoint Analysis ................................................................................................. 23 
3.2 
Known and Potential Risks and Benefits to Participants ............................................... 23 
3.2.1 
Risks Associated with Rituximab ........................................................................ 23 
3.2.2 
Risks Associated with Obinutuzumab ................................................................. 24 
3.2.3 
Data and Safety Monitoring Board (DSMB) ...................................................... 24 
3.3 
Rationale for Study Design and Control Group ............................................................. 25 
3.3.1 
Rationale for the Study Design ............................................................................ 25 
3.3.2 
Rationale for the Dose Selection .......................................................................... 25 
3.3.3 
Rationale for the 16-Week Glucocorticoid Tapering Schedule.......................... 26 
3.3.4 
Selection of the Primary and the Key Secondary Endpoints .............................. 26 
3.4 
Study Duration and Dates ............................................................................................... 26 
4 
STUDY POPULATION SELECTION .................................................................................... 27 
4.1 
Study Population .............................................................................................................. 27 
4.2 
Inclusion Criteria ............................................................................................................. 27 
4.3 
Exclusion Criteria ............................................................................................................ 27 
5 
STUDY TREATMENTS .......................................................................................................... 29 
5.1 
Description of Treatments ............................................................................................... 29 
5.1.1 
Obinutuzumab ....................................................................................................... 29 
5.1.2 
Rituximab .............................................................................................................. 29 
5.1.3 
Infusion Solution ................................................................................................... 29 
5.2 
Treatments Administered ................................................................................................ 29 
5.2.1 
Pre-Medication ...................................................................................................... 29 
5.2.2 
Obinutuzumab or Rituximab ................................................................................ 30 
5.2.3 
Handling Potential Infusion Reactions ................................................................ 30 


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5.3 
Selection and Timing of Dose for Each Patient ............................................................. 31 
5.4 
Method of Assigning Patients to Treatment Groups ...................................................... 31 
5.4.1 
Pre-Registration of a Subject ................................................................................ 31 
5.4.1.1 
– Pre-registration Tests/Procedures ......... Error! Bookmark not defined. 
5.4.2 
Documentation of IRB approval .......................................................................... 32 
5.4.3 
Registration and Randomization of a Subject ..................................................... 32 
5.4.3.1 
– Verification of Materials ....................... Error! Bookmark not defined. 
5.4.4 
Correlative Research ............................................................................................. 33 
5.4.5 
Treatment on Protocol .......................................................................................... 33 
5.4.6 
Treatment Start ...................................................................................................... 33 
5.4.7 
Pretreatment .......................................................................................................... 33 
5.4.8 
Study Drug ............................................................................................................ 34 
5.4.9 
Randomization Procedures ................................................................................... 34 
5.5 
Blinding ............................................................................................................................ 34 
5.6 
Concomitant Therapy ...................................................................................................... 35 
5.6.1 
Antimicrobial Prophylaxis ................................................................................... 35 
5.6.2 
Glucocorticoid Taper ............................................................................................ 36 
5.7 
Restrictions ....................................................................................................................... 37 
5.7.1 
Prior Therapy ........................................................................................................ 37 
5.7.2 
Fluid and Food Intake ........................................................................................... 37 
5.7.3 
Patient Activity Restrictions ................................................................................. 37 
5.7.4 
Immunization ........................................................................................................ 38 
5.8 
Treatment Compliance .................................................................................................... 38 
5.9 
Packaging and Labeling .................................................................................................. 38 
5.10 
Storage and Accountability ............................................................................................. 38 
5.11 
Investigational Product Retention at Study Site ............................................................. 38 
6 
STUDY PROCEDURES ........................................................................................................... 39 
6.1 
Screening for I/E Criteria ................................................................................................ 39 
6.2 
Medical and Surgical History .......................................................................................... 39 
6.2.1 
Demographics ....................................................................................................... 39 
6.2.2 
Significant Medical and Surgical History ............................................................ 39 
6.2.3 
Prior Medication History ...................................................................................... 39 
6.2.4 
AAV Disease History ........................................................................................... 40 
6.3 
Efficacy Assessments ...................................................................................................... 40 
6.3.1 
BVAS/WG Assessment ....................................................................................... 40 
6.3.2 
PR3-ANCA Assay ................................................................................................ 40 
6.3.3 
AAV-Patient Reported Outcomes (AAV-PRO) ................................................. 40 
6.3.4 
VCRC WG/MPA Disease Activity and Transition Assessment ........................ 41 


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6.3.5 
Biomarker assessments ......................................................................................... 41 
6.3.6 
Vital Signs ............................................................................................................. 41 
6.3.7 
Clinical Laboratory Tests and Parameters ........................................................... 41 
6.3.8 
Electrocardiograms (ECG) ................................................................................... 43 
6.3.9 
Adverse Events ..................................................................................................... 43 
6.3.9.1 
Definition of Adverse Events .................................................................... 43 
6.3.9.2 
Unexpected Adverse Drug Experience ..................................................... 45 
6.3.9.3 
Eliciting Adverse Events ........................................................................... 45 
6.3.9.4 
Specific Instructions for Recording Adverse Events ............................... 45 
6.3.9.5 
Definition of Serious Adverse Events ....................................................... 48 
6.3.9.6 
Initial notification of an SAE ..................................................................... 48 
6.3.9.7 
Other Safety Findings Requiring Expedited Reporting ........................... 50 
6.3.9.8 
Pregnancy ................................................................................................... 50 
6.3.9.9 
AEs of Special Interest (AESIs) ................................................................ 50 
6.3.9.11 
Follow-up of AEs ....................................................................................... 52 
6.3.9.12 
Follow-up of Post-Treatment SAEs .......................................................... 53 
6.3.9.13 
Other Special Situations Reports ............................................................... 53 
6.3.9.14 
Product Complaints .................................................................................... 53 
6.3.9.15 
Exchange of Single Case Reports with Genentech .................................. 54 
6.3.10 
Concomitant Medication Assessments ................................................................ 60 
6.3.11 
Glucocorticoid Toxicity Index (GTI)................................................................... 60 
6.3.12 
Vasculitis Damage Index (VDI) .......................................................................... 60 
6.4 
Removal of Patients from the Trial or Study Drug ........................................................ 61 
6.4.1 
Patient Withdrawal ............................................................................................... 61 
6.4.2 
Other Special Situations Reports ......................................................................... 61 
6.4.3 
Patient Lost to Follow-up ..................................................................................... 61 
6.5 
Early Termination of the Trial ........................................................................................ 61 
6.6 
Dispensing Study Drug ................................................................................................... 62 
7 
STUDY ACTIVITIES ............................................................................................................... 62 
7.1 
Screening Visit V1 (Up to 14 days Before Day of Randomization) ............................. 63 
7.2 
Remission Induction Period (Day 0 to Month 6) ........................................................... 63 
7.2.1 
Pre-Treatment of Methylprednisolone ................................................................. 63 
7.2.2 
Visit 2 (Day 0) Procedures ................................................................................... 64 
7.2.3 
Visit 3 (Day 14 ± 2 days) Procedures .................................................................. 64 
7.2.4 
Visit 4 (1 month after the first infusion) Procedures ........................................... 64 
7.2.5 
Visit 5 (2 months after the first infusion) Procedures ......................................... 65 
7.2.6 
Visit 6 (Month 4) Procedures ............................................................................... 65 
7.2.7 
Visit 7 (Month 6) Procedures ............................................................................... 65 
7.3 
Maintenance Period ......................................................................................................... 66 
7.3.1 
Visits 8, 9 and 10 (Months 9, 12, and 15) Procedures ........................................ 66 


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7.3.2 
Visits 11 (Month 18) Procedures ......................................................................... 66 
7.3.3 
Visit 99 (Unscheduled Visit) Procedures ............................................................ 67 
7.4 
Early Termination Procedures ........................................................................................ 67 
7.5 
Study Activities for Treatment Failure Patients ............................................................. 68 
8 
QUALITY CONTROL AND ASSURANCE ......................................................................... 68 
9 
PLANNED STATISTICAL METHODS ................................................................................. 69 
9.1 
General Considerations ................................................................................................... 69 
9.2 
Determination of Sample Size ........................................................................................ 69 
9.3 
Analysis Populations ....................................................................................................... 69 
9.3.1 
Intention-to-treat Analysis Set:............................................................................. 69 
9.3.2 
Modified Intention-to-Treat Analysis Set ............................................................ 70 
9.3.3 
Safety Analysis Set ............................................................................................... 70 
9.4 
Demographics and Baseline Characteristics .................................................................. 70 
9.5 
Primary Efficacy Endpoint .............................................................................................. 70 
9.6 
Primary Safety Endpoints ................................................................................................ 71 
9.7 
Secondary Endpoints ....................................................................................................... 72 
9.8 
Other Assessments or Analyses ...................................................................................... 72 
9.9 
Interim Analysis ............................................................................................................... 73 
10 
ADMINISTRATIVE CONSIDERATIONS ............................................................................ 73 
10.1 
Investigators and Study Administrative Structure ......................................................... 73 
10.2 
Institutional Review Board (IRB) Approval .................................................................. 74 
10.3 
Ethical Conduct of the Study .......................................................................................... 74 
10.4 
Patient Information and Consent..................................................................................... 75 
10.5 
Patient Confidentiality and Disclosure of Data .............................................................. 75 
10.6 
Study Monitoring ............................................................................................................. 76 
10.7 
Data Handling and Record Keeping ............................................................................... 76 
10.7.1 
Confidentially ........................................................................................................ 76 
10.7.2 
Source Documents ................................................................................................ 76 
10.7.3 
Case Report Forms ............................................................................................... 77 
10.7.4 
Data Management ................................................................................................. 77 
10.7.5 
Data Processing ..................................................................................................... 77 
10.7.6 
Data Security and Confidentiality ........................................................................ 77 
10.7.7 
Data Quality Assurance/Data Clarification Process ............................................ 78 
10.7.8 
Data Clarification Process .................................................................................... 78 
10.8 
Retention and Availability of Records............................................................................ 78 
10.9 
Independent Data Safety Monitoring Board (DSMB) ................................................... 78 
10.10 Protocol Violations/Deviations ....................................................................................... 79 
10.11 Access to Source Documentation ................................................................................... 79 


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10.12 Retention of Data ............................................................................................................. 79 
10.13 Financial Disclosure ........................................................................................................ 80 
10.14 Audits and Inspections .................................................................................................... 80 
11 
REFERENCE LIST ................................................................................................................... 81 
 
LIST OF TABLES 
Table 1 Glucocorticoid Tapering Schedule ................................................................................. 36 
Table 2 Prednisone Equivalents ................................................................................................... 36 
Table 3 Examples of Biologic DMARDs ................................................................................... 37 
Table 4 List of Laboratory Tests .................................................................................................. 41 
Table 5 Study Visit Schedule ....................................................................................................... 62 
Table 6 Laboratory Sample Handling ......................................................................................... 88 
LIST OF FIGURES 
Figure -1 PRRR Study Design ..................................................................................................... 23 
Figure 2 (Jones et al. Arthritis & Rheumatism Vol. 60, No. 7, July 2009, pp 2156–2168) ...... 26 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events ..................................................................................... 83 
Appendix 2 
Schedule of Laboratory Testing ................................................................ 85 
Appendix 3 
Chapel Hill Consensus Conference ........................................................... 89 
Appendix 4 
CKD-EPI Creatinine Equation .................................................................. 91 
Appendix 5 
BVAS/WG ................................................................................................. 92 
Appendix 6 
AV-PRO Assessment ................................................................................ 95 
Appendix 7 
VCRC WG/MPA Disease Activity and Transition Assessment ............. 98 
Appendix 8 
Vasculitis Damage Index ........................................................................... 99 
Appendix 9 
Glucocorticoid Toxicity Index 2.0 ............................................................ 99 
Appendix 10 
Clinical Trial Management Systems (CTMS) ........................................ 110 
Appendix 11 
Principal Investigator Signatures ............................................................. 110 
Appendix 12 
Clinical Investigator’s Signature ............................................................. 112 
 
 
 


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SYNOPSIS 
Sponsor: 
Ulrich Specks, MD  
Name of Target Finished Product: 
Obinutuzumab for infusion 
Name of Target Active Ingredient: 
Obinutuzumab 
Study Title: 
A Randomized, Double-Blind, Active Comparator-Controlled Study to Evaluate the Effect 
of Obinutuzumab versus Rituximab in PR3-Patients with Anti-Neutrophil Cytoplasmic 
Antibody (ANCA)-Associated Vasculitis  
Brief Title: 
PR3-AAV Resilient Remission (PRRR) 
Study Number:  21-012197 
Primary Objective(s):  
The primary objective of this study is to determine the proportion of patients achieving both 
complete remission and seronegativity for ANCA at 6 months.  Complete remission is 
defined as a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis 
(BVAS/WG) of 0 without glucocorticoids beyond the prescribed prednisone taper. 
Seronegativity for ANCA is defined as a negative test for antibodies directed against serine 
proteinase 3 (i.e., a negative PR3-ANCA assay). 
 
Secondary Objectives: 
The secondary objectives of this study are:  
• To compare the proportion of subjects who achieve sustained complete remission at 
month 6 after administration of obinutuzumab or rituximab.  Complete remission is 
defined as BVAS/WG = 0 without glucocorticoids. 
• To compare the proportion of subjects who achieve sustained complete remission at 
month 12 after administration of obinutuzumab or rituximab. 
• To compare the proportion of subjects who achieve sustained complete remission at 
month 18 after administration of obinutuzumab or rituximab. 
• To compare the time to treatment failure through month 18 by administration of 
obinutuzumab or rituximab; Patients will be considered treatment failures if the 
glucocorticoid dose has to be increased at any point during the 18-month study period 
because of a disease relapse.  Disease relapse is defined as an increase in the 
BVAS/WG of ≥ 1 point accompanied by a decision on the part of the investigator 
to increase treatment for PR3-AAV 
 
Follow-up in the trial will continue until all patients have been followed for 18 months.  


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Exploratory Objectives: 
The exploratory objectives are to compare between the two treatment groups for following 
outcomes: 
• The number of disease relapses as defined as an increase in the BVAS/WG of ≥1 
point accompanied by a decision on the part of the investigator to increase treatment 
for PR3-AAV.  
• The Glucocorticoid Toxicity Index (GTI) scores (Cumulative Worsening Score and 
Aggregate Improvement Score) over time; 
• The cumulative glucocorticoid dose; 
• The number of severe relapses.  Severe relapse is defined as at least one major 
BVAS/WG item or a BVAS/WG ≥3 and the investigator deems standard 
treatment for severe disease is necessary. 
• The changes from baseline in Vasculitis Damage Index (VDI) over time; 
• The time to clinical remission; 
• The changes in estimated glomerular filtration rate (eGFR); 
• The proportion of patients achieving and maintaining complete peripheral blood B 
cell depletion (CD19+) at each study visit using high-sensitivity flow cytometry 
(HSFC); 
• The kinetics of ANCA: 
- 
Time to negative testing for ANCA  
- 
Time to recurrence of a positive test for ANCA (after negative testing); 
• The kinetic of recurrence of PR3-specific (autoantigen-specific) B cells after B cell 
depletion 
• The changes from baseline on AAV patient reported outcome (AAV-PRO) 
assessment over time 
• Vasculitis Clinical Research Consortium (VCRC) Granulomatosis with polyangiitis/ 
microscopic polyangiitis (WG/MPA) disease activity and transition assessment over 
time 
 
 
Study Design: 
This is a double-blind, randomized, active controlled multi-center phase 2 study to evaluate 
the efficacy and safety of obinutuzumab for the treatment of PR3-AAV. The study will 
enroll 30 patients who have clinical diagnoses of either granulomatosis with polyangiitis or 
microscopic polyangiitis. All patients enrolled must have positive serum assays for PR3-
ANCA, manifestations of severe disease. Severe disease is defined as at least one major 
BVAS/WG item or a BVAS/WG ≥3 and the investigator deems standard treatment 
for severe disease is necessary. 
Patients who are positive for serum assays for ANCA directed against myeloperoxidase 
(MPO-ANCA) will be excluded. 


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Eligible patients will be randomly assigned in a 1:1 ratio to receive two intravenous doses of 
either rituximab or obinutuzumab (both drugs dosed at 1000 mg per infusion). Infusions will 
be given approximately two weeks apart, on day 0 and on day 14.   
All randomized patients will be prescribed a specified glucocorticoid regimen, to include:   
• One to three intravenous pulses of methylprednisolone (1000 mg each) starting on 
or within 10 calendar days of study day 0. Decision on number of pulses of 
methylprednisolone per investigator. 
• The intravenous methylprednisolone will be followed by oral prednisone at a dose 
of 60 mg per day. The glucocorticoid dose will be tapered so that by week 2 of 
glucocorticoid treatment taper, the patients will take 30 to 40 mg/day prednisone 
equivalent.  All patients who have a remission without disease flares will be off 
glucocorticoids completely by week 16. Patients will complete clinic visits at 
months 1, 2, 4, and 6 after the first infusion of study drug has been administered. 
Patients who have received intravenous methylprednisolone and/or have started their oral 
glucocorticoid treatment as a part of standard of care will not repeat this therapy as a part of 
protocol requirements. Once patients are enrolled, they will continue oral glucocorticoid 
therapy according to the protocol specified tapering schedule.  
Patients who achieve clinical remission will enter the maintenance phase and be evaluated 
every 3 months after the 6-month primary outcome assessment for a total of 18 months 
from the first dose. 
Patients will be considered treatment failures if the glucocorticoid dose has to be increased 
either during the prednisone taper or after remission because of a disease relapse or if any 
other treatment for ANCA-associated vasculitis is prescribed to treat a disease relapse. The 
patients who experienced treatment failure with detectable B cells (≥5 cells/μl) will be 
offered open-label obinutuzumab accompanied by one to three intravenous 
methylprednisolone pulses (1000 mg each) starting on or within 10 calendar days of 
obinutuzumab followed by oral glucocorticoid dosing at the discretion of the investigator 
(but not to exceed the original specified glucocorticoid tapering regimen) to control the 
disease. Patients who experience a treatment failure and B cells are still depleted should be 
treated according to best medical judgment. Patients who respond to the re-treatment and 
achieve clinical remission will enter the maintenance phase and be evaluated every 3 
months until the study completes. Any patient who experiences treatment failure should 
continue with study follow-up visits per the schedule of assessments through the end of 
study. 
The study is completed when all randomized patients have been followed up for 18 months 
or have withdrawn prematurely.  The study design is illustrated below. 


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Study Population:  
30 patients with newly diagnosed or recurring PR3-AAV are planned. Each patient must 
meet the following criteria to be enrolled in this study. 
1. Fulfillment of the definitions of the Second Chapel Hill Consensus Conference for 
ANCA-associated vasculitis (either granulomatosis with polyangiitis or microscopic 
polyangiitis).  
2. Positivity for ANCA, directed against proteinase-3 (PR3). 
3. Severe newly-diagnosed disease or relapsing disease. 
4. Minimum BVAS/WG of 3 and the investigator deems standard treatment for severe 
disease is necessary. 
5. Relapsing patients must have B cells detectable in the peripheral blood. 
6. Patients must have completed the COVID-19 vaccination per current recommended 
CDC guidelines at least 4 weeks  prior to enrollment.  Patients who have recovered from 
COVID-19 prior to screening with a positive spike protein antibody test result but have 
not been vaccinated are also eligible. 
 
Test Product, Dose, and Mode of Administration:  
For patients assigned to the obinutuzumab arm: two infusions of obinutuzumab of 1000 mg 
each, administered 2 weeks apart  
For patients assigned to the rituximab arm: two infusions of rituximab of 1000 mg each, 
administered 2 weeks apart 
For patients who require re-treatment: two infusions of obinutuzumab of 1000 mg each, 
administered 2 weeks apart 
Duration of Treatment with rituximab or obinutuzumab:  
For all randomized patients: one course of  treatment (2 infusions) completed in < 3 weeks.  
For patients who require re-treatment: two courses of treatments, each course completed in 
< 3 weeks. 


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Efficacy Assessments: 
• BVAS/WG 
• PR3-ANCA assay 
 
Exploratory Assessments: 
• Mechanistic study comparing obinutuzumab and rituximab effects on changes in the 
peripheral blood cells by flow cytometry. The biomarker samples are intended to 
profile B cells and other relevant cell populations in patients with PR3-AAV before 
and after administration of obinutuzumab or rituximab. 
 
Safety Assessments: 
• Treatment-emergent adverse events 
• Electrocardiogram 
• Clinical laboratory testing 
• Glucocorticoids Toxicity Index 2.0 assessment 
• Vasculitis Damage Index assessment 
 
Statistical Methods:  
PRRR is an exploratory proof-of-concept study to evaluate the potential utility of 
obinutuzumab for the treatment of PR3-ANCA associated vasculitis.  The planned sample 
size of 30 patients in two equal size groups is not powered to test the hypothesis that 
obinutuzumab is superior to rituximab. No sensitivity analyses (e.g., to account for missing 
data) and no adjustment for multiple comparisons will be conducted. Nominal p-values will 
be used to examine any trends in the endpoint. 
The primary efficacy endpoint is defined as the proportion of patients achieving complete 
remission and ANCA negativity at month 6. Complete remission is defined as: 
• BVAS/WG of 0; and 
• No requirement for glucocorticoids beyond the prescribed 16-week prednisone 
taper.  
 
Patients must achieve a complete remission as defined above and be ANCA-negative at 
month 6 in order to meet the primary efficacy endpoint. 
The primary efficacy analysis is to compare the proportion of patients assigned to the 
obinutuzumab group who meet the primary efficacy endpoint criteria at month 6 to the 
proportion of patients assigned to the rituximab group who meet the primary efficacy 
endpoint criteria at month 6. Descriptive statistics (number and percent of subjects meet the 
primary efficacy endpoint criteria) will be reported by treatment group.  


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The following null (H0) and alternative (Ha) hypotheses will be tested using Fisher’s Exact 
test: 
H0: п obinutuzumab - п rituximab = 0 
Ha: п obinutuzumab - п rituximab ≠ 0 
п obinutuzumab: proportion of patients assigned to the obinutuzumab group who achieve 
complete remission and ANCA negativity at month 6 month 
п rituximab: proportion of patients assigned to the rituximab group who achieve complete 
remission and ANCA negativity at month 6 
Two-sided Newcombe-corrected 95% confidence intervals of the risk difference between 
treatments with respect to the primary efficacy endpoint success rate will also be presented.  
It is not expected that the null hypothesis will be rejected at a two-sided 0.05 level of 
significance given the proof-of-concept nature of the study and given the small sample size; 
trends seen between treatment groups in the primary endpoint rate will be used to define 
future studies. 
The above analyses on the primary efficacy endpoint success rate will be performed when 
all subjects have completed 6 months of follow-up (or would have completed 6 months of 
follow-up) had they not prematurely withdrawn. 
Safety data includes adverse events (AEs), vital signs, ECG results, and clinical lab results 
including serum chemistry, hematology, and urinalysis. 
The secondary endpoints are: 
• To compare the proportion of subjects who achieve sustained complete remission at 
months 6, 12, and 18 (BVAS/WG = 0 without glucocorticoids) by administration of 
obinutuzumab or rituximab. These comparisons will be carried out using Fisher’s 
Exact test. 
 
• To compare the time to treatment failure through month 18 by administration of 
obinutuzumab or rituximab; patients will be considered treatment failures if the 
glucocorticoid dose has to be increased because of a disease relapse either during the 
prednisone taper or after the remission is achieved.  A disease relapse is defined as 
an increase in the BVAS/WG of 1 point or more accompanied by a decision on the 
part of the investigator to increase treatment for PR3-AAV.  Time-to-treatment 
failure will be compared between treatments using the log-rank test; Kaplan-Meier 
plots of time to treatment failure through 18 months will be generated for each 
randomized treatment group; patients not experiencing treatment failure will be 
censored at last known follow-up for these analyses. 
 
The exploratory objectives are to be analyzed as comparison between the two treatment 
arms.  Descriptive statistics will be reported by treatment group. 


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The exploratory biomarker samples and results will be analyzed and reported separately. 
Study Conduct: 
The clinical trial will be conducted in compliance with regulations (21 CFR 312, 50, and 
56), guidelines for Good Clinical Practice (ICH Guidance E6), and in accordance with 
general ethical principles outlined in the Declaration of Helsinki; informed consent will be 
obtained from all participating patients; the protocol and any amendments will be subject to 
approval by the designated IRB prior to implementation, in accordance with 21 CFR 
56.103(a); and subject records will be stored in a secure location and subject confidentiality 
will be maintained. The investigator will be thoroughly familiar with the appropriate use of 
the study drug as described in the protocol and Investigator’s Brochure. Essential clinical 
documents will be maintained to demonstrate the validity of the study and the integrity of 
the data collected. Master files should be established at the beginning of the study, 
maintained for the duration of the study and retained according to the appropriate 
regulations. 
 
Date of Original Approved Protocol: Version  11JAN2021 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
AAV 
ANCA-associated vasculitides 
ADCC 
antibody-dependent cellular cytotoxicity 
AE 
adverse event 
ANCA 
antineutrophil cytoplasmic antibody 
BVAS/WG 
Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis  
CD20 
pan-B cell antigen 
CDC 
complement-dependent cytotoxicity 
CLL 
chronic lymphocytic leukemia 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMARDs 
disease-modifying antirheumatic drugs  
ECG 
electrocardiograms 
eGFR 
estimated glomerular filtration rate 
FL 
follicular lymphoma 
FSH 
follicle-stimulating hormone 
GBM 
glomerular basement membrane  
GClb 
obinutuzumab, in combination with chlorambucil  
GPA 
granulomatosis with polyangiitis 
GTI 
Glucocorticoids Toxicity Index 
HACA 
human anti-chimeric antibodies 
HSFC 
high-sensitivity flow cytometry 
ICH 
International Council for Harmonisation 
IRR 
infusion related reactions 
IWRS 
Interactive Web Response system  
MDRD 
Modification of Diet in Renal Disease  
MPA 
microscopic polyangiitis 
MPO 
myeloperoxidase 
PBMC 
peripheral blood mononuclear cells 
PML 
progressive multifocal leukoencephalopathy 
PR3 
proteinase 3 
RTX 
rituximab 
SAE 
serious adverse event 
SF-36 
Short-Form Health Survey  
SUSAR 
suspected unexpected serious adverse reaction 


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TB 
tuberculosis 
VDI 
Vasculitis Damage Index  
Definition of Terms 
Severe disease 
at least one major BVAS/WG item or a BVAS/WG score ≥ 3 and the 
investigator deems standard treatment for severe disease is necessary. 
Relapse 
An increase in the BVAS/WG of ≥ 1 point accompanied by a decision on the 
investigator to increase treatment for PR3-AAV. 
Severe relapse 
at least one major BVAS/WG item or a BVAS/WG score ≥3 and the 
investigator deems standard treatment for severe disease is necessary.  
Infusion 
related 
reactions (IRR) 
any AEs during infusion or within 24 hours of completing the infusion that 
are considered related to the investigational products by the investigator 
Complete 
remission 
complete remission is defined as BVAS/WG = 0 without glucocorticoids 
 
 
 
 


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1 
INTRODUCTION 
The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis or AAV are rare 
autoimmune diseases of unknown cause, characterized by inflammatory cell infiltration causing 
necrosis of blood vessels. The AAV comprise granulomatosis with polyangiitis (GPA) and 
microscopic polyangiitis (MPA). The two ANCA specificities relevant to systemic vasculitis are 
myeloperoxidase (MPO) and proteinase 3 (PR3). The prevalence of AAV is estimated to be 
between 46 and 184 cases per million. These diseases are slightly more common in men than in 
women and are also more common among individuals older than 60 years of age, but the AAV 
are known to occur in individuals of all ages (Kitching et al., 2020).  
Despite treatment advances over the past ten years, the AAV remain among the most aggressive 
forms of autoimmune disease. As discussed below, GPA is the form of AAV associated with the 
greatest unmet medical need. GPA, typically linked to the presence of anti-PR3-ANCA, can target 
virtually any organ but has particular predilections for the lungs, kidneys, peripheral nerves, eyes, 
and upper respiratory tract.  If not diagnosed promptly and treated aggressively, PR3-AAV 
consistently leads to organ failure (e.g., mechanical ventilation, renal replacement therapy, 
crippling neuromuscular dysfunction), other major organ dysfunction, and death (Kitching et al., 
2020; Yates and Watts, 2017).  
The current treatment options for induction of remission in AAV include high doses of 
glucocorticoids accompanied by either rituximab or cyclophosphamide. We have conducted a 
randomized, double-blind, double-dummy controlled trial known as the RAVE trial, in which 
rituximab dosed at 375 mg m-2 once a week for four infusions plus glucocorticoids was shown to 
be non-inferior to cyclophosphamide plus glucocorticoids. The RAVE trial involved 197 AAV 
patients. The rituximab regimen in RAVE was shown to be non-inferior to the cyclophosphamide 
regimen, with 64% of the subjects in the rituximab group (compared to 53% in the 
cyclophosphamide group) achieving the primary outcome of complete remission at 24 weeks 
(Stone et al, 2010; Specks et al, 2013).   
PR3-AAV is associated with high unmet medical need. Despite the overall success of 
rituximab in RAVE in comparison to the previous standard of care (cyclophosphamide), the 
subset of patients with PR3-AAV continues to experience major unmet need with regard to 
therapeutics.  Several pieces of data illustrate this point: 
• The RAVE trial showed that 29% of the PR3-AAV patients failed the primary outcome 
because of active disease, despite pulse methylprednisolone (1000 mg) times three doses, 
a prednisone taper of 5.5 months, and either rituximab or cyclophosphamide. 
• The PR3-AAV patient population is at the highest risk for relapse following successful 
remission induction, thus requiring frequent retreatment with glucocorticoids and other 
agents exposing patients to cumulative morbidity and organ damage from cumulative 
glucocorticoid exposure and disease activity.  The RAVE trial results confirmed this 
clearly: 
• All 10 early treatment failures were PR3-ANCA+  
• 11 of the 12 severe flares were PR3-ANCA+  
• 17 of the 25 limited flares were PR3-ANCA+  


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• Only 23 of 65 PR3-ANCA+ patients achieved the outcome of complete clinical and 
serological remission at 24 weeks.  
 
The achievement of ANCA negativity predicts long term disease control. In the RAVE trial only 1 
(non-severe/limited) relapse was recorded when ANCA was still undetectable after rituximab 
treatment (Specks et al., 2013); all other relapses occurred in patients who did not achieve ANCA-
negativity. Several other studies have confirmed that ANCA-negativity portends stable sustained 
clinical remission. A recent report from the UK showed that the PR3-ANCA-negative status after 
remission induction with rituximab is significantly associated with a longer time to relapse (PR3-
ANCA-negative status: hazards ratio, 0.08 [95% confidence interval, 0.01-0.63, p = 0.016] 
(McClure et al., 2019). Another study from the Netherlands reported that patients who achieved 
and maintained PR3-ANCA negativity after remission induction with rituximab (n = 29) had few 
relapses (3%), whereas persistent PR3-ANCA positivity (n = 49) and reappearance of PR3-
ANCA (n = 10) associated significantly with more relapses (37%, P = 0.002 and 50%, P = 0.002) 
(van Dam et al., 2020).  
Obinutuzumab (GAZYVA™, GAZYVARO™), a humanized, glycoengineered Type II anti-
CD20 monoclonal antibody (mAb), is directed to CD20, a membrane protein expressed on B 
lymphocytes. Obinutuzumab is licensed for use in oncology indications. Obinutuzumab, in 
combination with chlorambucil (GClb), has received regulatory approval for the treatment of 
previously untreated patients with chronic lymphocytic leukemia and for follicular lymphoma. 
The properties of obinutuzumab include increased direct cell death induction and reduced 
complement-dependent cytotoxicity (CDC) activity as compared to rituximab, a chimeric Type I 
CD20 antibody. Obinutuzumab is the product of glycoengineering that results in increased 
binding affinity for FcγRIII, which leads to significantly improved cellular cytotoxicity in in vitro 
antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis 
(ADCP)-based assays. In particular, the binding affinity of obinutuzumab to the low affinity 
FcγRIIIa (F158) is substantially increased, such that it exceeds that of rituximab for the high 
affinity FcγRIIIa (V158) receptor. As a result of improved direct cell death induction and 
ADCC/ADCP potency, obinutuzumab has the potential to deplete CD20+ B-cells, including 
tissue-resident CD20+ B-cells, to a greater degree than other anti-CD20 antibodies. The potency 
of obinutuzumab with regard to its ability to kill B-cells is approximately 100 times the potency of 
rituximab. This feature may lead to greater clinical efficacy (Gagez and Cartron et al, 2014). 
In ex vivo autologous whole blood B-cell depletion studies with blood from healthy volunteers as 
well as CLL patients, obinutuzumab mediates superior B-cell depletion. In line with these 
findings, obinutuzumab showed superior ex vivo B-cell depletion relative to rituximab in blood 
samples from autoimmune patients with rheumatoid arthritis or systemic lupus erythematosus. 
Obinutuzumab was at least twofold more efficient than rituximab at inducing B-cell cytotoxicity 
in in vitro whole blood assays. The data generated to date imply that obinutuzumab is 
representative of a novel class of therapeutic anti-CD20 antibodies that may have superior efficacy 
compared with classical Type I and non-ADCC enhanced CD20 antibodies. Based on these 
nonclinical data, it can be anticipated that the combination of the recognition of a Type II epitope 
together with improved ADCC and ADCP potency exclusive to obinutuzumab might translate 


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into superior clinical efficacy for the treatment of autoimmune diseases where B-cell depletion 
may be effective. Details of the clinical experience of obinutuzumab are available in the 
Investigator’s Brochure. 
Results of a randomized, placebo-controlled phase II trial in patients with lupus nephritis 
(NOBILITY, NCT02550652) showed that obinutuzumab was superior to placebo for the 
achievement of complete and overall renal responses at week 52 when added to mycophenolate 
and glucocorticoids and that improved renal responses with obinutuzumab compared to placebo 
continued through week 104. No increase in the incidence of serious adverse events, serious 
infections or death compared with placebo were observed in this study (Furie et al., 2022). 
A recent case report indicated that obinutuzumab was well tolerated, effectively depleted B-cells 
and induced remission in 3 patients with AAV in whom rituximab was contraindicated because of 
a previous anaphylactic reaction to rituximab (Amudala et al 2021).  These properties have led to 
the hypothesis that obinutuzumab has greater efficacy compared to rituximab for the treatment of 
certain immune-mediated conditions, and that obinutuzumab will achieve this greater efficacy 
through deeper and more sustained depletion of pathogenic B-cells in secondary lymphoid organs 
and tertiary lymphoid structures.   
This randomized, double-blind, active controlled study is designed to demonstrate that treating 
patients diagnosed with PR3-ANCA AAV with obinutuzumab may result with a sustained 
remission and proof the concept that a more complete B-cell depletion may predict a better 
clinical outcome. 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to determine the proportion of patients achieving both 
complete remission and seronegativity for ANCA at 6 months.  Complete remission is defined as 
a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis (BVAS/WG) of 0 without 
glucocorticoids beyond the prescribed prednisone taper. Seronegativity for ANCA is defined as a 
negative test for antibodies directed against serine proteinase 3 (i.e., a negative PR3-ANCA 
assay). 
2.2 
Secondary Objectives 
The secondary objectives of this study are:  
• To compare the proportion of subjects who achieve sustained complete remission at 
month 6 after administration of obinutuzumab or rituximab.  Complete remission is 
defined as BVAS/WG = 0 without glucocorticoids 
• To compare the proportion of subjects who achieve sustained complete remission at 
month 12 after administration of obinutuzumab or rituximab. 
• To compare the proportion of subjects who achieve sustained complete remission at 
month 18 after administration of obinutuzumab or rituximab. 


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• To compare the time to treatment failure through month 18 by administration of 
obinutuzumab or rituximab; Patients will be considered treatment failures if the 
glucocorticoid dose has to be increased at any point during the 18-month study period 
because of a disease relapse.  Disease relapse is defined as an increase in the 
BVAS/WG of ≥ 1 point accompanied by a decision on the part of the investigator to 
increase treatment for PR3-AAV 
• Time to treatment failure. Treatment failure is defined as the event when the 
glucocorticoid dose has to be increased at any point during the 18-month study 
period because of a disease relapse.  
 
Follow-up in the trial will continue until all patients have been followed for 18 months. 
 
2.3 
Exploratory Objectives 
The exploratory objectives are to compare between the two treatment groups for following 
outcomes: 
• The number of disease relapses as defined in section 2.2.  
• The Glucocorticoid Toxicity Index (GTI) scores (Cumulative Worsening Score and 
Aggregate Improvement Score) over time; 
• The cumulative glucocorticoid dose administered orally; 
• The cumulative glucocorticoid dose administered via intravenous or oral route; 
• The number of severe relapses.  Severe relapse is defined as the occurrence of life- or 
organ-threatening disease manifestation(s); marked by an increase in the major 
BVAS/WG items of ≥ 3 at months 6, 12, 18 and the investigator deems standard 
treatment for severe disease is necessary.  
• The changes from baseline in Vasculitis Damage Index (VDI) over time; 
• The time to clinical remission; 
• The changes in estimated glomerular filtration rate (eGFR) based on CKD-Epi equation 
without correcting for race; 
• The proportion of patients achieving and maintaining complete peripheral blood B cell 
depletion (CD19+) at each study visit by high sensitive flow cytometry (HSFC) 
o Proportion of patients achieving B-cell depletion (HSFC) at specified timepoints. 
o Proportion of patients with sustained B-cell depletion (HSFC) over time. 
• The kinetics of ANCA: 
• Time to negative testing for ANCA  
• Time to recurrence of a positive test for ANCA (after negative testing); 
• The kinetic of recurrence of PR3-specific (autoantigen-specific) B cells after B cell 
depletion 
• The changes from baseline on AAV patient reported outcome (AAV-PRO) assessment 
over time 
• Vasculitis Clinical Research Consortium (VCRC) Granulomatosis with polyangiitis/ 
microscopic polyangiitis (WG/MPA) disease activity and transition assessment over time 
 


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2.4 
Safety Objectives 
To determine the safety profile of patients administered obinutuzumab by assessing: 
• Treatment emergent adverse events 
• Treatment emergent serious adverse events 
• Laboratory testing 
• Glucocorticoid use related toxicity using Glucocorticoids Toxicity Index (GTI) 2.0 
• Treatment emergent adverse events of special interest including: 
o Infusion related reactions (IRR) 
o Grade 3 or higher infections 
o Hepatitis B reactivation 
o Progressive multifocal leukoencephalopathy (PML) 
o Drug-related neutropenia 
o Drug-related thrombocytopenia 
o Gastrointestinal perforations 
o Worsening of pre-existing cardiac conditions. 
 
 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a double-blind, randomized, active controlled multi-center phase 2 study to evaluate the 
efficacy and safety of obinutuzumab for the treatment of PR3-AAV. The study will enroll 
approximately 30 patients who have clinical diagnoses of either granulomatosis with polyangiitis 
or microscopic polyangiitis. All patients enrolled must have positive serum assays for PR3-
ANCA, manifestations of severe disease, and a BVAS/WG of ≥ 3 (Thompson et al., 2020). 
Severe disease is defined as at least one major BVAS/WG item or a BVAS/WG>= 3 and the 
need for standard therapy for severe disease as per investigator. Patients who are positive for 
serum assays for ANCA directed against myeloperoxidase (MPO-ANCA) will be excluded. 
3.1.1 
Remission Induction Period 
Eligible patients will be randomly assigned in a 1:1 ratio to receive two doses of either rituximab 
or obinutuzumab (both drugs dosed at 1000 mg per infusion). Infusions will be given 
approximately two weeks apart, on day 0 and day 14.  All randomized patients will be prescribed 
a specified glucocorticoid regimen.  The glucocorticoid regimen will include one to three pulses of 
methylprednisolone (1000 mg each) starting on or within 10 calendar days of study day 0 
followed by prednisone at a dose of 60 mg per day. The glucocorticoid dose will be tapered so that 
by week 2 of glucocorticoid treatment taper, the patients will take no more than 40 mg/day 
prednisone equivalent.  All patients who have a remission without disease flares will be off 
glucocorticoids completely in 16 weeks. Patients will complete clinic visits at months 1, 2, 4 and 6 
after the first infusion has been administered.  
3.1.2 
Maintenance Phase 
Patients who respond to treatment and achieve clinical remission will enter the maintenance phase 
and be evaluated every 3 months after the 6-month primary outcome assessment for a total of 18 
months from the first dose. Patients will be considered treatment failures if the glucocorticoid dose 
has to be increased either during the prednisone taper or after remission because of a disease 
relapse or if any other treatment for ANCA-associated vasculitis is prescribed to treat a disease 
relapse. The patients who experienced treatment failure with detectable B cells (≥5 cells/μl) will 
be offered open-label obinutuzumab accompanied by one to three intravenous methylprednisolone 
pulses (1000 mg each) starting on or within 10 calendar days of obinutuzumab followed by oral 
glucocorticoid dosing at the discretion of the investigator (but not to exceed the original specified 
glucocorticoid tapering regimen) to control the disease. Patients who experience a treatment 
failure and B cells are still depleted should be treated according to best medical judgment. Patients 
who respond to the re-treatment and achieve clinical remission will enter the maintenance phase 
and be evaluated every 3 months until the entire study completes. Any patient who experiences 
treatment failure should continue with study follow-up visits per the schedule of assessments 
through the end of study. 
All patients will be followed until they will have completed 18 months of follow-up or withdraw 
from the study prematurely.   


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The specific visit schedule is presented in Section 7, Table 5. The study design is illustrated in 
Figure 1. 
 
 
3.1.3 
Endpoint Analysis 
The primary endpoint of comparing the proportion of patients who achieve complete remission 
and ANCA negativity will be conducted after all patients have completed the 6-month remission 
induction period.  The data pertinent to the primary efficacy analysis will be source verified, 
locked and transferred to an independent statistician to perform the limited analysis.  The 
statistical analysis plan will be developed and finalized prior to the analysis. This will be the only 
analysis to be conducted for the specified endpoint and the summary results without individual 
patient information will be available to a limited number of recipients.  The investigators will 
continue to be blinded to the patient treatment assignment throughout the remainder of the follow-
up period.   
The 6-month analysis will be treated as an interim analysis with regard to the blinding and data 
handling.  Since the treatment regimen will be completed after the second study drug infusion and 
the primary efficacy analysis is conducted once at the 6-month time point, no multiplicity 
adjustment will be used for the analysis.  
3.2 
Known and Potential Risks and Benefits to Participants 
3.2.1 
Risks Associated with Rituximab 
No dose-limiting adverse effects were observed in phase I–III trials that evaluated the safety and 
efficacy of rituximab in participants with lymphoma. The most commonly observed infusion-
Figure -1 PRRR Study Design 


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related adverse effects were chills or rigors, fever, fatigue, headache, hypotension, nausea, 
leukopenia, angioedema, and pruritus.  Fever, chills, headache, nausea, vomiting, rhinitis, and 
mild hypotension occurred primarily during rituximab infusions; these adverse events typically 
responded to interrupting and then resuming the infusion at a slower rate.  Infusion reactions were 
seen in 1 (1%) patient with AAV who was treated with rituximab in the RAVE study (Stone et al., 
2010). Details of the risks associated with rituximab treatment are described in rituximab 
prescribing information. Management of IRRs follows routine clinical protocols consistent with 
the prescribing information and the approved use of rituximab and obinutuzumab for other 
indications.  
3.2.2 
Risks Associated with Obinutuzumab 
Risks associated with obinutuzumab treatment are described in the obinutuzumab Investigator’s 
brochure Section 6.3. The most frequently observed adverse drug reactions in patients receiving 
obinutuzumab were infusion related reactions (IRRs) which occurred predominantly during 
infusion of the first 1000 mg. A decreased incidence of IRRs was observed after prevention of 
IRRs including adequate glucocorticoid, oral analgesic/anti-histamine, omission of 
antihypertensive medication was 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.  Management of IRRs follows 
routine clinical protocols consistent with the prescribing information and the approved use of 
rituximab and obinutuzumab for other indications. 
In the majority of patients, irrespective of indication, 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). The rates of Grade 3-4 
IRRs were similar before and after mitigation measures were implemented. 
3.2.3 
Data and Safety Monitoring Board (DSMB) 
An independent DSMB will include 2 to 3 physicians who are rheumatologists or experts in a 
related field and a statistician.  It is the DSMB’s responsibility to weigh risks and benefits 
throughout the study’s duration. Specifically, this role includes: monitoring evidence for treatment 
harm such as toxicity, adverse events, serious adverse events or deaths. The sponsor medical team 
will prepare the safety summary and participate in the safety review discussion. 
The DSMB will convene for safety data review meetings after 10 patients have been treated and 
completed the 1-month visit (V4) and once every 6 months until the study completion. Records 
for adverse events, laboratory values, vital signs and disease status will be reviewed. The DSMB 
may recommend the study protocol be modified if major safety concerns occur.  


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3.3 
Rationale for Study Design and Control Group 
3.3.1 
Rationale for the Study Design 
Rituximab has been shown to be non-inferior to cyclophosphamide for patients with AAV in a 
randomized controlled trial Rituximab in ANCA-Associated Vasculitis (RAVE) trial (Stone et al., 
2010). In the RAVE trial, 64% of the subjects in the rituximab group, compared to 53% in the 
cyclophosphamide group, achieving the primary outcome of complete remission at 24 weeks.  In a 
subgroup analysis, rituximab treatment was superior to cyclophosphamide in PR3-ANCA positive 
patients, and this difference was statistically significant.   
The subset of patients with PR3-AAV, which comprises approximately two thirds of patients 
evaluated in Western countries, represents the greatest unmet need in AAV. Results from the 
RAVE trial indicated that PR3-AAV patients had a higher rate of treatment failures and a higher 
percentage of severe relapses following successful remission induction, thus requiring frequent 
retreatment with glucocorticoids and other agents exposing patients to cumulative morbidity and 
organ damage from cumulative glucocorticoid exposure and disease activity.  It is hypothesized 
that obinutuzumab may be superior to rituximab for the treatment of PR3-positive AAV patients 
based on the improved B-cell elimination potency and longer duration of B-cell depletion than 
that of rituximab. 
This study is a randomized, double-blind, active-controlled trial to explore how obinutuzumab 
compares to rituximab for remission induction of PR3-AAV. The trial will also test the hypothesis 
that obinutuzumab treatment at baseline is associated with a longer time to relapse compared with 
rituximab treatment. 
3.3.2 
Rationale for the Dose Selection 
In the RAVE protocol, rituximab therapy comprised 4 doses of rituximab 375 mg/m2 per week in 
conjunction with glucocorticoids starting dose of 1 mg/kg/day and tapering to glucocorticoids free 
by month 5. This regimen has been modified to include two infusions of 1000 mg per dose 2 
weeks apart on day 0 and day 14. The induction and follow up rituximab dose is planned as 1000 
mg infusions. The rituximab regimen is selected based on the study by Jones et al. demonstrating 
that patients administered with 4 infusions of 375 mg/m2 or 2 infusions of 1000 mg two weeks 
apart had comparable B cell depletion and similar rates of remission as a function of time in 
patients with refractory AAV (shown in Figure 2 below) (Jones et al., 2009).  In addition, a recent 
study of comparison of two rituximab regimens for remission induction in ANCA-associated 
vasculitis showed a similar treatment effect whether rituximab was administered for 2 or 4 
infusions. (Renard V. Abstract 2048 at American College of Rheumatology, November 2020). 


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Reducing the requirement for clinical visits without compromising the effectiveness of the 
treatment likely results in better treatment compliance.  
 
3.3.3 
Rationale for the 16-Week Glucocorticoid Tapering Schedule 
A glucocorticoid tapering regimen that gradually reduces the prednisone dose from 60 mg per day 
on week 1 to 5 mg per day on week 13 to completely discontinues prednisone use by the end of 
week 16 is specified (section 5.6.2, ). A multicenter survey of rituximab therapy for refractory of 
ANCA+ AAV patients demonstrated that the glucocorticoid taper of 4 months compared to the 
5.5 months employed in the RAVE trial would not subject the patients to undue risk and will 
reduce the overall glucocorticoid use (Jones et al., 2009). The duration of the glucocorticoid taper 
will be extended to 16 weeks to maintain the goal of reducing the overall steroid use while 
approximating the standard 4 to 6 months of glucocorticoids tapering schedule. The tapering 
schedule would be consistent with the 2009 European League Against Rheumatism (EULAR) 
recommendations for AAV to be between 7.5 mg and 10 mg of prednisolone after 3 months of 
treatment. 
The investigator may increase the glucocorticoid dose if clinically indicated.  
3.3.4 
Selection of the Primary and the Key Secondary Endpoints 
Patients diagnosed with PR3-AAV represent the greatest unmet need in AAV.  The achievement 
of ANCA negativity following treatment is associated with long-term disease control, even though 
“cure” for PR3-AAV remains elusive. The achievement of sustained complete remission reduces 
patients’ risk from the combined threats of active AAV and complications of treatment, 
particularly glucocorticoids. (McClure et al., 2019; Specks et al., 2013; van Dam et al., 2020). 
3.4 
Study Duration and Dates 
The remission induction period of the study includes up to 14 days of screening and 6 months of 
monitoring.  The study maintenance period is 1 year after the 6-month induction period.  The total 
duration of the study is approximately 18.5 months for each patient. 
Figure 2 (Jones et al. Arthritis & Rheumatism Vol. 60, No. 7, July 2009, pp 2156–2168) 


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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
Thirty (30) patients with severe newly-diagnosed or recurring PR3-AAV are planned.   
4.2 
Inclusion Criteria 
Each patient must meet the following criteria to be enrolled in this study. 
1. Subjects aged 18 or greater. 
2. Fulfillment of the definitions of the Second Chapel Hill Consensus Conference for ANCA-
associated vasculitis (either granulomatosis with polyangiitis or microscopic polyangiitis).  
3. Positivity for ANCA, directed against proteinase-3 (PR3). 
4. Severe newly-diagnosed disease or severe relapsing disease.  Severe relapsing disease is 
defined as at least one major BVAS/WG item or a score ≥ 3 and the investigator deems 
standard treatment for severe disease is necessary.  
5. Minimum BVAS/WG of 3.  
6. Relapsing patients must have B cells detectable in the peripheral blood. 
7. Patients must have completed COVID-19 vaccination (per current recommended CDC 
guidelines) at least 4 weeks prior to enrollment. Patients who have recovered from COVID-19 
prior to screening with a positive spike protein antibody test result but have not been 
vaccinated are also eligible. 
8. Female subjects of childbearing potential who are not sterile must agree to use an acceptable 
method of contraception for 18 months after the last dose of infusion medication.  Male 
subjects who are not sterile whose female partners are of childbearing potential must agree to 
use an acceptable method of contraception for 180 days after the last dose of infusion 
medication.  
• Females of childbearing potential include any female who has not undergone 
successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or is not postmenopausal (to be considered postmenopausal, the 
patient must have had amenorrhea for >12 consecutive months).   
• Acceptable methods of contraception include the use of at least two of the following: 
1) intrauterine device; 2) hormonal contraceptives for at least 30 days prior to first 
dose infusion (oral, injectable, implant or ring); 3) barrier contraceptives (condom or 
diaphragm) with spermicide; or 4) abstinence. 
 
 
4.3 
Exclusion Criteria 
Patients who present any of the following criteria will be excluded from the study. 
1. Diagnosis with eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss 
syndrome) as defined by the Chapel Hill Consensus Conference.  
2. Positive serum assays for ANCA directed against myeloperoxidase (MPO-ANCA) 
3. Non-severe AAV, defined as disease that does not justify treatment with both B cell depletion 
and a four-month glucocorticoid taper. 


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4. Any of the co-morbidities: 
- 
Allergies: a history of severe allergic reactions to human or chimeric monoclonal antibodies 
or murine protein. 
- 
Infection (systemic): an active systemic infection at screening visit. 
- 
Infection (deep space): have been diagnosed as having a deep-space infection, such as 
osteomyelitis, septic arthritis, or pneumonia complicated by empyema or lung abscesses, 
within 6 months prior to the screening visit. 
- 
Infection (blood borne): active hepatitis B or active hepatitis C or a documented history of 
HIV, hepatitis B, or hepatitis C. 
- 
Infection (history): History of recurrent significant infection or history of recurrent bacterial 
infections 
- 
Liver disease: acute or chronic liver disease that is deemed sufficiently severe to impair 
their ability to participate in the trial.  
- 
Renal disease: a history of documented anti-glomerular basement membrane disease (anti-
GBM disease). 
- 
Malignancy: Active or history of malignancy in the last 5 years. Individuals with squamous 
cell orbasal cell skin carcinomas and individuals with cervical or ductal carcinoma in situ 
may be enrolled if they have received curative surgical treatment. 
- 
Active COVID-19 infection. 
- 
Uncontrolled disease: evidence of glucocorticoid dependent disease (such as asthma, 
COPD, psoriasis or IBD, etc.) requiring consistently greater than 10 mg of prednisone for 
disease control which might affect endpoint assessment or,  
- 
Other uncontrolled diseases, including any uncontrolled psychiatric disorders, drug and 
alcohol abuse, that could interfere with participation in the trial according to the protocol. 
5. Known diagnosis of human anti-chimeric antibodies (HACA) formation.    
6.  Subjects who are premenopausal and are: 
- 
Pregnant on the basis of a serum pregnancy test, 
- 
Breastfeeding, or 
- 
Do not agree to use effective method(s) of contraception. 
7. Use of prohibited medications: They have used any of the prohibited medication listed in 
Section 5.7.1. 
8. Plasma exchange: They have been treated with plasma exchange within the 3 months 
preceding the screening visit. 
9. History of intolerance to rituximab or other chimeric monoclonal antibodies (e.g., infliximab). 
10. Recent vaccination: They have had a live vaccine fewer than 4 weeks (28 days) before or 
during randomization (vaccination with live vaccine through the end of study participation is 
contraindicated). 
11. Daily use of non-steroidal anti-inflammatory drugs (NSAIDs)  
12. Exclusion criteria related to laboratory parameters: 
a. Bone marrow suppression as evidenced by a total white count < 4 x10 /l, hemoglobin < 7 
gm/dl or platelet count < 100,000/μl 


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b. Aspartate aminotransferase or alanine aminotransferase or amylase > 2.5 times the upper 
limit of normal, unless attributed to vasculitis 
 
5 
STUDY TREATMENTS 
5.1 
Description of Treatments 
5.1.1 
Obinutuzumab 
Obinutuzumab is a humanized and glycoengineered Type II anti-CD20 mAb of the IgG1 subclass. 
The molecular mass of the antibody is approximately 150 kDa. Obinutuzumab is provided as a 
single 1000 mg dose in a 50 mL glass vials containing 40 mL of 25 mg/mL liquid concentrate. In 
addition to the antibody, the liquid also contains histidine/histidine-HCl, trehalose, poloxamer 188 
and water. 
Obinutuzumab dosing solution will be prepared within 24 hours of scheduled dosing at 2°C to 
8°C (36°F to 46°F) by diluting 40 mL (1000 mg) of obinutuzumab into a 250 mL 0.9% sodium 
chloride infusion bag. 
5.1.2 
Rituximab 
Rituximab (RITUXAN) injection is a sterile, preservative-free, clear, colorless solution for 
intravenous infusion supplied as one 500 mg/50 mL (10 mg/mL) single-dose vial NDC 50242-
053-06. Rituximab dosing solution will be prepared within 24 hours of scheduled dosing at 2°C to 
8°C (36°F to 46°F) by diluting 1000 mg of rituximab into a 250 mL 0.9% sodium chloride 
infusion bag. 
5.1.3 
Infusion Solution 
Obinutuzumab or rituximab does not contain antimicrobial preservatives. Therefore, care must be 
taken to ensure that the solution for infusion is not microbiologically compromised during 
preparation. If not used immediately, the prepared solution may be stored up to 24 hours at 2-8°C. 
The infusion must be completed within 48 hours at room temperature (≤ 30°C/86°F) after the final 
dosing solution is prepared.  No incompatibilities between obinutuzumab or rituximab and 
polyvinyl chloride or polyolefin infusion materials have been observed in concentration ranges 
from 0.4 mg/mL to 20.0 mg/mL after dilution. 
5.2 
Treatments Administered 
5.2.1 
Pre-Medication 
Prior to start infusion, premedication with antihistamine (diphenhydramine 50mg) will be 
prescribed to reduce the potential infusion reactions.  All patients will be prescribed with 650 mg 
to 1000 mg acetaminophen approximately 30 minutes before study drug infusion starts. 


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5.2.2 
Obinutuzumab or Rituximab 
Obinutuzumab or rituximab is administered via intravenous infusion at 1000 mg per dose. Patients 
will receive two doses of obinutuzumab or rituximab administered on day 0 and on day 14 (+/- 2 
days). 
First infusion: Administer at 50 mg/hr. The rate of the infusion can be escalated in 50 mg/hr 
increments every 30 minutes to a maximum of 400 mg/hr. 
 
Subsequent infusions if no adverse events with first infusion: May start at 100 mg/hour and 
increase at 100 mg/hour every 30 minutes to maximum rate of 400 mg/hour if no adverse events 
occur. 
  
5.2.3 
Handling Potential Infusion Reactions 
 
The handling of potential infusion reaction is outlined in the Investigator’s Brochure and 
summarized below. If a patient experiences a reaction of any grade during infusion, adjust the 
infusion as the following:  
• Grade 4 (life threatening): Stop infusion immediately and permanently discontinue dosing. 
• Grade 3 (severe): Interrupt infusion and manage symptoms. Upon resolution of 
symptoms, consider restarting infusion at no more than half the previous rate (the rate 
being used at the time that the infusion reaction occurred) and, if patient does not 
experience any further infusion reaction symptoms, infusion rate escalation may resume at 
the increments and intervals as appropriate for the treatment cycle dose. Permanently 
discontinue treatment if patients experience a Grade 3 infusion related symptom at re-
challenge.  
• Grade 1-2 (mild to moderate): Reduce infusion rate or interrupt infusion and treat 
symptoms. Upon resolution of symptoms, continue or resume infusion and, if patient does 
not experience any further infusion reaction symptoms, infusion rate escalation may 
resume at the increments and intervals as appropriate for the treatment cycle dose.  
 
The following medications may be used for infusion reactions as needed: 
Drug 
Dose 
Indication 
Acetaminophen 
325 mg tablet 
650 mg PO 
Q 4 hours prn 
Infusion related reactions or 
temperature greater then 38 
degree Celsius (100.4 F) 
Diphenhydramine 25 mg/mL 
25 mg IVPU 
Q 4 hours prn 
Infusion related reactions; 
may repeat once if symptoms 
are not relieved within 15 
minutes of initial dose. 


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Meperidine 25 mg/mL 
25 mg IVPU 
Q 15 min, prn 
Rigors, may repeat once (Max 
dose 50 mg) 
Prochlorperazine 10 mg/mL 
10 mg IVPU 
Q 6 hours, prn 
Nausea  and Vomiting 
 
5.3 
Selection and Timing of Dose for Each Patient 
Rituximab and obinutuzumab will be dosed according to the same regimens.  The two doses of 
both drugs will be administered approximately 2 weeks apart, on Day 0 at week 1 and on day 14 
(±2 days). A window of ± 2 days is permitted to accommodate potential scheduling conflict. 
5.4 
Patients will be considered treatment failures if the glucocorticoid dose has to be 
increased either during the prednisone taper or after remission because of a disease 
relapse or if any other treatment for ANCA-associated vasculitis is prescribed to treat 
a disease relapse. The patients who experienced treatment failure with detectable B 
cells (≥5 cells/μl) will be offered open-label obinutuzumab accompanied one to three 
intravenous methylprednisolone pulses (1000 mg each) starting on or within 10 
calendar days of obinutuzumab followed by oral glucocorticoid dosing at the 
discretion of the investigator (but not to exceed the original specified glucocorticoid 
tapering regimen) to control the disease. Patients who experience a treatment failure 
and B cells are still depleted should be treated according to best medical judgment. 
Patients who respond to the re-treatment and achieve clinical remission will enter the 
maintenance phase and be evaluated every 3 months until the study completes. Any 
patient who experiences treatment failure should continue with study follow-up visits 
per the schedule of assessments through the end of study.Method of Assigning Patients 
to Treatment Groups 
The study will be conducted at 3 investigative sites in the US and will likely involve variable 
numbers of patients at each site. Enrollment will be on a competitive basis but will not exceed 15 
patients (50% of the total) per site. Eligible patients who have completed the screening period and 
meet all study inclusion/exclusion requirements will be randomized in a 1:1 ratio to receive 
investigational products. Patients will be assigned to treatment groups in sequential order as they 
qualify for the study following the randomization procedure provided in Section 5.4.9. 
Randomization will be stratified according to the baseline renal function (≥ 30 or < 30 mL min-1 
per 1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) equation without 
the race factor (Levey et al., 2009) (Appendix 4). 
5.4.1 
Pre-Registration of a Subject 
To pre-register a subject, access the Mayo Clinic Research Registration Application at 
.  The Research Registration Application is available 24 hours a day, 7 
days a week.  Back up and/or system support contact information is available on the website.  If 
unable to access the website, email the Research Registration Office at 
 
between the hours of 8:00 am and 4:30pm Central Time (Monday through Friday). 


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The instructions for the application are available on the Mayo Clinical Office of Clinical Trials 
web page 
 and detail the process for 
completing and confirming patient pre-registration.  Prior to registering/randomizing, this pre-
registration process must be completed in its entirety and a Mayo Clinic subject ID number must 
be available as noted in the instructions.   
5.4.1.1 – Verification of Materials 
Prior to accepting the pre-registration, the registration/randomization application will verify the 
following:  
• IRB approval at the registering institution 
• Patient Pre-Registration Eligibility 
• Existence of a signed informed consent form 
• Existence of a signed authorization for use and disclosure of protected health information.  
5.4.1.2 – Pre-registration Tests/Procedures 
Pre-registration tests/procedures must be completed with the guidelines specified on the test 
schedule. 
5.4.2 
Documentation of IRB approval 
Documentation of IRB approval must be on file in the Research Registration Office before an 
investigator may register any patients. 
In addition to submitting initial IRB approval documents, ongoing IRB approval documentation 
must be on file (no less than annually) with Research Site Management (Fax: 
 or 
email 
).  If the necessary documentation is not submitted in advance of 
attempting patient registration, the registration will not be accepted, and the patient may not be 
enrolled in the protocol until the situation is resolved. 
When the study has been permanently closed to patient enrollment, submission of annual IRB 
approvals to the Research Registration Office is no longer necessary. 
5.4.3 
Registration and Randomization of a Subject 
To register and randomize a patient, access the Mayo Clinic Research Registration Application at 
 The registration/ randomization application is available 24 hours a 
day, 7 days a week. Back up and/or system support contact information is available on the 
website. If unable to access the website, email Research Registration Office at 
 between the hours of 8 a.m. and 4:30 p.m. Central Time (Monday through 
Friday). 


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Prior to initiation of protocol treatment, this process must be completed in its entirety and an 
MCCC subject ID number must be available as noted in the instructions. It is the responsibility of 
the individual registering the patient to confirm the process has been successfully completed prior 
to release of the study agent. Patient registration via the registration/randomization application can 
be confirmed in any of the following ways: 
 
• Contact Research Registration Office at 
. If the patient was fully 
registered and randomized, the Research Registration Office staff can access the 
information from the centralized database and confirm the registration.  
• Refer to the Research Registration Application training course on the Mayo Clinic Office 
of Clinical Trials webpage (link above) for instructions on viewing the patient’s 
registration & randomization confirmation. 
5.4.4 
Correlative Research 
An optional correlative research component for biomarker sample testing is part of this study.  At 
the time of registration, the following will be recorded: 
• Patient has/has not given permission to store and use his/her sample(s) for future research 
of Anti-Neutrophil Cytoplasmic Antibody (ANCA-)Associated Vasculitis at Mayo.  
• Patient has/has not given permission to store and use his/her sample(s) for future research 
to learn, prevent, or treat other health problems. 
• Patient has/has not given permission for MCCC to give his/her sample(s) to researchers at 
other institutions.  
5.4.5 
Treatment on Protocol 
Treatment on this protocol must commence at an approved designated institution under the 
supervision of a medically licensed physician.  All required baseline symptoms must be 
documented and graded. 
5.4.6 
Treatment Start 
Treatment cannot begin prior to registration and must begin ≤14 days after registration. 
5.4.7 
Pretreatment 
Pretreatment tests/procedures (See Section 7.2.1) must be completed within the guidelines 
specified on the test schedule. 


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5.4.8 
Study Drug 
Study drug is verified as being available on site.  Obinutuzumab and rituximab will be shipped 
directly to each site from Genentech. (See Section 5.10 for Study drug storage and accountability).  
Each participating institution will be responsible for monitoring drug supplies and will order 
additional supplies as needed from Genentech.  
5.4.9 
Randomization Procedures 
After the patient has been registered into the study, the values of the stratification factors will be 
recorded, and the patient will be assigned to one of the following treatment groups using the 
Pocock and Simon dynamic allocation procedure which balances the marginal distributions of the 
stratification factors between the treatment groups (Pocock SH, Simon R. Sequential Treatment 
Assignment with Balancing for Prognostic Factors in the Controlled Clinical Trial. Biometrics 
31(1):103-115, 1975, Mar.) 
• Treatment 1: Two infusions of obinutuzumab of 1000 mg each administered 2 weeks 
apart. 
• Treatment 2: Two infusions of rituximab of 1000 mg each administered 2 weeks apart.  
After treatment assignment has been ascertained by the registration/randomization application as 
specified in section 5.4.3, the registration specialist will notify the designated unblinded data 
manager/nurse/pharmacist at the patient’s institution.  The name of this contact person is to be 
entered in the designated space on the eligibility checklist, so the Registration Office personnel 
have it for each patient at the time of registration.  Make sure this contact person will be available 
at the time of registration so they can take a call from the registration specialist if necessary.  This 
contact person may not be involved in assessing adverse events or any other outcome measure and 
should not be the same person listed on the Eligibility Checklist Form as the person completing 
the form.  The last page of the Eligibility Checklist Form should provide the sources of 
communication, either fax or email, and the appropriate contact information.  The registration 
specialist will then communicate the treatment assignment to the designated unblinded contact at 
the patient’s institution.  
The unblinded pharmacist will maintain records that indicate the identity of the patient and their 
corresponding treatment assignment.  
5.5 
Blinding 
During the study conduct, the Sponsor investigator, clinical investigators, clinical site staff, the 
data coordinating center will be blinded to the patient treatment assignment.  On the day of 
randomization, the research pharmacist who will prepare the dosing solution will obtain the 
randomization code for the patient based on a communication from the registration specialist  (See 
Section 5.4.9).  On the days of dosing, the pharmacist will prepare the dosing solution and label 
the infusion bag with the patient identification, the randomization number and date and time of the 
infusion solution preparation. 


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Situations requiring codes to be broken: 
There are two distinct situations in which it is appropriate to break the codes for individual 
patients enrolled in double-blind trials:  
• In the event of an emergency for an individual patient. 
• In the event that it would be helpful for the future clinical care of an individual patient 
after she/he has completed participation in the trial. 
If knowledge of the investigational product ingredients is needed on an emergency basis for 
clinical management of the subject’s condition, the investigator will contact the unblinded 
pharmacist to obtain the treatment assignment. If unblinding occurs for any reason, the time and 
reason for breaking the blind will be recorded on the case report form (CRF) and the sponsor 
investigator must be notified within 24 hours.  
If, in the judgment of the attending physician, it would be helpful for the future clinical care 
of the individual patient, the code may be broken after the patient has completed the study. 
That is, after the patient has been fully evaluated and all evaluation information has been 
recorded by the attending physician and the patient (if appropriate), the MCCC Registration 
Office may be emailed to find out which study therapy the patient was receiving. 
Unblinded data will be provided to the DSMB by a designated unblinded statistician. Unblinding 
will be an anticipated step in the evaluation of a suspected unexpected serious adverse reaction 
(SUSAR). Upon receipt of information supporting a potential SUSAR, the manager responsible 
for the pharmacovigilance will obtain the individual treatment assignment from the unblinded 
statistician and communicate it to the Mayo Clinic monitor to complete the submission of an 
expedited safety report.  
5.6 
Concomitant Therapy 
Concomitant medications are prescription medications, over-the-counter drugs, or dietary 
supplements that a study participant takes after enrollment in addition to the study drugs defined in 
the protocol. Concomitant medications may be used by patients for AAV or for other indications. 
Concomitant medications administered during the study are to be recorded on the CRF until the 
end of the study. The medication name, dose, frequency, route of administration, date(s) of 
administration and reason for administration must be recorded.  
5.6.1 
Antimicrobial Prophylaxis 
Antimicrobial prophylaxis is recommended.  The choice and timing of medication is at the 
investigator’s discretion (e.g., Bactrim-1 single strength tablet daily, dapsone-100 mg daily and 
atovaquone-700 mg twice daily). Specifically, prophylaxis against Pneumocystis Jirovecii 
Pneumonia is strongly recommended for the duration of the participation in the trial.  
The medication name, dose, frequency, route of administration, dates of administration and reason 
for administration must be recorded in the concomitant medication form. 


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5.6.2 
Glucocorticoid Taper 
All randomized patients will be prescribed the same glucocorticoid regimen.  The glucocorticoid 
regimen will include one to three pulses of methylprednisolone (1000 mg each) starting on or 
within 10 calendar days of study day 0 followed by prednisone at a dose of 60 mg per day. The 
initial treatment with methylprednisolone may start while data for eligibility confirmation are 
pending. If their first RTX/OBI infusion coincides with one of the methylprednisolone pulses of 
1000 mg, then the patient can receive the 1000 mg of methylprednisolone as their pre-RTX/OBI 
glucocorticoid infusion.  If the patients have already completed the three methylprednisolone 
pulses, they will receive only 60 mg of methylprednisolone before the rituximab or obinutuzumab 
infusion that day. 
The glucocorticoids dose is to be tapered so that by week 17, all patients who have achieved a 
clinical remission without disease flares will have discontinued glucocorticoids. The 
recommended tapering of glucocorticoids is outlined in Table 1. 
Table 1 Glucocorticoid Tapering Schedule 
Taper Week 
1 
2 
3 - 4 
5 - 6 7 - 8 9 – 10 11 - 12 13 - 14 
15 - 16 
17 
Prednisone 
Dose 
(mg/day) 
60 
30 - 40 25 - 30 
20 
15 
10 
7.5 
5 
2.5 
0 
 
Patients may take their own supply of glucocorticoid. The prednisone equivalents are outlined in 
Table 2 below: 
Table 2 Prednisone Equivalents 
Prednisone  
60 mg 
Hydrocortisone 
240 mg 
Prednisolone 
60 mg 
Triamcinolone 
48 mg 
Methylprednisolone 
48 mg 
Dexamethasone 
9 mg 
Betamethasone 
7.2 mg 
Cortisone 
300 mg 
 
Short term (up to 5 days) glucocorticoid treatment for the treatment of co-morbid conditions 
beyond the protocol specified taper may be permitted on a case-by-case basis. Investigators should 
contact the study medical monitor as soon as possible when this is needed. Patients approved by 
the medical monitor to receive short term (up to 5 days) glucocorticoids for the treatment of co-
morbid conditions will not be considered treatment failures as glucocorticoids are not given due to 
disease relapse. 


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5.7 
Restrictions 
5.7.1 
Prior Therapy 
Patients with a history of intolerance to rituximab or other chimeric monoclonal antibodies (e.g., 
infliximab) are not eligible.  Patients who have been treated with an anti-CD20 agent before are 
eligible if their CD19+20+ B lymphocytes have detectable B cells (minimum 5 cells/uL) in the 
peripheral blood at the time of enrollment. The following medications are prohibited: 
• Cyclophosphamide - prohibited within three months prior to baseline (Visit 2) 
• IVIg (for the purpose of treating AAV) - prohibited within one month of baseline 
• Plasma exchange - prohibited within one month of baseline 
• Avacopan is not allowed as adjunct therapy for remission induction or maintenance 
• Other biologic disease-modifying anti-rheumatic drugs (DMARDs) must be stopped one 
month before baseline or for five half-lives, whichever is longer.  Examples of DMARDs 
are listed in Table 3 below. 
 
Table 3 Examples of Biologic DMARDs 
Generic Name 
Trade Name 
Abatacept 
Orencia 
Adalimumab 
Humira 
Anakinra 
Kineret 
Certolizumab 
Cimzia 
Etanercept 
Enbrel 
Golimumab 
Simponi 
Infliximab 
Remicade 
Rituximab 
Rituxan 
Tocilizumab 
Actemra 
 
Patients taking methotrexate, azathioprine, mycophenolate mofetil, or leflunomide at the time of 
screening must stop these medications before the baseline visit. Patients taking leflunomide will 
have to undergo cholestyramine treatment for washout in addition to discontinuation of the drug. 
5.7.2 
Fluid and Food Intake  
There are no restrictions on the intake of fluids or food.  Patients who are on anti-hypertensive 
therapy should hold their medications on the morning of their RTX/OBI infusions but can resume 
them after the one-hour observation period following the infusion, assuming stable vital signs.  At 
the discretion of the investigator, anti-hypertensive medications can be administered on the 
morning of the RTX/OBI infusion according to the patient’s usual medication schedule before the 
infusion. 
5.7.3 
Patient Activity Restrictions 
There is no restriction on patient activity. 


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5.7.4 
Immunization 
Live vaccines are prohibited within one month (4 weeks) before administration of the 
investigational treatment and are prohibited until the return of B lymphocytes to normal 
concentrations following administration of the investigational treatment.  Recombinant vaccines 
can be administered at any time.  Patients and investigators must be aware that responses to 
vaccines of any type may be suboptimal following B cell depletion therapy until such time as B 
lymphocytes have been repleted to normal concentrations. 
Patients must have completed COVID-19 vaccination (including booster per current 
recommended CDC guidelines) at least 4 weeks (28 days) prior to enrollment. Patients who have 
recovered from COVID-19 prior to screening with a positive spike protein antibody test result but 
have not been vaccinated are also eligible. 
5.8 
Treatment Compliance 
The research pharmacy of each clinical site will be provided with the randomization by the 
designated data manager/nurse/pharmacist at the patient’s institution (See Section 5.4.9).  The 
investigator or designated site personnel will notify the study pharmacist that a patient is enrolled 
and provide a date for the first infusion. The pharmacist will dispense the final investigational 
products for each subject according to randomization assignment.  The date and time of infusion 
solution preparation will be recorded in the study drug accountability log. 
The investigator or designated site personnel will record the infusion start and stop date and time, 
the amount of administered drug and reasons for infusion interruption or discontinuation in the 
CRF. As drug is administered during the flush infusion, the flush infusion is included in the 
administered drug stop date and time.  
5.9 
Packaging and Labeling 
The investigational products, obinutuzumab and rituximab, will be provided to the site pharmacy 
directly by Genentech.  All investigational product supplies are labeled according to the 
requirements of local laws and regulations. 
5.10 Storage and Accountability 
The recommended storage condition for obinutuzumab and rituximab is between 2°C and 8°C, 
protected from light. The products should not be frozen or vigorously shaken. 
5.11 Investigational Product Retention at Study Site 
The investigational products will be stored in a secure area with limited access. The drug storage 
facility must comply with the medication storage instructions. The trial staff must record the 
amount of investigational product dispensed to each subject in the dosing record. The procedures 
for obtaining drug resupply will be provided in the pharmacy manual. All unused drugs will be 
destroyed with approved procedures after drug accounting is verified by the sponsor or its 
designee. 


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6 
STUDY PROCEDURES 
Before each patient is enrolled in the clinical study, the investigator will not undertake any 
investigation not part of standard of care and specifically required for the clinical study until 
written consent has been obtained. Written informed consent will be obtained according to the 
regulatory and legal requirements. As part of this procedure, the investigator must explain orally 
and in writing the nature, duration, and purpose of the study, and the action of the drug in such a 
manner that the study patient is aware of the potential risks, inconveniences, or adverse events that 
may occur. The investigator should educate potential patients about the scientific importance of 
their data and the vital role that their participation has for the outcome of the entire study. The 
patient must be informed that he/she is free to withdraw from the study at any time. He or she will 
receive all information that is required by federal regulations and the International Council for 
Harmonisation (ICH) guidelines. 
The informed consent document shall be signed and dated; one copy will be given to the patient, 
and the investigator will retain a copy as part of the clinical study records. The terms of the 
consent and when it was obtained must also be documented. 
Documentation of informed consent may involve the use or On-Site or Remote Electronic 
Consent technology.  The subject may print or electronically save the form. If the subject prefers 
not to use Electronic Consent technology, the study team will provide a paper consent form for 
their signature.  
6.1 
Screening for I/E Criteria 
At the initial screening, the investigator should review the inclusion and exclusion criteria based 
on the information collected at the screening visit.  The investigator should evaluate any change to 
status affecting conformance to inclusion and exclusion criteria at subsequent visits prior to 
randomization.  
6.2 
Medical and Surgical History 
The following information will be collected at the screening visit: 
6.2.1 
Demographics 
Year and month of birth, age, sex, and race, and whether a female patient is of childbearing 
potential will be documented.  
6.2.2 
Significant Medical and Surgical History 
Medical history of AAV is recorded in a specific disease history form. Surgical history related to 
AAV will be recorded on the AAV disease history form. 
6.2.3 
Prior Medication History 
Use of prescribed or non-prescribed medications, including over the counter drugs, vitamins, 
herbal preparations, and dietary supplements within the past 30 days prior to screening must be 


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recorded at study entry. Each medication history will include the agent used, indication for usage, 
start and stop dates, dose, and frequency. Previous immunosuppressant use for treating AAV will 
be recorded in the CRF. 
6.2.4 
AAV Disease History 
The following AAV disease related history will be documented: 
• The type of AAV (Granulomatosis with polyangiitis or microscopic polyangiitis) 
• Biopsy performed to confirm the AAV diagnosis (if so, organ(s) affected) 
• Newly diagnosed or relapsing AAV 
• Pre-enrollment disease duration (months, years) 
• Organs previously affected by AAV, including current presentation 
• Organ involvement 
 
6.3 
Efficacy Assessments 
6.3.1 
BVAS/WG Assessment 
The BVAS/WG is a method for assessing the activity of vasculitis. The scores range from 0 to 63, 
with higher scores indicating more active disease when any of the features are new or worse 
((Stone et al., 2001). The assessment form includes: 1) 34 separate disease items, categorized into 
9 groups; 2) an “other” section; 3) an asterisk by the 15 major items (see below); 4) tick boxes to 
indicate new/worse or persistent disease; 5) an area to total the scores; 6) a section for the 
designation of disease status; 7) the physician’s global assessment (PGA) of disease activity scale; 
and 8) a box for administrative use that contains information about the patient identification code 
and clinical center. Items on the BVAS/WG evaluation form are counted only if they result from 
active WG, and not from damage from previously active WG or another medical condition. The 
evaluation form is presented in Appendix 5. 
6.3.2 
PR3-ANCA Assay 
Serum samples are collected at the specified visits for PR3-ANCA assay using a direct enzyme-
linked immunosorbent assay (ELISA) (Damoiseaux et al., 2005).  
6.3.3 
AAV-Patient Reported Outcomes (AAV-PRO) 
ANCA-associated vasculitis patient reported outcomes (AAV-PRO) questionnaire is a validated 
instrument to assess the disease specific states reported by the patients. It is a 29-item 
questionnaire grouped into 6 domains: organ-specific symptoms (5 items), systemic symptoms (4 
items), treatment side effects (5 items), social and emotional impact (6 items), concerns about the 
future (5 items) and physical function (4 items) (Robson et al., 2018).  Each item has 5 ordinal 
integer response options scored 0 to 4, higher scores representing greater severity or impact as 
shown in Appendix 6. 


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6.3.4 
VCRC WG/MPA Disease Activity and Transition Assessment 
Patient-reported disease severity will be assessed on an 11-point scale (0–10) where the data will 
be transformed to a scale of 0–100 to allow for comparable data for both cohorts (Tomasson et al., 
2012).  The data form is presented in Appendix 7. 
6.3.5 
Biomarker assessments  
Biomarker assessments will be conducted to compare the effect of obinutuzumab and rituximab 
on changes in the peripheral blood cells by flow cytometry. These assessments are intended to 
profile B cells and other relevant cell populations in PR3-AAV patients before and after 
obinutuzumab or rituximab administration.  
Whole Blood, serum and plasma samples will be collected at specified clinic visits (appendix 1 
and appendix 2), and transferred to the analytical laboratory for analyses. Research may involve 
extraction of DNA and RNA for analysis of non-inherited BCR and TCR sequences and genomic 
profiling through use of NGS of comprehensive panel of immune cell genes.  NGS methods will 
not include whole genome sequencing (WGS) or whole exome sequencing (WES).  Details of the 
collection procedures and sample handling will be provided in the laboratory manual. 
6.3.6 
Vital Signs 
Vital signs will be measured at the time points indicated in the Schedule of Events and will 
include seated blood pressure measurements, pulse, and temperature. 
Devices designed to measure BP from the finger or wrist may not be used. At each visit, BP 
measurements will be obtained using a calibrated sphygmomanometer. A single pulse rate 
measurement should be taken just prior to the BP evaluation in the seated position. 
6.3.7 
Clinical Laboratory Tests and Parameters 
Clinical laboratory tests are listed in Table 4. Patients will be in a seated or supine position during 
blood collection. Blood samples for hematology and chemistry should be taken using 
venipuncture techniques and will be sent to the local laboratory for testing. The time points of 
sampling are indicated in the Table 4 and in Appendix 2 Schedule of Laboratory Testing. 
Whole blood will be collected and shipped to a designated laboratory to analyze the effects of 
obinutuzumab and rituximab on the numbers and activation status of peripheral blood 
mononuclear cells (PBMC) and their subsets.  
Table 4 List of Laboratory Tests 
Category 
Test Names 
Hematology/ 
whole blood 
hemoglobin, hematocrit, erythrocyte count (red blood cell [RBC] count), 
thrombocyte count (platelets), leukocyte count (white blood cell [WBC] 
count) with differential in absolute counts (including neutrophils, 


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Category 
Test Names 
eosinophils, basophils, lymphocytes, and monocytes), erythrocyte 
sedimentation rate 
Serum chemistry/ 
serum 
aspartate aminotransferase (AST); alanine aminotransferase (ALT); total, 
direct, and indirect bilirubin levels; alkaline phosphatase (ALP); albumin, 
creatinine; estimated GFR, blood urea nitrogen (BUN); total protein; and 
glucose (random), c-reactive protein, complete metabolic panel, carbon 
dioxide (C02) 
Hemoglobin A1c / 
whole blood 
Percentage of glycated hemoglobin 
Lipid panel/ serum 
total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides 
Immunology/ 
serum 
ANCA antibody 
Immunoglobulin/ 
serum 
Total immunoglobulin, IgG, IgM, IgA, and IgE 
Infectious disease 
testing/ serum 
hepatitis B (surface antigen and core antibodies), HCV, and HIV, 
tuberculosis (TB) testing, COVID-19 by nasal swab 
Infectious disease will be tested at screening (V1) and when clinically 
indicated. Preferred TB test method is QuantiFERON gold. 
Pregnancy (WCBP 
only)/ urine 
 
Follicle 
Stimulating 
Hormone (FSH)/ 
serum 
Urine pregnancy test (UPT) must be performed at Screening, and at all 
other trial time points for women of childbearing potential. Any woman 
of age ≥ 55 years with amenorrhea for >1 year, will be considered as 
having confirmed menopause and FSH or pregnancy testing will not be 
needed. Postmenopausal females <55 years of age (defined as amenorrhea 
> 1 year) must have menopause confirmed by elevated follicle-stimulating 
hormone (FSH) levels at screening. Surgically sterile females do not 
require any further confirmation of menopause and will not be considered 
to have reproductive potential. 
Urinalysis/ urine 
pH, specific gravity, protein, glucose, ketones, bilirubin, blood, nitrites, 
urobilinogen, leukocytes, and reflex microscopy 
Biomarker 
samples: Whole 
blood, RNA, 
PBMC, serum and 
plasma 
Whole blood samples will be drawn at the visit specified in Appendix 2. 
Peripheral blood mononuclear cells (PBMC) will be processed and 
cryopreserved for further biomarker assessments.   
. 
 
An investigator can perform additional laboratory testing to diagnose or to follow up an adverse 
event progression or resolution. Clinical safety samples may be analyzed in a local laboratory only 
if needed within the same day to determine an urgent treatment plan. Subjects will be in a seated 
or supine position during blood collection.  


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6.3.8 
Electrocardiograms (ECG) 
A 12-lead ECG will be obtained at screening to evaluate eligibility criteria. Patients should be 
lying down (Supine) for at least 5 minutes prior to the safety ECG. Times of the 12-lead ECGs are 
documented in the Schedule of Events. The Investigator may perform additional ECGs for safety 
at other times, if deemed necessary. 
Safety ECGs will be interpreted, signed, and dated by the Investigator. The ECGs will be 
classified as normal, not clinically significant (NCS), or having a clinically significant abnormality 
(CS). In addition, ECG parameters of ventricular rate, PR interval, QRS duration, and QT interval 
(Fridericia’s correction and uncorrected) will be noted on the case report form (CRF). 
6.3.9 
Adverse Events 
Safety assessments will consist of monitoring and reporting adverse events (AEs) and serious 
adverse events (SAEs) per protocol. This includes death, and any other study specific issue of 
concern. 
6.3.9.1 
Definition of Adverse Events 
An AE is any untoward medical occurrence in a participant or clinical investigation participant 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with the intervention. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of an investigational product, regardless of attribution.  
This includes the following: 
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with  
ANCA Associated Vasculitis that were not present prior to the AE reporting period. 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations) 
If applicable, AEs that occur prior to assignment of study treatment associated with medication 
washout, no treatment run-in, or other protocol-mandated intervention. 
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period. 
 
 
6.3.9.1.1 
INTENSITY: 
All clinical AEs encountered during the clinical study will be reported on the AE page of the CRF. 
Intensity of AEs will be graded based on a modified National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), Version 5.0 and reported as indicated on the 
CRF. 


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For any AEs not found in the CTCAE, a description of intensity grading can be found below: 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2: 
Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age- appropriate instrumental activities of daily living. 
Grade 3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living. 
Grade 4: 
Life-threatening consequences; urgent intervention indicated: by definition 
also a SAE. 
Grade 5: 
Death related to AE (Grade 5 is not appropriate for some AEs and therefore is 
not an option) 
Death is an outcome of an adverse event, although in some cases it is noted in severity in CTCAE 
criteria. Not all CTCAE criteria have an outcome of Grade 5. The cause of death must be listed as 
the adverse event term in the eCRF and the outcome box of (fatal) on the AE page is also checked. 
6.3.9.1.2 
INVESTIGATIONAL PRODUCT CAUSALITY: 
Investigators should use their knowledge of the study participant, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an AE is 
considered to be related to the obinutuzumab or rituximab treatment. The following guidance 
should be taken into consideration: 
• Temporal relationship of event onset to the initiation of study drug dosing  
• Course of the event, considering especially the effects of dose reduction, discontinuation 
of trial medication, or reintroduction of the study drug 
• Known association of the event with the obinutuzumab or rituximab 
• Known association of the event with ANCA-associated AAV under study 
• Presence of risk factors in the study participant 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. 
 
The clinical investigator must assign an attribution to the AE using the following attribution 
categories. 
Relationship 
Description 
Unrelated to the 
investigational product 
The AE is clearly NOT related to the intervention 
The AE is doubtfully related to the intervention 
The AE may be related to the intervention 


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Relationship 
Description 
Related to the 
investigational product 
The AE is likely related to the intervention 
The AE is clearly related to the intervention 
 
6.3.9.2 Unexpected Adverse Drug Experience 
Any adverse drug experience that is not listed in the current labeling for the drug product 
including events that may be symptomatically and pathophysiologically related to an event listed 
in the labeling but differ from the event because of greater severity or specificity.  
"Unexpected," as used in this definition, refers to an adverse drug experience that has not been 
previously observed (i.e., included in the labeling or investigator’s brochure) rather than from the 
perspective of such experience not being anticipated from the pharmacological properties of the 
pharmaceutical product. 
6.3.9.3 Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation time points should be adopted. 
Examples of non-directive questions include: 
• “How have you felt since your last clinical visit?” 
• “Have you had any new or changed health problems since you were last here?” 
 
6.3.9.4 Specific Instructions for Recording Adverse Events 
 
Investigators should use correct medical terminology/concepts when reporting AEs or 
SAEs. Avoid colloquialisms and abbreviations. 
 
a.   Diagnosis vs. Signs and Symptoms 
 
If known at the time of reporting, a diagnosis should be reported 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, it is acceptable to report 
the information that is currently available. If a diagnosis is subsequently established, it should be 
reported as follow-up information. 
 
b.   Deaths 
 
All deaths that occur during the protocol-specified AE reporting period, regardless of attribution, 
will be reported to the appropriate parties. When recording a death, the event or condition that 
caused or contributed to the fatal outcome should be reported as the single medical concept. If the 
cause of death is unknown and cannot be ascertained at the time of reporting, report “Unexplained 
Death”. 
 
c.   Preexisting Medical Conditions 
 


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A preexisting medical condition is one that is present at the start of the study. Such conditions 
should be reported as medical and surgical history. A preexisting medical condition should be 
reassessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or 
character of the condition worsens during the study. When reporting such events, it is important to 
convey the concept that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”). 
 
d.   Hospitalizations for Medical or Surgical Procedures 
 
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE. If a subject is hospitalized to undergo a medical or surgical procedure as a 
result of an AE, the event responsible for the procedure, not the procedure itself, should be 
reported as the SAE. For example, if a subject is hospitalized to undergo coronary bypass 
surgery, record the heart condition that necessitated the bypass as the SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for preexisting conditions 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study or 
• Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of 
the study 
 
e. Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will be 
reported appropriately. Each reported AE or SAE will be described by its duration (i.e., start and 
end dates), regulatory seriousness criteria if applicable, suspected relationship to the 
obinutuzumab or rituximab (see following guidance), and actions taken. 
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline: 
 
• Related: There is a plausible temporal relationship between the onset of the AE and 
administration of the obinutuzumab or rituximab, and the AE cannot be readily explained 
by the subject’s clinical state, intercurrent illness, or concomitant therapies; and/or the AE 
follows a known pattern of response to the obinutuzumab or rituximab or with similar 
treatments; and/or the AE abates or resolves upon discontinuation of the obinutuzumab or 
rituximab or dose reduction and, if applicable, reappears upon re- challenge. 
 
• Not Related: Evidence exists that the AE has an etiology other than the obinutuzumab 
or rituximab (e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the AE has no plausible temporal relationship to 
obinutuzumab or rituximab administration (e.g., cancer diagnosed 2 days after first dose 
of study drug). 


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The investigator is responsible for ensuring all SAEs, AE of special interest and unexpected AEs 
that are observed or reported during the study are collected and reported to the FDA, appropriate 
IRB(s), in accordance with CFR 312.31 (IND Safety Reports) and to Genentech, Inc. 
The AE Collection Period begins after obtaining informed consent and ends 30 days following the 
last administration of study treatment or study discontinuation/termination, whichever is later. 
After this period, investigators should only report SAEs that are attributed to study treatment. 
Adverse events that are reported after obtaining informed consent will be captured as pre-
treatment adverse events. After receipt of the first dose, the adverse events will be captured as 
Treatment Emergent Adverse events (TEAEs).   
The below guidelines should be followed when recording AEs: 
Surgical or diagnostic procedures: 
For medical or surgical procedures (e.g., colonoscopy, biopsy), the medical condition that led to 
the procedure is an AE. Elective procedures (e.g., vasectomy), planned hospitalizations, and 
procedures for treatment of conditions noted in the patient’s medical history that have not 
worsened are not considered AEs. 
Chronic disease: 
In the case of disease (excluding AAV) that is progressing, if the disease is known when the 
participant enters the trial, only worsening (increased frequency or intensity of the episodes or 
attacks) will be documented as an AE. If the disease is detected during the trial, and if repeated 
episodes enable diagnosis of a chronic disease, the diagnosis will be recorded as the adverse event. 
Underlying disease conditions: 
Unchanged (stable), chronic conditions, or those related to the underlying disease that are 
consistent with the disease’s natural progression are not AEs and are not to be recorded on the AE 
page of the CRF. These conditions are considered part of the patient’s medical history and must be 
adequately documented on the appropriate page of the CRF. Day-to-day fluctuations of pre-
existing disease should not be recorded as an AE on the AE CRF. 
Disease under study: 
Unexpected progression, signs, or symptoms of the disease under study are not AEs and are not to 
be recorded on the AE page of the CRF unless the event meets the definition of an SAE or is not 
consistent with the typical clinical course of the patient’s disease as established by the patient’s 
medical history. Worsening of the disease under study or other disease-related symptoms 
should be recorded as an AE only if the event meets the definition of an SAE or is not 
consistent with the typical clinical course of the disease 
Laboratory abnormalities: 
An isolated, out-of-range laboratory result in the absence of any associated, clinical finding may or 
may not be considered an AE; the Investigator’s evaluation should be based on a consideration of 
the overall clinical context.  


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An out-of-range laboratory result will be considered clinically significant and recorded as an AE 
when it is part of a clinical abnormality requiring specific medical intervention or follow-up. 
The test will be repeated, and the patient will be followed-up until the test value has returned to the 
normal range or baseline, or the Investigator has determined that the abnormality is chronic or 
stable. The Investigator will exercise medical judgment in deciding whether out-of-range values 
are clinically significant and document the assessment in the source records Serious Adverse 
Event Reporting 
 
6.3.9.5 Definition of Serious Adverse Events 
An SAE is any experience (clinical AE or abnormal laboratory test) that suggests a significant 
hazard, contraindication, side effect, or precaution. An SAE must fulfill at least one of the 
following criteria at any dose level: 
• is fatal (results in the outcome death)* 
• is life-threatening (i.e., the AE, in the view of the investigator, places the subject at 
immediate risk of death. It does not include an AE that, had it occurred in a more severe 
form, might have caused death.). 
• requires in-patient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions). 
• is a congenital anomaly/birth defect 
• is medically significant or requires intervention to prevent one or other of the outcomes 
listed above 
* Note that the term "sudden death" should only be used when the cause is of a cardiac origin as 
per standard definition. The terms "death" and "sudden death" are clearly distinct and must not 
be used interchangeably. 
 
Any clinical adverse event or abnormal laboratory test value that is serious and which occurs 
during the course of the study (as defined above), occurring from the enrollment visit (start of 
study Screening procedures), including long term follow-up must be reported to: 
• The Sponsor (or designee) and trial monitor within 24 hours of the Investigator becoming 
aware of the event (expedited reporting). 
• The investigational site’s IRB by the Investigator in accordance with their regulations. 
 
6.3.9.6 Initial notification of an SAE 
The sponsor must be informed in writing 24 hours from the time the site investigational team first 
become aware of the event using the SAE report form. Delivery of the SAE form should not be 
delayed for the purpose of awaiting complete information. Instead, updates should be provided as 
additional information becomes available. 


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The SAE form including a written, narrative description of any SAE must be emailed to the 
Sponsor within 24 hours after awareness of the event. 
If paper SAE forms are used, the paper originals of the initial and all follow-up SAE report forms 
that have been emailed must be retained in the Investigator Site File. 
In addition to reporting the SAE via email, the SAE report should be entered into the EDC once 
the system is available. 
As further information regarding the SAE becomes available, such follow-up information should 
be documented as an update in the EDC system and on a new SAE report form, marked as a 
follow-up report and emailed to RSTANCA2021SAFETY@mayo.edu with the site’s CRA in 
copy. 
Starting after informed consent, SAEs must be reported within 24 hours (e.g., SAEs related to 
invasive Screening procedures such as biopsies, or SAEs related to glucocorticoid treatment 
during Screening).  
Related SAEs MUST be collected and reported regardless of the time elapsed from the last 
administration of the study drug, even if the study has been closed. 
Unrelated SAEs must be collected and reported during the study and for up to 30 days after the 
last dose of study medication. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) are reported to Investigators at each 
site and associated IRB when the following conditions occur: 
• The event is a SAE 
• There is a reasonable possibility that the event is an adverse reaction caused by the 
administered drug 
• The adverse reaction is unexpected, that is to say, not foreseen in the Investigator 
Brochure 
• When all participants at a particular site are off treatment, as defined by the protocol, 
individual SUSAR reports will be forwarded to the site and its associated IRB on an 
expedited basis. 
 
Individual SUSARs considered to be a significant safety issue and/or which result in a change to 
the informed consent form will be reported in an expedited manner to all Investigators and IRBs. 
Reporting of any SAEs to applicable regulatory authorities will be the responsibility of the Local 
Sponsor in compliance with local regulations. 


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6.3.9.7 Other Safety Findings Requiring Expedited Reporting 
Significant safety findings will be reported to the Investigator by the sponsor as obtained from the 
manufacturer of the study drug products. The site investigator is responsible for reporting to the 
investigational site’s IRB in accordance with their regulations. Reporting to applicable regulatory 
authorities will be the responsibility of the Sponsor investigator in compliance with local 
regulations. 
6.3.9.8 Pregnancy 
Pregnancy in a Female Clinical Trial Participant:   If a female subject becomes pregnant while 
receiving the study drug or within 18 months after the last dose of study drug, or if the female 
partner of a male study subject becomes pregnant while the study subject is receiving the study 
drug or within 180 days, a report should be completed and expeditiously submitted to the 
Investigator and  Genentech, Inc. Pregnancies will be followed-up until the outcome of the 
pregnancy is known, whenever possible, based upon due diligence taken to obtain the 
follow-up information. Abortion, whether accidental, therapeutic, or spontaneous, should always 
be classified as serious, and expeditiously reported as an SAE. Similarly, any congenital 
anomaly/birth defect in a child born to a female subject exposed to the study drug should be 
reported as an SAE. 
The participant should be counseled by a specialist, to discuss the risks of continuing with the 
pregnancy and the possible effects on the fetus. Monitoring of the participant should continue until 
the outcome of the pregnancy is known. The Investigator should report all pregnancies in clinical 
trial participants to the Sponsor within 24 hours of becoming aware of them, using the Clinical 
Trial Pregnancy Reporting Form. 
Protocol required procedures after discontinuation of investigational product must be performed 
on the patient unless contraindicated by pregnancy (e.g., x-ray studies) or the subject withdraws 
consent. Other appropriate pregnancy follow-up procedures should be considered if indicated. In 
addition, the investigator must report to the sponsor, on the appropriate Pregnancy Surveillance 
Form, follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome. Infants will be followed for a minimum of six months. 
6.3.9.9 AEs of Special Interest (AESIs) 
AESIs are a subset of scientific and medical concern specific to the product, for which ongoing 
monitoring and rapid communication by the Investigator to the Sponsor is required. Such an event 
might require further investigation to characterize and understand it. Depending on the nature of 
the event, rapid communication by the trial Sponsor to other parties (e.g., Regulatory Authorities) 
may also be warranted. 
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: 


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o Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin 
 2  ULN 
o Treatment-emergent ALT or AST  3  ULN in combination with clinical 
jaundice 
• Data related to a suspected transmission of an infectious agent by the study drug (STIAMP), 
as defined below: 
o 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 
Adverse Events of Special Interest for Obinutuzumab 
INFUSION RELATED REACTIONS (IRR) 
The IRR is defined as any AEs during infusion or within 24 hours of completing the infusion that 
are considered related to the investigational product by the investigator. 
The most frequently observed adverse drug reactions (ADRs) in patients receiving obinutuzumab 
were IRRs which occurred predominantly during infusion of the first 1000 mg. 
DRUG-RELATED NEUTROPENIA 
Since neutropenia is often associated with autoimmune disease, only neutropenia attributed to 
study drug by the investigator are considered AESIs.  
DRUG-RELATED THROMBOCYTOPENIA 
Thrombocytopenia events assessed as investigational product related by the investigator are 
considered as AESIs to distinguish these AESIs from thrombocytopenia as a symptom of the 
autoimmune disease. 
WORSENING OF PRE-EXISTING CARDIAC CONDITIONS 
In patients with underlying cardiac disease, arrhythmias (such as atrial fibrillation and 
tachyarrhythmia), angina pectoris, acute coronary syndrome, myocardial infarction, and heart 
failure have occurred when treated with obinutuzumab. These events may occur as part of an IRR 
and can be fatal. Patients with a history of cardiac disease should be monitored closely. In 
addition, these patients should be hydrated with caution to prevent a potential fluid overload. 
 GRADE 3 OR HIGHER INFECTIONS 
B-cell depletion may have an impact on the incidence and severity of infections. Due to the 
pharmacological class of obinutuzumab and the mechanism of action, the Sponsor considers 


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infections to be an event of special interest. In obinutuzumab and rituximab clinical trials 
involving non-oncologic patients, the most common infections included urinary tract infection, 
bronchitis, upper respiratory tract infection, herpes zoster, pharyngitis, influenza, nasopharyngitis, 
and conjunctivitis. 
HEPATITIS B REACTIVATION 
HBV reactivation is defined as confirmed presence of HBV DNA > 100 IU/mL in the serum after 
baseline. 
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) 
The diagnosis of PML should be considered in any patient presenting with new-onset or changes 
to preexisting neurologic manifestations. The symptoms of PML are nonspecific 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 magnetic resonance imaging (MRI), and lumbar 
puncture (cerebrospinal fluid testing for John Cunningham Virus [JCV] DNA). The patient should 
be referred to a neurologist for the evaluation and treatment of PML. 
GASTROINTESTINAL PERFORATIONS 
Gastrointestinal (GI) perforation may result in peritonitis with a potentially fatal outcome.  It 
generally requires a surgical intervention.  GI perforation may affect the upper or lower GI tract.  
Upper bowl perforation can be either free (when bowel contents spill freely into the abdominal 
cavity, causing diffuse peritonitis e.g. duodenal or gastric perforation) or contained (when a full-
thickness defect is created but free spillage is prevented because contiguous organs wall off the 
area e.g. duodenal ulcer perforation into the pancreas).  Lower bowel perforation (e.g. in patients 
with acute diverticulitis or appendicitis) results in free intraperitoneal contamination and 
peritonitis.  
6.3.9.10 Other Important Medical Events 
HYPERSENSITIVITY REACTIONS 
Hypersensitivity reactions with immediate (e.g., anaphylaxis) and delayed onset (e.g., serum 
sickness), have been reported in patients treated with obinutuzumab. If a hypersensitivity reaction 
is suspected during or after an 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. Hypersensitivity may be clinically difficult to distinguish from infusion 
related reactions. 
6.3.9.11 Follow-up of AEs 
Adverse events, especially those related to the study drug should be followed up until they return 
to baseline status or stabilized. If after follow-up a return to baseline or stabilization cannot be 


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established and explanation should be recorded, and the ongoing status box noted in the EDC 
CRF. 
6.3.9.12 Follow-up of Post-Treatment SAEs 
SAEs that are identified on the last scheduled contact must be recorded on the AE CRF page and 
reported to the pharmacovigilance group according to the reporting procedures outlined in Section 
0. These may include unresolved previously reported SAEs, or new SAEs. The investigator 
should follow these SAEs until the events are resolved, or the patient is lost to follow-up. 
Resolution means the patient has returned to the baseline state of health, or stabilization (e.g., the 
investigator does not expect any further improvement or worsening of the patient’s condition). 
The investigator should continue to report any significant follow-up information to the sponsor 
until the event has been resolved. 
Any new SAEs reported by the patient to the investigator that occur after the last dose of the 
investigational product should be reported to the pharmacovigilance group. The investigator 
should follow SAEs identified after the last scheduled contact until the events are resolved, or the 
patient is lost to follow-up. The investigator should continue to report any significant follow-up 
information to the sponsor until the event has been resolved. This study requires that patients be 
actively monitored for SAEs for at least 4 weeks after the last treatment or till the end of the 
follow-up period, whichever is longer. 
If the investigator should become aware of the development of cancer or a congenital anomaly in 
a subsequently conceived offspring of a female subject [including pregnancy occurring in the 
partner of a male study subject] who participated in the study, this should be reported as an SAE 
adequately to Genentech drug Safety during follow-up period.      
6.3.9.13 Other Special Situations Reports 
The following other Special Situations Reports should be collected even in the absence of an 
Adverse Event and transmitted to Genentech: 
• Data related to the Product usage during breastfeeding 
• Data related to overdose, abuse, misuse, or medication error (including potentially exposed 
or intercepted medication errors) 
• In addition, reasonable attempts should be made to obtain and submit the age or age group 
of the patient, in order to be able to identify potential safety signals specific to a particular 
population 
 
6.3.9.14 Product Complaints 
A Product Complaint is defined as any written or oral information received from a complainant 
that alleges deficiencies related to identity, quality, safety, strength, purity, reliability, durability, 
effectiveness, or performance of a product after it has been released and distributed to the 
commercial market or clinical trial. 


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6.3.9.15 Exchange of Single Case Reports with Genentech  
Mayo Clinic will be responsible for collecting all protocol-defined Adverse Events (AEs)/Serious 
Adverse Events (SAEs), pregnancy reports (including pregnancy occurring in the partner of a 
male study subject), other Special Situation reports, AESIs and Product Complaints with an AE 
where the patient has been exposed to the Product. The completed MedWatch form must be sent 
to the Genentech contact specified below. Transmission of these reports (initial and follow-up) 
will be either electronically via email or by fax and within the timelines specified below: 
Fax: 
 
Email: 
 
All Product Complaints without an AE should call via: 
PC Hotline Number: 
 (M-F: 5 am to 5 pm PST) 
 
Transmission of these reports (initial and follow-up) will include the Safety Reporting Fax Cover 
Sheet and be sent either electronically or by fax within the timelines specified below: 
Serious Adverse Drug Reactions (SADRs) 
15 calendar days of the awareness date 
Other SAEs 
30 calendar days of the awareness date. 
Special Situation Reports (Pregnancy)  
Special Situation Reports (Other)  
30 calendar days of the awareness date. 
30 calendar days of the awareness date. 
Product Complaints  
15 calendar days of the awareness date. 
AESIs 
15 calendar days of the awareness date. 
 
 
 


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Case Transmission Verification 
The parties will verify that all single case reports have been adequately received by Genentech via 
Mayo Clinic emailing Genentech a Quarterly line-listing documenting single case reports sent by 
Dr. Specks to Genentech in the preceding time period.  
● The periodic line-listing will be exchanged within seven (7) calendar days of the end of 
the agreed time period. Confirmation of receipt should be received within the time period 
mutually agreed upon. 
● If discrepancies are identified, the Sponsor and Genentech will cooperate in resolving the 
discrepancies. The responsible individuals for each party shall handle the matter on a case-by-
case basis until satisfactory resolution. The sponsor shall receive reconciliation guidance 
documents within the ‘Activation Package’. 
● Following Case Transmission Verification, single case reports which have not been 
received by Genentech shall be forwarded by Mayo Clinic to Genentech within five (5) 
calendar days from request by Genentech. 
At the end of the study, a final cumulative Case Transmission Verification report (cumulative line-
listing) will be sent to Genentech. 
Monthly or quarterly line-listings, and cumulative/final CTV should be sent to 
 
MEDWATCH 3500A REPORTING GUIDELINES 
In addition to completing appropriate patient demographic (Section A) and suspect medication 
information (Section C & D), the report should include the following information within the Event 
Description (Section B.5) of the MedWatch 3500A form: 
● Protocol number and title description  
● Description of event, severity, treatment, and outcome if known 
● Supportive laboratory results and diagnostics (Section B.6) 
● Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
Follow-Up Information 
Additional information may be added to a previously submitted report by any of the following 
methods: 
• Adding to the original MedWatch 3500A report and submitting it as follow-up 


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• Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form 
• Summarizing new information and faxing it with a cover letter including patient identifiers 
(i.e., D.O.B. initial, patient number), protocol description and number, if assigned, brief 
adverse event description, and notation that additional or follow-up information is being 
submitted (The patient identifiers are important so that the new information is added to the 
correct initial report) 
MedWatch3500A (Mandatory Reporting) form is available at 
https://www.fda.gov/media/69876/download. 
Reporting to Regulatory Authorities, Ethics Committees and Investigators 
Dr. Specks, as the Sponsor of the Study, will be responsible for the expedited reporting of safety 
reports originating from the Study to the Regulatory Authorities (FDA) where it has filed a clinical 
trial approval, in compliance with local regulations, unless an IND exemption has been obtained. 
If this study becomes IND-exempt, Genentech as the Marketing Authorization Holder will be 
responsible for the reporting of individual case safety reports from the study to the regulatory 
authority in compliance with applicable regulations. 
Dr. Specks, as the Sponsor of the Study, will be responsible for the expedited reporting of safety 
reports originating from the study to the European Medicine Agency (EMA) through 
Eudravigilance Clinical Trial Module (EVCTM), where applicable.  
Dr. Specks will be responsible for the expedited reporting of safety reports originating from the 
Study to the Independent Ethics Committees/ Institutional Review Boards (IEC/IRB) of the 
Concerned Member States, where applicable. 
Dr. Specks as the Sponsor of the Study, will be responsible for the preparation of six-monthly 
Suspected Unexpected Serious Adverse Reaction (SUSAR) reports and their submission to 
Investigators, Regulatory Authorities and the Institutional Review Board/Independent Ethics 
Committee (IRB/IEC), where applicable 
Dr. Specks will be responsible for the distribution of safety information to its own investigators, 
where relevant, in accordance with local regulations. 
Additional Reporting Requirements for IND Holders:  
For Investigator-Initiated IND Studies, some additional reporting requirements for the FDA apply 
in accordance with the guidance set forth in 21 CFR §600.80. 
Events meeting the following criteria need to be submitted to the Food and Drug Administration 
(FDA) as expedited IND Safety Reports according to the following guidance and timelines: 
7 Calendar Day Telephone or Fax Report: 


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The Investigator is required to notify the FDA of any fatal or life-threatening adverse event that is 
unexpected and assessed by the Investigator to be possibly related to the use of obinutuzumab or 
rituximab. An unexpected adverse event is one that is not already described in the obinutuzumab 
or rituximab Investigator Brochure. Such reports are to be telephoned or faxed to the FDA and 
Genentech within 7 calendar days of first learning of the event. 
15 Calendar Day Written Report 
The Investigator is also required to notify the FDA and all participating investigators, in a written 
IND Safety Report, of any serious, unexpected AE that is considered reasonably or possibly 
related to the use of obinutuzumab or rituximab. An unexpected adverse event is one that is not 
already described in the obinutuzumab or rituximab investigator brochure. 
Written IND Safety reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR § 312.32. All safety reports previously filed by the investigator with the IND 
concerning similar events should be analyzed and the significance of the new report in light of the 
previous, similar reports commented on. 
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, 
Genentech, and all participating investigators within 15 calendar days of first learning of the event. 
The FDA prefers these reports on a MedWatch 3500 form, but alternative formats are acceptable 
(e.g., summary letter). 
FDA fax number for IND Safety Reports: 
Fax: 
 
All written IND Safety Reports submitted to the FDA by the Investigator must also be faxed to 
Genentech Drug Safety: 
Fax: 
 
Email: 
 
And Dr. Specks will be responsible for the distribution of safety information to Site IRB: 
[Mayo Clinic IRB, 200 First Street SW, Rochester, MN 55905 / Fax: 
] 
For questions related to safety reporting, please contact Genentech Drug Safety: 
Tel: 
 
Fax: 
 
Aggregate Reports 
IND Annual Reports 


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All IND annual reports submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech 
Copies of such reports should be emailed to Genentech at:  Genentech Drug Safety CTV mail 
box:
 
Dr. Specks will forward a copy of the Final Study Report to Genentech upon completion of the 
Study.  
 
RANDOMIZATION CODES FOR BLINDED CLINICAL TRIALS 
The blind will be broken for ADR reports that are Serious and Unexpected, unless otherwise 
agreed with applicable regulatory authorities. 
REPORTING REQUIREMENTS FOR ADVERSE EVENTS ORIGINATING FROM 
PATIENT REPORTED OUTCOMES 
Although sites are not expected to review the PRO data, if physician/study personnel become 
aware of a potential adverse event during site review of the PRO questionnaire data, he/she will 
determine whether the criteria for an adverse event have been met and, if so, these must be 
reported using the Adverse Event and Special Situation Reporting Form. 
ADVERSE EVENT REPORTING 
Fax MedWatch form immediately to Genentech Safety at: 
Fax: 
 
Email:  
 
Product Complaints Without AE should call via : PC Hotline Number: 
 (M-F: 5 
AM TO 5 PM PST) 
STUDY CLOSE-OUT 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. This includes all IND annual reports and the Clinical Study Report (final study report). 
Additionally, any literature articles that are a result of the study should be sent to Genentech. 
Copies of such reports should be mailed to the assigned Clinical Operations contact for the study: 
 
 
And to Genentech Drug Safety CTV oversight mail box at: 
 
QUERIES 


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Queries related to the overall study design and safety will be answered by Dr. Specks.  However, 
responses to all safety queries from regulatory authorities, Ethics Committees and Institutional 
Review Board  or  for publications will be discussed and coordinated between the Parties. The 
Parties agree that Genentech shall have the final say and control over safety queries relating to the 
Product. Dr. Specks agrees that it shall not answer such queries from regulatory authorities and 
other sources relating to the Product independently but shall redirect such queries to Genentech. 
Both Parties will use all reasonable effort to ensure that deadlines for responses to urgent requests 
from Regulatory Authorities and/or IRB/IEC for information or review of data are met. The 
Parties will clearly indicate on the request the reason for urgency and the date by which a response 
is required. 
SIGNAL MANAGEMENT AND RISK MANAGEMENT  
Genentech is responsible for safety signal management (signal detection and/or evaluation) for 
their own Product. However, it is agreed that Dr. Specks as Sponsor of the Study, will be 
primarily responsible for assessment of the benefit-risk balance of the Study. 
If Dr. Specks issues a safety communication relevant for Genentech (i.e., a safety issue that 
notably impacts the benefit-risk balance of the Study and / or triggers any changes to the Study) 
this will be sent to Roche within five (5) business days of its internal approval. 
As needed, Genentech will reasonably assist Dr. Specks with signal and risk management 
activities related to the Product within the Study. 
Genentech will also provide Dr. Specks with any new relevant information that may modify or 
supplement known data regarding the Product (e.g., relevant Dear Investigator Letter).  
COMPLIANCE WITH PHARMACOVIGILANCE AGREEMENT / AUDIT 
The Parties shall follow their own procedures for adherence to AE reporting timelines. Each Party 
shall monitor and, as applicable, request feedback from the other Party regarding AE report 
timeliness in accordance with its own procedures. The Parties agree to provide written responses 
in a timely manner to inquiries from the other Party regarding AE reports received outside the 
agreed upon Agreement timelines. If there is any detection of trends of increasing or persistent 
non-compliance to transmission timelines stipulated in this Agreement, both Parties agree to 
conduct ad hoc or institute a regular joint meeting to address the issue. 
In case of concerns related to non-compliance of processes, other than exchange timelines, with 
this Agreement, the Parties will jointly discuss and collaborate on clarifying and resolving the 
issues causing non-compliance. Every effort will be made by the non-compliant Party to solve the 
non-compliance issues and inform the other Party of the corrective and preventative actions taken. 
Upon justified request, given sufficient notice of no less than sixty (60) calendar days, an audit 
under the provisions of this Agreement can be requested by either Party. The Parties will then 
discuss and agree in good faith upon the audit scope, agenda and execution of the audit. The 
requesting Party will bear the cost of the audit. 


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6.3.10   Concomitant Medication Assessments 
A concomitant medication is any medication that the patient has been taking prior to enrollment 
and that the patient is expected to continue to take for some portion of the trial, as well as any 
medication other than the investigational product that the patient takes during the course of the 
trial. 
The medications or treatment for controlling the ANCA-AAV must be recorded as concomitant 
medications in the CRF. 
All prescription and over-the-counter medications, including vitamins and herbal supplements, 
that patients receive during the trial must be documented on the CRF. This documentation should 
continue until the patients complete the study. All medications should be evaluated to if they are 
prohibited or not and the appropriate action should be taken. 
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHO-DD). A table of concomitant medications based on the anatomic therapeutic chemical 
classification (ATC) and preferred name will be produced.  
6.3.11 Glucocorticoid Toxicity Index (GTI)  
The GTI  is a validated tool permitting investigators to assess the use of glucocorticoids and its 
toxicity that is relevant to patients (McDowell et al., 2020). The GTI is designed to measure 
change in GC toxicity between 2 points in time and includes 2 components, a Composite Index 
and a Specific List. The full Composite Index includes 9 domains and a total of 31 unique 
weighted items. Data from the GTI provide two scores: 
• The Cumulative Worsening Score (CWS) – The CWS is designed to assess cumulative 
GC toxicity, regardless of whether the toxicity has lasting effects or is transient.  New 
toxicities that occur are added, but toxicities that appear to resolve on follow-up are not 
removed.  Thus, the CWS serves as a lasting record of and GC toxicity that occurs.  The 
CWS can only increase or remain the same over time. 
 
• The Aggregate Improvement Score (AIS) – The AIS is designed to capture improvement 
in glucocorticoid toxicity.  With the AIS, toxicities can be removed if improvement occurs 
(and added if worsening occurs). If an item of toxicity is present at baseline or occurs 
during the trial resolves over the course of follow-up, then that improvement is reflected in 
a negative AIS for that Item during that interval.  The AIS scores improvement in GC 
toxicity the same as a corresponding worsening of GC toxicity.  
 
6.3.12 Vasculitis Damage Index (VDI) 
VDI is a standardized clinical assessment of damage in the systemic vasculitides (Merkel et al., 
2011).  The VDI consists of 64 items of damage selected by expert consensus as representative of 
the forms of damage developed by subjects with systemic vasculitis (Appendix 8). The VDI is that 
it has provided investigators with a method to ensure that items of damage are uniformly collected 
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6.4 
Removal of Patients from the Trial or Study Drug 
6.4.1 
Patient Withdrawal 
All patients have the right to withdraw consent and discontinue participation without prejudice at 
any time during the trial. Every effort should be made to comply with the protocol; however, 
patients will be withdrawn from the trial entirely with no further trial visits if any of the following 
situation arise: 
• Withdrawal of patient’s consent or patient’s request to discontinue from the trial for any 
reason. 
• The patient is unwilling or unable to comply with the protocol 
 
Patients who are withdrawn from the trial will not be replaced. The reason for the patient’s 
withdrawal from the trial should be recorded on the electronic case report form (eCRF).  
6.4.2 
Other Special Situations Reports 
The following other Special Situations Reports should be collected even in the absence of an 
Adverse Event and transmitted to Genentech: 
• Data related to the Product usage during breastfeeding 
• Data related to overdose, abuse, misuse or medication error (including potentially exposed 
or intercepted medication errors) 
• In addition, reasonable attempts should be made to obtain and submit the age or age group 
of the patient, in order to be able to identify potential safety signals specific to a particular 
population 
 
6.4.3 
Patient Lost to Follow-up 
At the start of the study, the Investigator should try to obtain all relevant contact details for the 
patient to facilitate contacting the patient, if necessary. In addition, each patient should be 
encouraged to attend all trial visits for which the patient is scheduled. 
If a patient discontinues the study without notifying the investigator, the investigator must make 
every effort to contact the patient to identify the reason for the patient’s withdrawal and to 
encourage the patient to complete the applicable Early Withdrawal/End of Study visit assessments 
(Appendix 1, Schedule of Events). If documented attempts to contact the patient fail, and a reason 
for the patient’s discontinuation is undiscoverable, the investigator can declare the patient as “lost 
to follow-up” at the end of the study. The investigator should document in the corresponding 
medical record all efforts to contact the patient. 
6.5 
Early Termination of the Trial 
In the event that the trial is terminated early, the sponsor or its designee will complete the 
following tasks within 7 days: 


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• Notify all investigational sites, IRB/EC, and DSMB that the trial is terminated 
• Discontinue shipment of any new investigational products to the sites, if applicable 
 
The investigators will contact all study patients and schedule the End of Study visit promptly upon 
the notification that the trial has ended. 
The investigator may withdraw a patient from the PRRR study for any of the following reasons: 
• A protocol violation occurs, 
• A serious or intolerable adverse event occurs, 
• A clinically significant change in a laboratory parameter occurs,  
• The sponsor or investigator terminates the study, or 
• The patient requests to be discontinued from the study. 
 
6.6 
Dispensing Study Drug 
The study drug for infusion will be prepared by the site pharmacist who has access to the 
randomization schedule following the procedures in the Pharmacy Manual. 
7 
STUDY ACTIVITIES 
The study activities at each clinic visit listed below are presented in Schedule of Events and 
Schedule of Laboratory Testing. Detailed study procedures are described in Section 6. 
A visit window is allowed for all visits except visit V2. Visit 2 is the first day of dosing and the 
basis for the visit window. 
Table 5 Study Visit Schedule 
Visit 
No. 
Visit 
Study 
Day 
Visit Window 
1 
Screening 
Varies 
Before baseline visit (up to 14 days prior to the 
baseline visit) 
1a 
IV steroid #1 
G1 
Within 10 days of baseline up to day of baseline 
(V2) 
1b 
IV steroid #2  
G2 
Optional, Within 24 hours after IV steroid 1 
1c 
IV steroid #3 
G3 
Optional, within 24 hours after IV steroid 2 
2 
Infusion 1 
(Baseline) 
0 
Within 14 days from screening 
3 
Infusion 2 
14 
±2 days of the targeted date 
4 
Month 1 
30 
± 2 days of the targeted date 
5 
Month 2 
60 
±3 days of the targeted date 
6 
Month 4 
120 
±5 days of the targeted date 


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7 
Month 6 
180 
±10 days of the targeted date 
8 
Month 9 
270 
±10 days of the targeted date 
9 
Month 12 
360 
±10 days of the targeted date 
10 
Month 15 
450 
±10 days of the targeted date 
11 
Month 18 
540 
±10 days of the targeted date 
99 
When disease 
flares 
unschedul
ed 
 
 
7.1 
Screening Visit V1 (Up to 14 days Before Day of Randomization) 
• Explain the content of the informed consent materials to the patient and collect signed 
informed consent  
• Collect needed information and evaluate conformance to inclusion and exclusion criteria  
• Obtain Demographic Information  
• Obtain medical history including AAV disease history 
• Record pre-treatment medications  
• Record current glucocorticoid use 
• Measure vital signs, including blood pressures, pulse, and temperature  
• Perform a 12-lead ECG measurement  
• Complete the BVAS/WG Score 
• Complete the VCRC-Disease activity and Transition Assessment by the investigator 
• Draw blood for clinical laboratory tests. The specific laboratory tests scheduled for this 
visit are listed in Appendix 2 
• Collect a clean-catch, mid-stream urine sample for urinalysis 
 
7.2 
Remission Induction Period (Day 0 to Month 6) 
7.2.1 
Pre-Treatment of Methylprednisolone 
Eligible patients will start the one to three pulses of glucocorticoid of methylprednisolone starting 
on or within 10 calendar days of study day 0 (1000 mg each, iv infusion). The initial treatment 
with methylprednisolone may start while data for eligibility confirmation are pending. If their first 
RTX/OBI infusion coincides with one of the methylprednisolone pulses of 1000 mg, then the 
patient can receive the 1000 mg of methylprednisolone as their pre-RTX/OBI glucocorticoid 
infusion.  If the patients have already completed the one to three methylprednisolone pulses, they 
will receive only 60 mg of methylprednisolone before the rituximab or obinutuzumab infusion 
that day. The pre-RTX/OBI treatment with methylprednisolone may be substituted with the IV 
pulse for one of the pre-treatment infusions. 


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7.2.2 
Visit 2 (Day 0) Procedures 
• Confirm the subject eligibility 
• Perform randomization procedures (The randomization procedure may start the day before 
the scheduled Day 1 visit by the pharmacist. The dosing solution must be prepared within 
24 hours of scheduled dosing.) 
• Record vital signs, including blood pressures, pulse, and temperature prior to infusion 
• Complete the BVAS/WG Score prior to infusion 
• Complete the VCRC-Disease activity and Transition Assessment by the investigator 
• Review glucocorticoid use prior to infusion 
• Complete AAV-PRO by the patients prior to infusion 
• Complete GTI assessment prior to infusion 
• Complete VDI assessment prior to infusion 
• Draw blood for clinical laboratory tests prior to infusion 
• Collect samples for mechanistic biomarker assessments prior to infusion 
• Collect a clean-catch, mid-stream urine sample for urinalysis prior to infusion 
• Assess adverse events prior to, during and after infusion 
• Record medications used prior to, during and after infusion 
• Administer study drug infusion and observe for 2 hours after infusion is complete 
 
7.2.3 
Visit 3 (Day 14 ± 2 days) Procedures 
• Record vital signs, including blood pressures, pulse, and temperature prior to infusion 
• Complete the BVAS/WG Score prior to infusion 
• Complete the VCRC-Disease activity and Transition Assessment by the investigator 
• Draw blood for clinical laboratory tests prior to infusion 
• Collect a clean-catch, mid-stream urine sample prior to infusion 
• Record medications used prior to, during and after infusion 
• Review glucocorticoid use prior to infusion 
• Assess adverse events prior to, during and after infusion 
• Administer study drug infusion and observe for 2 hours after infusion is complete 
 
7.2.4 
Visit 4 (1 month after the first infusion) Procedures 
• Draw blood for clinical laboratory tests (during clinic visit only) 
• Collect a clean-catch, mid-stream urine sample for urinalysis (during clinic visit only) 
• Collect samples for mechanistic biomarker assessments 
• Complete the BVAS/WG Score 


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• Complete the VCRC-Disease activity and Transition Assessment by the investigator 
• Record medications used 
• Review glucocorticoid use 
• Assess adverse events 
 
7.2.5 
Visit 5 (2 months after the first infusion) Procedures 
• Record vital signs, including blood pressures, pulse, and temperature  
• Complete the BVAS/WG Score 
• Complete the VCRC-Disease activity and Transition Assessment by the investigator 
• Draw blood for clinical laboratory tests 
• Collect samples for mechanistic biomarker assessments 
• Collect a clean-catch, mid-stream urine sample for urinalysis 
• Perform VDI assessment 
• Record medications used 
• Review glucocorticoid use 
• Assess adverse events 
 
 
7.2.6 
Visit 6 (Month 4) Procedures 
• Record vital signs, including blood pressures, pulse, and temperature  
• Complete the BVAS/WG Score 
• Complete the VCRC-Disease activity and Transition Assessment by the investigator 
• Draw blood for clinical laboratory tests 
• Collect samples for mechanistic biomarker assessments 
• Collect a clean-catch, mid-stream urine sample for urinalysis 
• Record medications used 
• Review glucocorticoid use 
• Assess adverse events 
 
 
7.2.7 
Visit 7 (Month 6) Procedures 
• Record vital signs, including blood pressures, pulse, and temperature  
• Perform a 12-lead ECG measurement 
• Complete the BVAS/WG Score 
• Complete GTI assessment. 
• Collect a clean-catch, mid-stream urine sample  


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• Perform VDI assessment 
• Complete AAV-PRO by the patient 
• Complete the VCRC-Disease activity and Transition Assessment by the investigator 
• Draw blood for clinical laboratory tests 
• Collect samples for mechanistic biomarker assessments 
• Record medications used 
• Assess adverse events 
 
7.3 
Maintenance Period 
7.3.1 
Visits 8, 9 and 10 (Months 9, 12, and 15) Procedures 
Study participants will be scheduled to complete a clinic visit every 3 months.   
• Record vital signs, including blood pressures, pulse, and temperature  
• Complete the BVAS/WG Score 
• Complete the VCRC-Disease activity and Transition Assessment by the investigator 
• Complete AAV-PRO by the patients at month 12 
• Complete GTI assessment  
• Perform VDI assessment 
• Draw blood for clinical laboratory tests  
• Collect samples for mechanistic biomarker assessments 
• Collect a clean-catch, mid-stream urine sample for urinalysis 
• Record medications used 
• Assess adverse events 
 
7.3.2 
Visits 11 (Month 18) Procedures 
Study participants will be scheduled to complete a final clinic visit.   
• Record vital signs, including blood pressures, pulse, and temperature  
• Complete the BVAS/WG Score 
• Complete the VCRC-Disease activity and Transition Assessment by the investigator 
• Complete AAV-PRO by the patient  
• Complete GTI assessment 
• Perform VDI assessment 
• Draw blood for clinical laboratory tests  
• Collect samples for mechanistic biomarker assessments 
• Perform a 12-lead ECG measurement 


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• Collect a clean-catch, mid-stream urine sample for urinalysis 
• Record medications used 
• Assess adverse events 
• Complete End of Study record 
 
7.3.3 
Visit 99 (Unscheduled Visit) Procedures 
• Record vital signs, including blood pressures, pulse, and temperature 
• Complete the BVAS/WG Score 
• Complete the VCRC-Disease activity and Transition Assessment by the investigator 
• Complete AAV-PRO by the patients 
• Complete GTI assessment 
• Draw blood for clinical laboratory tests  
• Collect samples for mechanistic biomarker assessments 
• Record medications used 
• Assess adverse events 
 
7.4 
Early Termination Procedures 
Patients who withdraw consent early, procedures outlined for the Month 18 visit (V11) should be 
completed.  


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7.5 
Study Activities for Treatment Failure Patients 
8 
PATIENTS WILL BE CONSIDERED TREATMENT FAILURES IF THE 
GLUCOCORTICOID DOSE HAS TO BE INCREASED EITHER DURING THE 
PREDNISONE TAPER OR AFTER REMISSION BECAUSE OF A DISEASE 
RELAPSE OR IF ANY OTHER TREATMENT FOR ANCA-ASSOCIATED 
VASCULITIS IS PRESCRIBED TO TREAT A DISEASE RELAPSE. THE 
PATIENTS WHO EXPERIENCED TREATMENT FAILURE WITH 
DETECTABLE B CELLS (≥5 CELLS/ΜL) WILL BE OFFERED OPEN-LABEL 
OBINUTUZUMAB ACCOMPANIED ONE TO THREE INTRAVENOUS 
METHYLPREDNISOLONE PULSES (1000 MG EACH) STARTING ON OR 
WITHIN 10 CALENDAR DAYS OF OBINUTUZUMAB FOLLOWED BY ORAL 
GLUCOCORTICOID DOSING AT THE DISCRETION OF THE INVESTIGATOR 
(BUT NOT TO EXCEED THE ORIGINAL SPECIFIED GLUCOCORTICOID 
TAPERING REGIMEN) TO CONTROL THE DISEASE. PATIENTS WHO 
EXPERIENCE A TREATMENT FAILURE AND B CELLS ARE STILL 
DEPLETED SHOULD BE TREATED ACCORDING TO BEST MEDICAL 
JUDGMENT. PATIENTS WHO RESPOND TO THE RE-TREATMENT AND 
ACHIEVE CLINICAL REMISSION WILL ENTER THE MAINTENANCE PHASE 
AND BE EVALUATED EVERY 3 MONTHS UNTIL THE STUDY COMPLETES. 
ANY PATIENT WHO EXPERIENCES TREATMENT FAILURE SHOULD 
CONTINUE WITH STUDY FOLLOW-UP VISITS PER THE SCHEDULE OF 
ASSESSMENTS THROUGH THE END OF STUDY.QUALITY CONTROL AND 
ASSURANCE 
The clinical research facility will be monitored by the study monitor to ensure correct performance 
of the study procedures and to ensure that the study is conducted according to the protocol and 
relevant regulatory requirements. CRF entries will be verified with the source documentation. 
Quality control principles will be applied throughout the performance of this study by following 
the Standard Operating Procedures (SOPs) of the contract research organization (CRO) and the 
Principal Investigator. Review procedures will be implemented at the CRO for all documents that 
are generated in relation to the study. 
The laboratory testing will be performed by a CLIA certified central laboratory to ensure the 
laboratory values are determined consistently. 
The overall procedures for quality assurance of clinical trial data, including data collection and 
management, will be described in the Data Management Plan. 
Accurate and reliable data collection will be assured by verification and crosscheck of the eCRF 
against the Investigator’s records by the trial monitor (source document verification), and the 
maintenance of drug accountability by the Investigator. 
Data for this trial will be recorded in the trial electronic case report forms (eCRFs) using Medidata 
RAVE. The data will be entered by the trial center from the source documents into the eCRF or 
will be loaded from other files. 


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A comprehensive validation check program will verify the data and discrepancy reports will be 
generated accordingly for resolution by the Investigator. All discrepant data will be resolved in the 
EDC database and data entered in the database will be independently compared with the original 
Investigator’s records. 
For classification purposes, preferred terms will be assigned to the original terms recorded on the 
eCRF, using MedDRA for AEs, diseases and surgical and medical procedures, and the WHO drug 
dictionary for drug and herbal treatments. 
9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
The following sections provide a summary of the planned analysis of the trial, but a full statistical 
analysis plan (SAP) will be developed as a separate document and will become the final plan prior 
to primary efficacy 6-month endpoint analysis. All statistical analyses will be performed using 
SAS Version 9.4 or higher.   
Data summaries will use descriptive statistics (number of subjects [N], mean, standard deviation 
[SD], median, quartiles, minimum, and maximum) for continuous variables, and frequency and 
percentage of subjects in each category for categorical and ordinal variables.  If there are missing 
values, the number missing will be presented, but without a percentage. 
Unless otherwise specified, all tests will be two-tailed using a 0.05 level of significance.  All 
confidence intervals (CIs) will be two-sided 95% confidence intervals.   
9.2 
Determination of Sample Size 
PRRR is an exploratory proof-of-concept study to evaluate the potential utility of obinutuzumab 
for the treatment of PR3-ANCA associated vasculitis.  We anticipate the proportion of patients in 
the obinutuzumab group that will achieve complete remission and ANCA negativity is 0.55 and 
the proportion of patients in the rituximab group that will achieve complete remission and ANCA 
negativity is 0.30; the planned sample size of 30 patients in two equal size groups is not powered 
to test the hypothesis that obinutuzumab is superior to rituximab. No sensitivity analyses (e.g., to 
account for missing data) and no adjustment for multiple comparisons will be conducted. Nominal 
p-values will be used to examine any trends in the endpoint. 
9.3 
Analysis Populations  
9.3.1 
Intention-to-treat Analysis Set: 
All subjects who are randomized regardless of treatment adherence or availability of follow up 
data will be included in the intention-to-treat analysis set (ITT). All analyses of the ITT will be 
based on each subject’s assigned treatment. The ITT will be the secondary analysis set used for 
the efficacy endpoint analyses where specified. 


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9.3.2 
Modified Intention-to-Treat Analysis Set 
All subjects who are included in the intention-to-treat analysis set (ITT), have received any 
amount of the study drug will be included in the modified intention-to-treat (mITT) analysis set.  
The mITT will be the primary analysis set used for the efficacy endpoint analyses.  
9.3.3 
Safety Analysis Set 
All subjects who are randomized and have received any amount of the study drug will be included 
in the Safety Analysis Set. Safety analyses will be based on the medication that was actually 
dispensed to each patient. This is the primary analysis set for safety.  
9.4 
Demographics and Baseline Characteristics 
Patients must meet all inclusion criteria and none of the exclusion criteria in order to participate in 
the study. Demographic characteristics include age, gender, race, ethnicity, and study center. 
Summary descriptive statistics will include counts and percentages for discrete variables and 
estimation of means, standard deviations, medians, quartiles, minimum and maximum for 
continuous metrics.  These analyses will be carried out for the ITT, mITT and safety analysis sets. 
9.5 
Primary Efficacy Endpoint 
The primary efficacy endpoint is defined as the proportion of patients achieving complete 
remission and ANCA negativity at month 6. Complete remission is defined as: 
• BVAS/WG of 0; and 
• No requirement for glucocorticoids for treatment of PR3-ANCA associated vasculitis 
beyond the prescribed 16-week prednisone taper.  
 
Patients must achieve a complete remission as defined above and be ANCA-negative at month 6 
in order to meet the primary efficacy endpoint. 
The primary efficacy analysis is to compare the proportion of patients assigned to the 
obinutuzumab group who meet the primary efficacy endpoint criteria at month 6 to the proportion 
of patients assigned to the rituximab group who meet the primary efficacy endpoint criteria at 
month 6. 
Descriptive statistics (number and percent of subjects meet the primary efficacy endpoint criteria) 
will be reported by treatment group.  
The following null (H0) and alternative (Ha) hypotheses will be tested using Fisher’s Exact test the 
mITT analysis set: 
H0: п obinutuzumab - п rituximab = 0 
Ha: п obinutuzumab - п rituximab ≠ 0 
п obinutuzumab: proportion of patients assigned to the obinutuzumab group who achieve 
complete remission and ANCA negativity in 6 months 


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п rituximab: proportion of patients assigned to the rituximab group who achieve complete 
remission and ANCA negativity in 6 months 
The above null hypothesis will be tested using Fisher’s Exact test. Two-sided Newcombe-
corrected 95% confidence intervals of the risk difference between treatments with respect to the 
primary efficacy endpoint success rate will also be presented.   It is not expected that the null 
hypothesis will be rejected at a two-sided 0.05 level of significance given the proof-of-concept 
nature of the study and given the small sample size; trends seen between treatment groups in the 
primary endpoint rate will be used to define future studies. 
The above analyses on the primary efficacy endpoint success rate will be performed when all 
subjects have completed 6 months of follow-up (or would have completed 6 months of follow-up) 
had they not withdrawn. 
9.6 
Primary Safety Endpoints 
Safety data includes adverse events (AEs), vital signs, ECG results and clinical lab results 
including serum chemistry, hematology, and urinalysis. Observed data will be described as counts 
and percentages for discrete variables and estimation of means, standard deviations, medians, 
inter-quartile range, minimum and maximum for continuous metrics. All patients who are 
randomized and dispensed double-blind study medication will be included in the safety analysis. 
Data collected from subjects who were enrolled but not randomized will be presented separately. 
All safety data will be presented in by-subject listings and included in the clinical trial report. 
Adverse events will be mapped to preferred term and body system using the Medical Dictionary 
for Regulatory Activities (MedDRA) dictionary. The number and percentage of patients reporting 
treatment emergent adverse events will be presented overall, by MedDRA System Organ Class 
(SOC) and by MedDRA Preferred Term (PT) within each SOC.  A treatment emergent adverse 
event is an event that begins or worsens in severity at or after the start of randomized treatment.  
This analysis will be repeated for serious treatment emergent adverse events, for treatment 
emergent adverse events of special interest, (see list provided below) and for treatment emergent 
adverse events at least possibly related to study drug. In addition, the number and percent of 
patients with treatment emergent adverse events will be presented by severity for each SOC and 
PT.  Patients experiencing more than one treatment emergent adverse event within a given SOC 
and PT will be assigned to most severe category experienced.  
Adverse event listings will be provided for the following subsets: 
• All treatment emergent AEs 
• All TEAEs at least possibly related to the investigational product 
• Serious TEAEs 
• TEAEs leading to dosing discontinuation or study withdrawal 
• GTI scores (Cumulative Worsening Scores and Aggregate Improvement Scores 
(McDowell et al., 2020) 
 
The adverse events of special interest include: 


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• Infusion related reactions (IRR) 
• Neutropenia 
• Thrombocytopenia 
• Worsening of pre-existing cardiac conditions 
• Infections (infections include all PTs in the SOC of Infections and Infestations) 
• Hepatitis B reactivation 
• Progressive multifocal leukoencephalopathy (PML) 
 
9.7 
Secondary Endpoints 
No sensitivity analyses and adjustment for multiple comparisons will be conducted for the 
secondary endpoints. Nominal p-values will be used to examine any trends in these endpoints.  
The analyses will be carried out on the ITT and mITT populations, with no imputation for missing 
data.  The secondary endpoints are: 
• To compare the proportion of subjects who achieve sustained complete remission at 
months 6, 12 and 18 (BVAS/WG = 0 without glucocorticoids) by administration of 
obinutuzumab or rituximab. These comparisons will be carried out using Fisher’s Exact 
test. 
 
• To compare the time to treatment failure through month 18 by administration of 
obinutuzumab or rituximab; patients will be considered treatment failures if the 
glucocorticoid dose has to be increased because of a disease relapse either during the 
prednisone taper or after the remission is achieved.  A disease relapse is defined as an 
increase in the BVAS/WG of 1 point or more accompanied by a decision on the part of the 
investigator to increase treatment for PR3-AAV.  Time-to-treatment failure will be 
compared between treatments using the log-rank test; Kaplan-Meier plots of time to 
treatment failure through 18 months will be generated for each randomized treatment 
group; patients not experiencing treatment failure will be censored at last known follow-up 
for these analyses. 
 
9.8 
Other Assessments or Analyses 
The exploratory objectives are to compare: 
• the number of relapses, defined as an increase in the BVAS/WG by at least one point 
accompanied by an increase in the intensity of treatment; 
• the Glucocorticoid Toxicity Index (GTI)  scores (Cumulative Worsening Score and 
Aggregate Improvement Score) over time; 
• the cumulative glucocorticoid dose; 
• the number of severe relapses, defined as the occurrence of life- or organ-threatening 
disease manifestation(s) or marked by an increase in the BVAS/WG of ≥ 3 and the 
investigator deems re-treatment is required; 
• the changes from baseline in Vasculitis Damage Index (VDI) over time; 
• the time to clinical remission; 


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• the changes in estimated glomerular filtration rate (eGFR); 
• the proportion of patients achieving and maintaining complete peripheral blood B cell 
depletion (CD19+) at each study visit using high-sensitivity flow cytometry (HSFC); 
• the kinetics of ANCA: 
• Time to ANCA negativity 
• Time to ANCA recurrence; 
• the kinetic of recurrence of PR3-specific (autoantigen-specific) B cells after B cell 
depletion 
• the changes from baseline on AAV patient reported outcome (AAV-PRO) assessment 
over time 
• VCRC WG/MPA disease activity and transition assessment over time 
 
The mechanistic study results will be analyzed and reported separately. 
9.9 
Interim Analysis 
The primary endpoint analysis will occur after all patients have completed the month 6 study visit. 
This technically represents an interim analysis and will be handled as described in detail in section 
3.1.3. 
10 ADMINISTRATIVE CONSIDERATIONS 
10.1 Investigators and Study Administrative Structure 
The Sponsor investigator is: 
Ulrich Specks, MD 
Division of Pulmonary and Critical Care Medicine 
 
Mayo Clinic College of Medicine and Science 
 
The Mayo Clinic will function as the data coordinating center. The Mayo Clinic will be 
responsible for the clinical operation and management of vendors that will perform protocol 
specified functions. Genentech will provide the investigational products and funding to support 
the clinical conduct. 
The information on serious adverse events experienced by study participants will be reported to 
the IRB/EC, to the Sponsor Investigator and to Genentech, Inc. 
Information regarding other key personnel involved in the conduct of the study, including names 
and contact details of participating clinical investigators, monitors, clinical laboratories, and 
technical departments and/or institutions, as well as information on members of additional study 
committees, will be found in the study files of the investigational site. 


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10.2 Institutional Review Board (IRB) Approval 
Protocol amendments must be made only with the prior approval of the Sponsor. The IRB must be 
informed of all amendments and give approval for all amendments. For studies conducted outside 
of the US, approval of substantial amendments must be obtained from the relevant Competent 
Regulatory Authority before implementation. The Investigator must send a copy of the approval 
letter from the IRB to the Sponsor and/or the Sponsor’s designee. 
Approval must be obtained before any changes can be implemented, except for changes necessary 
to eliminate an immediate hazard to trial participants, or when the change(s) involves only 
logistical or administrative aspects of the trial [e.g., change in monitor(s), change of telephone 
number(s)]. 
This protocol and any accompanying material provided to the participant (such as participant 
information sheets or descriptions of the trial used to obtain informed consent), as well as any 
advertising or compensation given to the participant, will be submitted by the principal 
Investigator or coordinating Investigator to the relevant institutional IRB responsible for the 
investigational trial. 
An approval letter or certificate (specifying the protocol number and title) from the IRB must be 
obtained before starting the trial (initiation). The approval letter to the Investigator should specify 
the date on which the committee met and granted the approval. The Sponsor (or designee) must 
also obtain relevant competent authority approvals before starting the trial. 
The investigator is responsible for keeping the IRB informed of the progress of the study and of 
any changes made to the protocol as deemed appropriate, but in any case, at least once a year. The 
investigator must also keep the IRB informed of any SAEs occurring to patients under their t 
supervision. 
10.3 Ethical Conduct of the Study 
The Investigator will ensure that this trial is conducted in full conformance with the ethical 
principles that have their origin in the “Declaration of Helsinki”, and that are consistent with the 
principles outlined in the current “Guideline for Good Clinical Practice” ICH Tripartite Guideline 
GCP E6 or with the laws and regulations (e.g., Title 21 Code of Federal Regulations Parts 50, 54, 
56, 312, and 314, where appropriate), whichever affords the greater protection to the individual. 
An inspection by the regulatory authorities’ representatives may occur at any time. The 
investigator must agree to the inspection of study-related records by the regulatory 
authority/Sponsor representatives and must allow direct access to source documents to the 
regulatory authority/sponsor representatives. 
The clinical investigators are responsible for complying with the protocol and all appropriate 
regulations and guidelines governing global clinical research. Additionally, he/she is responsible 
for ensuring that all participating staff members are adequately trained and competent to perform 
his/her assigned tasks. 


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Any deviations from the protocol must be fully explained and documented by the investigator. 
The circumstances, action taken, and impact of the deviation on the trial must be communicated 
by the principal investigator to the designated medical monitor. Significant protocol deviations 
may lead to discontinuation of investigational product at the discretion of the Sponsor. Any 
subsequent actions will be assessed by the designated medical monitor and documented. 
10.4 Patient Information and Consent 
Prior to the beginning of the study, the investigator must have received from the IRB the written 
approval or favorable opinion of the informed-consent form and any other written information to 
be provided to patients. The written approval of the IRB together with the approved patient 
information/informed consent forms must be filed in an appropriate electronic or paper study 
regulation binder. The informed consent form must contain all elements required by authorized 
regulatory authorities and the ICH GCP guidelines (E6), in addition to any other elements required 
by local regulations or institutional policy. 
Written informed consent must be obtained before any study-specific procedure takes place. 
Participation in the study and date of informed consent given by the patient should be documented 
appropriately in the patient’s files. A copy of the signed informed consent form must be provided 
to the patient. If applicable, it will be provided in a certified translation in the language understood 
by the patient, if not English. Signed consent forms must remain in each patient’s study file and 
must be available for verification by study monitors at any time. 
Documentation of informed consent may involve the use or On-Site or Remote Electronic 
Consent technology.  The subject may print or electronically save the form. If the subject prefers 
not to use Electronic Consent technology, the study team will provide a paper consent form for 
their signature.  
10.5 Patient Confidentiality and Disclosure of Data 
The Investigator must ensure that each patient’s anonymity is maintained as described below. 
On the eCRFs or other documents submitted to the Sponsor and/or its designee, patients must only 
be identiﬁed by trial, Patient Identification Number, and demographics, and pertinent restrictions 
of local regulations. No other personal identifiers will be used, and data will be de-identified in a 
manner compliant with Privacy Laws and, for US patients, the HIPAA regulations. Documents 
that are not for submission to the Sponsor and/or its designee (e.g., signed ICFs and Patient 
Information Sheets) should be kept in strict conﬁdence by the Investigator in compliance with 
Federal regulations or other applicable laws or International Conference on Harmonization (ICH) 
and Good Clinical Practice (GCP) Guidelines. The Investigator and institution must permit 
authorized representatives of the Sponsor and/or its designee, by representatives of the FDA, 
national and local health authorities, and the IRB direct access to review the patient’s original 
medical records for veriﬁcation of trial-related procedures and data. Direct access includes 
examining, analyzing, verifying, and reproducing any records and reports that are needed for the 
evaluation of the trial. The Investigator is obligated to inform the patient in the ICF that his/her 
trial-related records will be reviewed, by the above-named representatives. 


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Participants will be informed that data will be held on ﬁle, by the Sponsor, and that these data may 
be viewed by staff including the trial monitor and by external auditors on behalf of the Sponsor 
and appropriate regulatory authorities. Participants will also be informed that a (trial) study report 
will be prepared and may be submitted to regulatory authorities and for publication. However, 
participants will be identiﬁed in such reports only by Patient Identiﬁcation Number and 
demographics, pertinent to restrictions of local regulations. All patient data will be held in strict 
conﬁdence, as allowed by law. 
Upon the patient’s permission, medical information may be given to the patient’s personal 
physician or other appropriate medical personnel responsible for the patient’s welfare. 
10.6 Study Monitoring 
A representative of the data coordinating center will conduct site visits to inspect study data, 
patients’ medical records, and CRFs in accordance with ICH guidelines, GCP, and the respective 
national and local government regulations and guidelines. 
The clinical investigator will permit authorized representatives of the Sponsor and the respective 
national or local health authorities, other authorized regulatory authorities, and IRB to inspect 
facilities and records relevant to this study. 
10.7 Data Handling and Record Keeping 
10.7.1 Confidentially 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those 
regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study  
• Who will have access to that information and why  
• Who will use or disclose that information  
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts will be 
made to obtain permission to collect at least vital status (long term survival status that the subject 
is alive) at the end of their scheduled stud period. 
 
10.7.2 Source Documents  
Source data is all information, original records of clinical findings, observations, or other activities 
in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are 


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contained in source documents. Examples of these original documents, and data records include: 
hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial. 
10.7.3 Case Report Forms  
Data will be captured at each participating site by qualified study staff who will perform primary 
data collection from source-document reviews to electronic case report forms (eCRF) via 
Medidata Rave, the information technology endorsed by Mayo Clinic’s Clinical Trial 
Management System (CTMS) as described in Appendix/Attachment (please fill in 
Appendix/Attachment location info within protocol). Data reported in the eCRF derived from 
source documents should be consistent with the source documents or the discrepancies should be 
explained. Data will be entered for this study utilizing one or a combination of the following 
methods:  
1. Data may be captured electronically, without use of paper.  
2. Data may be transcribed from the Electronic Medical Record (EMR-an electronic source 
that must be available for review) into an EDC system, without use of paper.  
3. Data may be captured on paper (considered source documentation) and transcribed into 
the EDC system, BUT paper documentation must be retained and available for review  
 
10.7.4 Data Management  
Study sites will transcribe subject source data into eCRFs using Medidata Rave. The Medidata 
Rave system is compliant with 21 CFR (Code of Federal Regulations) Part 11 FDA (Food and 
Drug Administration) requirements. Edit checks, electronic queries, and audit trails are built into 
the system to ensure accurate and complete data collection and security. Data will be transmitted 
via the internet from investigational sites to a central hosting site, utilizing state-of-the-art 
encryption mechanisms to ensure security and confidentiality.  
10.7.5 Data Processing  
All data is entered into electronic case report forms (eCRF’s) through the Medidata Rave system. 
Case report forms are automatically rolled out based on a predetermined, visit based schedule to 
improve study staff workflow and data quality. Data is exported nightly to a secure FTP for 
analysis and reporting.  
10.7.6 Data Security and Confidentiality 
The Medidata Rave database access model is role based and fully auditable at the study, form, and 
field levels. Data is de-identified whenever possible and the ability to update data is limited to 
necessary staff. Access is managed by the Mayo Clinic Research Service Center, under a 


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controlled and monitored access request system. Metadata’s platform specifically supports 
Electronic Record and Electronic Signature (ER/ES) requirements, including US 21 CFR part 11. 
10.7.7 Data Quality Assurance/Data Clarification Process  
Each eCRF contains edit checks and custom functions to ensure the highest possible data quality. 
Only necessary eCRF’s are available for data entry to reduce the possibility of erroneous entry.  
10.7.8 Data Clarification Process  
The edit checks and custom functions on the eCRF’s trigger queries requesting the attention of 
appropriate study staff. The fields are marked in pink to allow study staff to quickly identify the 
data fields that require attention or actions. Additionally, secure email notifications are sent for 
adverse event tracking and monitoring. The data collected in the source documents for this trial 
will be entered into the trial EDC eCRF. An audit trail will maintain a record of initial entries and 
changes made; time and date of entry; and name of person making entry or change. For each 
participant enrolled, an eCRF must be completed and electronically signed by the investigator or 
authorized delegate from the trial staff. If a participant withdraws from the trial, the reason must 
be noted in the eCRF. If a participant is withdrawn from the trial because of a treatment-limiting 
adverse event, thorough efforts should be made to clearly document the outcome. 
The Investigator should ensure the accuracy, completeness and timeliness of the data reported to 
the Sponsor in the CRFs and in all required reports. 
10.8 Retention and Availability of Records 
The Investigator is required to retain the trial records and reports until at least 2-years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2-years have elapsed since the 
formal discontinuation of clinical development of the investigational product. If no marketing 
application is to be filed, or an application is not approved for the drug, the Investigator will retain 
the study (trial) records for 15 years after shipment and delivery of the drug for investigational use 
is discontinued and the Sponsor has so notified the FDA, per 21 CFR 312.57. Study (trial) records 
should, however, be retained longer if required by the applicable national and/or local regulatory 
requirements. 
The Investigator must make study (trial) data accessible to the monitor, other authorized 
representatives of the Sponsor, and regulatory agency inspectors upon request. A ﬁle for each 
patient must be maintained that includes the signed ICF and the Investigator’s copies of all source 
documentation related to that patient. The Investigator must ensure the reliability and availability 
of source documents from which the information on the CRF was transcribed. 
10.9 Independent Data Safety Monitoring Board (DSMB) 
The DSMB is an independent group consisting of qualified clinicians and at least one statistician. 
The DSMB will review the safety data, from the study. The DSMB will operate under a charter 
and will convene for safety review meetings at the interval.  


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10.10 Protocol Violations/Deviations 
Protocol violations include deviations from the inclusion and exclusion criteria, concomitant 
medication restrictions, and any other protocol requirement that results in a significant added risk 
to the patient or has an impact on the quality of the data collected or the outcome of the study. A 
deviation occurs when there is non-adherence to study procedures or schedules, as specified by the 
protocol, which does not involve inclusion/exclusion criteria or the primary endpoint and which 
does not place the patient at any added risk or affect the data quality or study outcome. Examples 
of deviations may include common out-of-window visits, a missed procedure, etc. Protocol 
violations will be reported in the final clinical study report, whereas protocol deviations may be 
mentioned but are not required to be reported. 
It is important to conduct the study according to the protocol. Protocol deviation waivers will not 
be prospectively granted by the sponsor. If minor protocol deviations occur, the clinical 
investigator must decide the most appropriate way to proceed with study activities and should 
consult the study representative for assistance. If major protocol deviations occur, the sponsor’s 
Medical Monitor must be notified immediately so that a decision about whether to keep the patient 
in the study can be made. 
Only when an emergency occurs that requires a departure from the protocol for an individual 
patient can there be a departure without the Sponsor’s pre-approval. The nature and reasons for the 
protocol deviation/violations will be recorded in the patient’s CRF, and the investigator must 
notify the Sponsor. 
Protocol deviations/violations will be reported in the final study report. 
10.11 Access to Source Documentation 
Authorized sponsor representatives will conduct site visits to inspect study data, patients’ medical 
records, and CRFs in accordance with ICH guidelines, GCPs, and the respective local and national 
government regulations and guidelines. 
The investigator will permit authorized representatives of the sponsor and the respective national 
or local health authorities, other authorized regulatory authorities, and IRB to inspect facilities and 
records relevant to this study. 
Each center will be visited at regular intervals by a monitor to ensure compliance with the study 
protocol, GCP, and legal aspects. This will include on-site checking of the CRFs for completeness 
and clarity, cross-checking with source documents, and clarification of administrative matters. 
All CRF data will be entered into a clinical database. Following the correction of any errors, the 
clinical database will be locked. 
10.12 Retention of Data 
The study file and all source data should be retained until notification is given by the sponsor for 
destruction. 


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If the investigator withdraws from the trial and relinquishes his/her responsibility for the 
maintenance and retention of records, he/she must notify the sponsor in writing so that 
arrangements can be made to properly store the trial materials. 
10.13 Financial Disclosure  
Clinical investigator/ sub-investigator must provide financial information and promptly update this 
information if any relevant changes occur during the course of the investigation and for one year 
following completion of the study. “The course of the study” refers to the time from the date the 
clinical investigator entered into an agreement with the Sponsor to conduct the study until the 
completion of the study. Completion of the study means that all study patients have been enrolled 
and follow-up of study data on all patients has been completed in accordance with the clinical 
protocol.  
A financial disclosure form (FDF) will be provided to the clinical investigator and all sub-
investigators who are directly involved in the treatment or evaluation of research patients prior to 
the site initiation visit. Clinical investigators are required to provide an updated FDF if there are 
changes in disclosable financial interests, arrangements or payments. Types of disclosable 
financial interests are provided on the FDF. Copies of the FDF will be included in the study Trial 
Master File. 
Upon the patient’s permission, medical information may be given to the patient’s personal 
physician or other appropriate medical personnel responsible for the patient’s welfare. 
10.14 Audits and Inspections 
In accordance with ICH, GCP and the Sponsor and/or its designee audit plans, this trial may be 
selected for audit. Inspection of site facilities (e.g., pharmacy, drug storage areas, laboratories) and 
review of trial-related records will occur to evaluate the trial conduct and compliance with the 
protocol, ICH, GCP, and applicable regulatory requirements. The Investigator/ institution should 
make available for direct access all requested trial-related records (ICH GCP 4.9.7) to 
appropriately qualified personnel from the Sponsor or its designees, or to health authority 
inspectors after appropriate notification. The verification of the CRF data must be by direct 
inspection of source documents. The Investigator/institution should take measures to prevent 
accidental or premature destruction of these documents (i.e., completed CRFs, Investigator site 
files, and any source documents should be stored in a protected secure location [ICH GCP 
4.9.4]). 
If for any reason the study trial records are moved to another location, the Investigator should 
notify the Sponsor of the new location. 
 
 


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11 REFERENCE LIST 
Amudala, N. A., Boukhlal, S., Sheridan, B., Langford, C. A., Geara, A., Merkel, P. A., Cornec, D. 
(2021). Obinutuzumab as Treatment for ANCA-Associated Vasculitis. Rheumatology (Oxford). 
Doi: 10.1093/rheumatology/keab916. 
Damoiseaux, J.G., Slot, M.C., Vaessen, M., Stegeman, C.A., Van Paassen, P., and Tervaert, J.W. 
(2005). Evaluation of a new fluorescent-enzyme immuno-assay for diagnosis and follow-up of 
ANCA-associated vasculitis. J Clin Immunol 25, 202-208. 
Furie,R.A., Aroca, G., Cascino, M.D., Garg, J.P., Rovin, B.H., Alvarez, A., Fragoso-Loyo, H., 
Zuta-Santillan, E., Schindler, T., Brunetta, P., Looney, C.M., Hassan, I.,  and Malvar, A. (2022). 
B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a 
randomised, double-blind, placebo-controlled trial. Ann Rheum Dis 81, 100-107.  
Gagez, A-L, Cartron, G. (2014). Obinutuzumab: a new class of anti-CD20 monoclonal antibody.  
Curr Opin Oncol 26, 484-491. 
Jones, R.B., Ferraro, A.J., Chaudhry, A.N., Brogan, P., Salama, A.D., Smith, K.G., Savage, C.O., 
and Jayne, D.R. (2009). A multicenter survey of rituximab therapy for refractory antineutrophil 
cytoplasmic antibody-associated vasculitis. Arthritis Rheum 60, 2156-2168. 
Kitching, A.R., Anders, H.J., Basu, N., Brouwer, E., Gordon, J., Jayne, D.R., Kullman, J., Lyons, 
P.A., Merkel, P.A., Savage, C.O.S., et al. (2020). ANCA-associated vasculitis. Nat Rev Dis 
Primers 6, 71. 
Levey, A.S., Stevens, L.A., Schmid, C.H., Zhang, Y.L., Castro, A.F., 3rd, Feldman, H.I., Kusek, 
J.W., Eggers, P., Van Lente, F., Greene, T., et al. (2009). A new equation to estimate glomerular 
filtration rate. Ann Intern Med 150, 604-612. 
McClure, M.E., Wason, J., Gopaluni, S., Tieu, J., Smith, R.M., Jayne, D.R., and Jones, R.B. 
(2019). Evaluation of PR3-ANCA Status After Rituximab for ANCA-Associated Vasculitis. J 
Clin Rheumatol 25, 217-223. 
McDowell, P.J., Stone, J.H., Zhang, Y., Honeyford, K., Dunn, L., Logan, R.J., Butler, C.A., 
McGarvey, L.P.A., and Heaney, L.G. (2020). Quantification of Glucocorticoid-Associated 
Morbidity in Severe Asthma Using the Glucocorticoid Toxicity Index. J Allergy Clin Immunol 
Pract. 
Merkel, P.A., Aydin, S.Z., Boers, M., Direskeneli, H., Herlyn, K., Seo, P., Suppiah, R., Tomasson, 
G., and Luqmani, R.A. (2011). The OMERACT core set of outcome measures for use in clinical 
trials of ANCA-associated vasculitis. J Rheumatol 38, 1480-1486. 
Robson, J.C., Dawson, J., Doll, H., Cronholm, P.F., Milman, N., Kellom, K., Ashdown, S., 
Easley, E., Gebhart, D., Lanier, G., et al. (2018). Validation of the ANCA-associated vasculitis 
patient-reported outcomes (AAV-PRO) questionnaire. Ann Rheum Dis 77, 1157-1164. 
Specks, U., Merkel, P.A., Seo, P., Spiera, R., Langford, C.A., Hoffman, G.S., Kallenberg, C.G., St 
Clair, E.W., Fessler, B.J., Ding, L., et al. (2013). Efficacy of remission-induction regimens for 
ANCA-associated vasculitis. N Engl J Med 369, 417-427. 
Stone, J.H., Hoffman, G.S., Merkel, P.A., Min, Y.I., Uhlfelder, M.L., Hellmann, D.B., Specks, U., 
Allen, N.B., Davis, J.C., Spiera, R.F., et al. (2001). A disease-specific activity index for Wegener's 
granulomatosis: modification of the Birmingham Vasculitis Activity Score. International Network 
for the Study of the Systemic Vasculitides (INSSYS). Arthritis Rheum 44, 912-920. 
Stone, J.H., Merkel, P.A., Spiera, R., Seo, P., Langford, C.A., Hoffman, G.S., Kallenberg, C.G., St 
Clair, E.W., Turkiewicz, A., Tchao, N.K., et al. (2010). Rituximab versus cyclophosphamide for 
ANCA-associated vasculitis. N Engl J Med 363, 221-232. 


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Thompson, G.E., Fussner, L.A., Hummel, A.M., Schroeder, D.R., Silva, F., Snyder, M.R., 
Langford, C.A., Merkel, P.A., Monach, P.A., Seo, P., et al. (2020). Clinical Utility of Serial 
Measurements of Antineutrophil Cytoplasmic Antibodies Targeting Proteinase 3 in ANCA-
Associated Vasculitis. Front Immunol 11, 2053. 
Tomasson, G., Boers, M., Walsh, M., LaValley, M., Cuthbertson, D., Carette, S., Davis, J.C., 
Hoffman, G.S., Khalidi, N.A., Langford, C.A., et al. (2012). Assessment of health-related quality 
of life as an outcome measure in granulomatosis with polyangiitis (Wegener's). Arthritis Care Res 
(Hoboken) 64, 273-279. 
van Dam, L.S., Dirikgil, E., Bredewold, E.W., Ray, A., Bakker, J.A., van Kooten, C., Rabelink, 
T.J., and Teng, Y.K.O. (2020). Proteinase-3-anti-neutrophil cytoplasmic antibodies (PR3-
ANCAs) predict relapses in ANCA-associated vasculitis patients after rituximab. Nephrol Dial 
Transplant. 
Yates, M., and Watts, R. (2017). ANCA-associated vasculitis. Clin Med (Lond) 17, 60-64. 
 


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Appendix 1 
Schedule of Events 
(A) Procedures During the Remission Induction Period 
Study Procedures 
Screening 
 
Remission Induction Period 
Visit 
V11 
V1 
a-c 
V2 
V3 
Month 
1/V4  
Month 
2/V5 
Month 
4/V6 
Month 
6/V7 
Visit Day 
-14 - 0 
 
0 
14 
30 
60 
120 
180 
Visit Window 
 
 
 
±2 
±2 
±3 
±5 
±10 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
X 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
Medical hist. 
including AAV 
history and prior 
medication 
X 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
Study drug 
administration2 
 
 
X 
X 
 
 
 
 
Glucocorticoid use3 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
 
X 
X 
X 
X 
X 
X 
Physical 
Examination 
X 
 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
X 
AE assessment 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication 
 
X 
X 
X 
X 
X 
X 
X 
BVAS/ WG Score/ 
Remission/Relapse 
evaluation 
X 
 
 
X 
X 
X 
X 
X 
AAV-PRO 
 
 
X 
 
 
 
 
X 
VCRC WG/MPO 
Disease Activity & 
Transition 
Assessment 
X 
 
 
X 
X 
X 
X 
X 
GTI assessment 
 
 
X 
 
 
 
 
X 
VDI 
 
 
X 
 
 
X 
 
X 
Clinical Laboratory 
Test Collection 
X4 
 
 
X 
X 
X 
X 
X 
Blood sample for 
HSFC and/or 
TBNK5 
X 
 
X 
 
X 
X 
X 
X 
Serum for ANCA 
Antibody5 
X 
 
 
 
 
 
 
X 
Blood for PBMC5 
X 
 
X 
 
 
X 
X 
X 
Serum for 
biomarkers5 
 
 
X 
 
X 
X 
X 
X 
PAXgene RNA5 
 
 
X 
 
X 
 
 
X 
Whole Blood 
EDTA tube for 
 
 
X 
 
X 
 
 
X 


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Study Procedures 
Screening 
 
Remission Induction Period 
Visit 
V11 
V1 
a-c 
V2 
V3 
Month 
1/V4  
Month 
2/V5 
Month 
4/V6 
Month 
6/V7 
Visit Day 
-14 - 0 
 
0 
14 
30 
60 
120 
180 
Visit Window 
 
 
 
±2 
±2 
±3 
±5 
±10 
molecular B cell 
enumeration 
Plasma for 
biomarkers5 
 
 
X 
X 
X 
X 
X 
X 
1 Any required screening assessments conducted as part of standard of care within 14 days of Day 0 may be used as a part of 
screening. 
2 For subjects who meet treatment failure criteria, dosing with obinutuzumab and glucocorticoids should be administered as 
soon as possible.  The clinic visits will follow the same schedule as the first day of dosing (V2) 
3 Glucocorticoid regimen must be recorded for the first 16 weeks and in subsequent visits if glucocorticoid use is needed. 
4 ANCA test to be performed at local lab for assessment of study eligibility. 
5 Samples will be drawn before administration of study drug on dosing days. 
 
 


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(B) Procedures During the Maintenance Period 
Study Procedures 
Follow-Up Period 
Visit 
Month 9 
V8 
Month 
12 V9 
Month 
15 V10 
Month 
18 V11 
Unscheduled 
V991 
Visit Day 
D270 
D360 
D450 
D540 
N/A 
Visit Window 
±10 
±10 
±10 
±10 
 
Informed consent 
 
 
 
 
 
Inclusion/exclusion 
 
 
 
 
 
Demography 
 
 
 
 
 
Medical history including AAV history and 
prior medication 
 
 
 
 
 
Randomization 
 
 
 
 
 
Study drug administration 
 
 
 
 
 
Glucocorticoid use2 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
ECG 
 
 
 
X 
 
AE assessment 
X 
X 
X 
X 
X 
Concomitant medication 
X 
X 
X 
X 
X 
BVAS/ WG Score/ Remission/Relapse 
evaluation 
X 
X 
X 
X 
X 
AAV-PRO 
 
X 
 
X 
X 
VCRC WG/MPO Disease Activity & 
Transition Assessment 
X 
X 
X 
X 
X 
GTI assessment 
X 
X 
X 
X 
X 
VDI 
X 
X 
X 
X 
 
Clinical Laboratory Test Collection 
X 
X 
X 
X 
X 
Blood sample for HSFC and/or TBNK3 
X 
X 
X 
X 
X 
Serum for ANCA Antibody3 
X 
X 
X 
X 
X 
Blood sample for PBMC3 
X 
X 
X 
X 
X 
Serum for biomarkers3 
X 
X 
X 
X 
X 
PAXgene RNA3 
 
X 
 
X 
 
Whole Blood EDTA Tube for molecular B cell 
enumeration 
 
X 
 
X 
 
Plasma for biomarkers3 
X 
X 
X 
X 
X 
1 Subjects who experience signs or symptoms that indicate disease recurring should make an unscheduled visit so 
appropriate evaluation and treatment can be initiated. If the visit fits the window of a pre-scheduled visit, only one visit is to 
be completed and the data should be captured in the pre-scheduled visit case report forms. 
2 Glucocorticoid regimen must be recorded for the first 16 weeks and in subsequent visits if glucocorticoid use is needed. 
3 Samples will be drawn before administration of study drug on dosing days.


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Appendix 2 
Schedule of Laboratory Testing 
Study Procedures 
Screening 
Remission Induction Period 
Maintenance Period 
Visit 
V11 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
11 
V99 
Visit Day 
D-14 – D0 
D0 
D14 
D30 
D60 
D120 
D180 
D270 
D360 
D450 
D540 
Unscheduled 
Hematology2 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry3  
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
HbA1c & lipids4 
 
X 
 
 
 
X 
X 
 
X 
 
X 
 
ANCA negativity5 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Immunoglobulins6  
 
X 
 
 
 
 
X 
 
 
 
X 
 
CD197  
X 
X 
 
 
 
 
X 
 
 
 
 
X 
Infectious disease testing8,9 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy (WCBP only); 
FSH10 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood sample for flow 
cytometry (TBNK)11  
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Blood sample for HSFC11 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Serum for biomarkers11 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood sample for 
PBMCs11,12  
X 
X 
 
 
X 
 
X 
 
 
 
X 
 
PAXgene RNA11 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
Whole Blood EDTA tube 
for molecular B cell 
enumeration 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
Plasma for biomarkers11 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 Any required screening assessments conducted as part of standard of care within 14 days of Day 0 may be used as a part of screening. 
2 Hematology tests include: hemoglobin, hematocrit, erythrocyte count (red blood cell [RBC] count), thrombocyte count (platelets), leukocyte count (white blood cell 
[WBC] count) with differential in absolute counts (including neutrophils, eosinophils, basophils, lymphocytes, and monocytes, erythrocyte sedimentation rate (ESR). 
3 Serum chemistry tests include: comprehensive metabolic profile including aspartate aminotransferase (AST); alanine aminotransferase (ALT); total, direct, and indirect 
bilirubin levels; alkaline phosphatase (ALP); albumin, creatinine; estimated GFR, blood urea nitrogen (BUN) carbon dioxide (C02, and glucose (random)); total protein; C-
Reactive Protein.   
4 Hemoglobin A1c and Lipids: total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides should be drawn on Baseline, Month 4, 6, 12 and 18 only. 


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5 PR3 ANCA antibody will be determined centrally at the Mayo clinical laboratory; MPO ANCA and PR3 ANCA antibodies will be measured by local laboratory at 
screening visit only to determine eligibility. 
6 Total immunoglobulin, IgG, IgM, IgA, and IgE will be measured. 
7 Whole blood flow cytometry will be performed to determine CD19+ B cells in relapsing patients only. 
8 Infectious disease tests include: hepatitis B (surface antigen and core antibodies), HCV, and HIV, tuberculosis (TB) testing, COVID-19 by nasal swab. Infectious disease 
will be tested at screening (V1) and when clinically indicated. 
9 Preferred tuberculosis (TB) testing method is QuantiFERON-TB Gold (QFT). If patient has a negative purified-protein derivative tuberculin skin test (PPD TST) result 
from a test performed with 1 year of day 0, QFT does not need to be performed at screening.  
10 Postmenopausal females < 55 years of age (defined as amenorrhea >1 year) must have menopause confirmed by elevated follicle-stimulating hormone (FSH) levels at 
screening. 
11 Samples will be drawn before administration of study drug on dosing days. 
12 PBMC will be processed and cryopreserved for the biomarkers. 
 
 


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Table 6 Laboratory Sample Handling 
Sample 
Tests 
Blood Vol. 
(mL) 
Testing / Storage 
Lab 
Storage/ Temp 
(ºC) 
Routine Safety Lab Testing 
Whole blood 
Hematology 
2 
Local 
N/A 
Whole blood 
HbA1c 
2 
Local 
N/A 
Whole blood 
Flow cytometry CD19 
3 
Local 
N/A 
Serum 
Comprehensive metabolic panel & Liver enzymes 
2 
Local 
N/A 
Serum (fasted) 
Lipid panel 
3 
Local 
N/A 
Serum 
ANCA antibody (screening) 
2 
Local 
N/A 
Serum 
Immunoglobulins 
5 
Local 
 
Serum/Nasal swab 
Infectious diseases 
3 
Local 
 
Urine (WOCBP) 
Pregnancy 
 
N/A 
In clinic 
N/A 
Serum (WOCBP) 
FSH menopause confirmation 
2 
Local 
N/A 
Urine 
Urinalysis 
N/A 
Local 
N/A 
Research Testing For Outcome Assessment 
Serum 
ANCA antibody 
3 
Mayo 
-80 
Mechanistic Study Biomarkers 
Whole blood 
Blood sample for HSFC and/or TBNK 
5 
LabCorp 
N/A  
PBMC 
Sample for biomarkers 
50 
Mayo 
-80  
Serum 
Sample for biomarkers 
5 
LabCorp 
-80  
Serum 
Sample for biomarkers 
10 
Mayo 
-80  
Plasma 
Sample for biomarkers 
6 
Mayo 
-80  
Paxgene RNA 
Sample for biomarkers 
5 
Mayo 
-80 
Whole Blood EDTA tube 
for molecular B cell 
enumeration 
Sample for biomarkers 
5 
LabCorp 
-80 
Abbreviation: PBMC: peripheral blood mononuclear cells; WOCBP: women of childbearing potential.  
 


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Appendix 3 
Chapel Hill Consensus Conference 
DIAGNOSTIC CRITERIA 
Widely accepted diagnostic criteria—as opposed to classification criteria or definitions—have not yet 
been developed for Wegener’s Granulomatosis (WG) and microscopic polyangiitis (MPA). In 1994, 
the Chapel Hill International Consensus Conference developed definitions for these vasculitides and 
some of their mimickers.1 These definitions, along with the American College of Rheumatology 
(ACR) Criteria for the classification of vasculitides,2 are useful in formulating the diagnostic criteria 
that will be applied to determine a participant’s eligibility for this clinical trial. 
Chapel Hill Consensus Conference Definitions for Microscopic Polyangiitis 
• Necrotizing vasculitis with few or no immune deposits affects small vessels (i.e., capillaries, 
venules, or arterioles). 
• Necrotizing arteritis involving small and medium-sized arteries may be present. 
• Necrotizing glomerulonephritis is very common.  
• Pulmonary capillaritis often occurs.   
ACR Criteria for the Classification of Wegener’s Granulomatosis 
Among a group of patients with various forms of systemic vasculitis, the presence of at least two of 
these four criteria is associated with a sensitivity of 88.2% and a specificity of 92.0% for WG. 
• Nasal or oral inflammation: painful or painless oral ulcers or purulent or bloody nasal 
discharge 
• Abnormal chest radiograph: nodules, fixed infiltrates, or cavities 
• Urinary sediment: microhematuria or red cell casts 
• Granulomatous inflammation on biopsy: granulomatous inflammation within the wall of an 
artery or in the perivascular area 
ACR Criteria for the Classification of Churg-Strauss Syndrome 
Although we wish to exclude Churg-Strauss syndrome (CSS) from this trial, we will use the following 
ACR criteria for the classification of this disorder: 
Among a group of patients with various forms of systemic vasculitis, the presence of at least four of 
these six criteria is associated with a sensitivity of 85.0% and a specificity of 99.7% for CSS. 
• Asthma: wheezing or high-pitched rales 
• Eosinophilia: >10% of white blood cell differential 
 
1Jennette JC et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis 
Rheum. 1994; 37:187–192. 
2 Fries JF et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis. Summary. Arthritis 
Rheum. 1990; 33:1135–1136. 


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• Mononeuropathy or polyneuropathy: mononeuropathy, multiple mononeuropathies, or 
polyneuropathy attributable to vasculitis 
• Pulmonary infiltrates, nonfixed: migratory or transitory pulmonary infiltrates 
• Paranasal sinus abnormality: acute or chronic paranasal sinus pain, tenderness, or radiographic 
opacification  
• 
Extravascular eosinophils: biopsy, including artery, arteriole, or venule showing 
accumulations of eosinophils in extravascular areas 
 
 
 


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Appendix 4 
CKD-EPI Creatinine Equation  
CKD-Epi equation is developed in 2009 by the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) and is the recommended method for estimating GFR in adults (Levey et al., 2009). It is 
designed for use with laboratory creatinine values that are standardized to the isotope dilution mass 
spectrometry (IDMS) and estimates GFR from serum creatinine, age, sex, and race. The CKD-Epi 
equation uses a 2-slope “spline” to model the relationship between estimated GFR and serum 
creatinine, and a different relationship for age, sex and race. 
For the PRRR study, the race will not be factored in to estimate the GFR.  The CKD-Epi equation 
expressed eGFR as a single equation is shown below: 
eGFR = 141 × min(SCr/κ, 1)α × max(SCr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] 
eGFR (estimated glomerular filtration rate) = mL/min/1.73 m2 
SCr (standardized serum creatinine) = mg/dL 
κ = 0.7 (females) or 0.9 (males) 
α = -0.329 (females) or -0.411 (males) 
min = indicates the minimum of SCr/κ or 1 
max = indicates the maximum of SCr/κ or 1 
age = years 
 
 


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Appendix 5 
BVAS/WG 
The BVAS for Wegener's granulomatosis (BVAS/WG) is a modification of BVAS specifically 
designed for use in studies of granulomatosis with polyangiitis (Wegener's) (Stone et al., 2001) 


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• Disease manifestations are to be scored only when they are attributable to active vasculitis. If there 
is reasonable evidence a manifestation is likely attributable to another etiology (e.g., infection, 
other co-morbidity), it should not be scored. 
• Persistent disease scoring should be used for all manifestations due to active (but not new or 
worsened) vasculitis. 
• Specialist opinion, or the results of laboratory or imaging investigations may be required for some 
items. 
• The items of serum creatinine in section 8. “Renal” should be scored only on the first visit. 
• There are several items, i.e. Nodules or cavities that are not compatible with persistent disease and 
can only be scored under new/worse scoring. 
• When the BVAS/WG is assessed for the first time in that patient or any of the features have 
started or deteriorated in the past month, please use the new/worse scoring. 
• Bold printed and starred items are given 3 points, whereas all other items are assigned 1 point. 
• Features persisting for >3 months represent damage rather than disease activity and should be 
scored on a Vasculitis Damage Index (VDI) form and not on a BVAS/WG form.  


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Appendix 6 
AV-PRO Assessment 
 
 
 


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Appendix 7 
VCRC WG/MPA Disease Activity and Transition Assessment 
 
 


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Appendix 8 
Vasculitis Damage Index 
Appendix 9 
Glucocorticoid Toxicity Index  


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(Excerpt from “Quantification of Glucocorticoid-Associated Morbidity in Severe Asthma Using the 
Glucocorticoid Toxicity Index”, 2020 Elsevier Inc.) 
 
Development of the GTI 
The original version of the GTI (GTI 1.0) underwent preliminary validation by a multispecialty 
group of 19 physician experts.E1 These experts represented 10 medical subspecialties: pulmonary 
medicine, rheumatology, pediatric rheumatology, nephrology, neurology, ophthalmology, 
dermatology, infectious disease, maternal-fetal medicine, and psychiatry. The investigator group, 
which included 10 researchers from the United States and 9 from Europe, Canada, or Australia, 
employed group consensus methods and multicriteria decision analysis (MCDA).E2 
 
A full explanation of how the items required to give a complete quantiﬁcation of glucocorticoid 
(GC)-related toxicity were determined is outlined in the paper by Miloslavsky et al.E1 In brief, 
items to be included in the GTI scoring were determined on the following principles: (1) they 
occur commonly in GC- exposed patients ( 5% of such patients); (2) they are independent of other 
items in the GTI; (3) they are more likely to result from GC exposure than from the underlying 
disease; (4) they are likely to change over a short period of time (i.e., to either improve or worsen 
over a period of at least 3 months); and (5) they can be measured simply and noninvasively. A small 
number of the measured variables may be outside the usual clinical measurements for a given 
disease, but these are easy to collect and important for assessing GC toxicity as part of routine care.  
 
The GTI assigns relative weights that have been determined systematically to each toxicity item 
in the Composite Index. These weights were developed through MCDAE2 using pairwise “forced-
choice” methods within the 1000Minds platform; all possible combinations of Composite Index 
items were ranked in order of toxicity severity. A point system reﬂecting the relative weight of 
each item in terms of toxicity was thereby derived. 
 
Scoring the GTI 
The fundamental principle with regard to the scoring approach is that an improvement in GC 
toxicity is given the same absolute weight as a worsening of GC toxicity of the same (but opposite) 
magnitude. This approach generated 2 scores from the Composite Index data called: (1) the 
Aggregate Improvement Score and (2) the Cumulative Worsening Score. 
Aggregate Improvement Score 
When starting a new treatment, the AIS is important in establishing that the new therapy is 
effective at diminishing any GC toxicity over time. With the AIS, toxicities are removed if they 
improve or resolve completely over longitudinal follow-up. Toxicities can also be added to the 
AIS over time if new or worsened GC toxicities occur. With the AIS, improvement in GC toxicity 
has the same absolute value as does worsening to the same degree in the opposite direction. 
 
Cumulative Worsening Score 
On the other hand, documentation of cumulative GC toxicity that occurs over the course of the 
trial or introduction of a new treatment is important, even if some toxicities are transient. The CWS 
is designed to assess the summative GC toxicity, regardless of whether the toxicity has lasting 
effects or resolves with time. New toxicities that occur are added to the CWS total, but toxicities 
that resolve on follow-up are not removed. The CWS serves as a lasting record of any GC toxicity 
that has occurred and can only increase or remain the same over time. 


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The GTI: Composite Index and Specific List 
The GTI is designed to measure change in GC toxicity between 2 points in time and includes 2 
components, a Composite Index and a Speciﬁc List. The full Composite Index includes 9 domains 
and a total of 31 unique weighted items (see below). The Composite Index captures information 
about common GC-induced morbidities that distinguish high GC users from low GC users. The 
domains of toxicity represented in the Composite Index are well recognized by both clinicians and 
patients as being important: BMI, glucose tolerance, blood pressure, lipids, GC- induced myopathy, 
bone mineral density, skin toxicity, neuro- psychiatric effects and infections. Important to the 
GTI’s purpose of recording change in GC toxicity, the domains of the Composite Index all 
represent elements of GC toxicity that are expected to either worsen or improve with variations in 
GC doses over time. 
 
The Speciﬁc List was created as the second component of the GTI because not all GC toxicities are 
either sufﬁciently common or easily measurable for inclusion in the Composite Index. Nevertheless, 
even relatively uncommon or difﬁcult-to-measure toxicities are important to record because such 
morbidities contribute substantially to the overall burden of GC use. The Speciﬁc List permits a 
more complete accounting of cumulative GC toxicity than that afforded by the Composite Index 
alone. Examples of toxicities included in the Speciﬁc List are osteonecrosis and posterior 
subcapsular cataracts, reﬂecting GC- induced damage that is irreversible. Because items in the  
Speciﬁc List occur rarely, often reﬂect cumulative GC toxicity, and frequently have a 
disproportionate impact on patients’ quality of life, weights are not assigned to Speciﬁc List items.  
 
The Speciﬁc List includes 11 domains (9 of which are also shared by the Composite Index) and 
23 unique items (see below). Together, the Composite Index and the Speciﬁc List aspire to capture 
the full sweep of GC toxicity that is relevant to patients. 
 
Weights 
The GTI assigns systematically determined relative weights to each toxicity item in the Composite 
Index. These weights were developed through MCDA.E2 Using pairwise “forced-choice” methods 
within the 1000Minds platform, all possible combinations of Composite Index items were ranked 
in order of toxicity severity. A point system reﬂecting the relative weight of each item in terms of 
toxicity was thereby derived. The MCDA method is more systematic than group consensus 
methods such as Delphi exercises, in which investigators are asked to order all possible toxicities or 
assign relative weights. The MCDA method also carries a lower cognitive burden for investigators 
involved in a consensus exercise, because investigators are required to compare only 2 items at a 
time. This MCDA approach has been employed now in multiple studies developing classiﬁcation 
criteria for immune-mediated diseases.E3-E6 
 
 


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Table E1.  Approach to calculating the baseline GTI Score: toxicities assigned weighted score: 
toxicities assigned weighted scores from the Composite Index to establish a baseline GTI score 
Toxicity Domain 
 
Points 
Body Mass Index 
BMI < 27 
0 
 
BMI ≥ 27 or < 30 
21 
 
BMI ≥ 30 
36 
Glucose Metabolism 
HgbA1c < 5.7  
0 
 
HgbA1c <5.7 but on medication  
32 
 
HgbA1c ≥ 5.7 
32 
 
HgbA1c ≥ 5.7 but on medication  
44 
 
Diabetic retinopathy, nephropathy, or 
neuropathy (count only one) 
44 
Blood Pressure 
Normotensive: systolic ≤ 120 and diastolic ≤ 85 
no medications 
0 
 
Systolic ≤ 120 and diastolic ≤ 85 but on 
medications 
19 
 
Systolic > 120 or diastolic > 85 on no 
medications 
19 
 
Systolic > 120 or diastolic >85 and on 
medications 
44 
 
Hypertensive emergency or PRES (count only 
one) 
44 
Lipid metabolism 
LDL ≤ target 
0 
 
LDL ≤ target but on medications  
10 
 
LDL > target on no medications  
10 
 
LDL > target on treatment  
30 
Bone/tendon 
Normal BMD or no known history of 
osteoporosis 
0 
 
Osteoporosis 
29 
 
Insufficiency fracture secondary to osteoporosis 29 
 
Osteonecrosis  
29 
 
Tendon rupture while on corticosteroid 
29 
Glucocorticoid myopathy 
No myopathy 
0 
 
Minor glucocorticoid myopathy 
9 
 
Moderate glucocorticoid myopathy  
63 
 
Sever glucocorticoid myopathy  
63 
Skin 
No skin toxicity 
0 
 
Minor skin toxicity (1 or more than 1 minor 
skin item) 
8 
 
Moderate skin toxicity ( 1 or more than 1 
moderate skin item) 
26 
 
Severe Skin toxicity (1 or more than 1 severe 
skin toxicity) 
26 
 
Select only 1 (minor, moderate or severe) 
 


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Neuropsychiatric 
No neuropsychiatric toxicity 
0 
 
Minor (1 or more than 1 minor NP item: 
Insomnia, mania, depression, cognitive) 
11 
 
Moderate (1 or more than 1 moderate NP item: 
insomnia, mania, depression, cognitive) 
74 
 
Severe (1 or more than 1 severe NP item: 
insomnia, mania, depression, cognitive) 
74 
 
Psychosis 
74 
 
Glucocorticoid-induced violence 
74 
 
Select only 1 (minor, moderate or severe) 
 
Infection 
No GTI-relevant infections within the 
prebaseline GTI interval of the study  
0 
 
Oral or vaginal candidiasis or noncomplicated 
zoster (<grade 3) within the prebaseline GTI 
interval of the study  
19 
 
Grade 3 or 4 infection within the pre-baseline 
GTI interval of the study  
93 
Ocular 
Increased IOP 
33 
 
Posterior subcapsular cataract 
33 
 
Central Serous retinopathy 
 33 
Gastrointestinal  
GI perf absence of NSAIDS 
33 
 
PUD without Helicobacter pylori 
33 
Endocrine 
Adrenal insufficiency 
33 
 
BMD, bone mineral density; GI, gastrointestinal; GTI, Glucocorticoid Toxicity Index; HgbA1c, glycated 
haemoglobin; IOP, intraocular pressure; LDL, low density lipoprotein; NP, neuropsychiatric; NSAID, 
nonsteroidal anti-inﬂammatory drug; PRES, posterior reversible encephalopathy syndrome; PUD, peptic ulcer 
disease.*Minor: Acneiform rash (grades 1-2), easy bruising (grade 1), hirsutism (grade 1), atrophy/striae 
(grade 1), erosions/ulceration (grade 1). Moderate: Acneiform rash (grades 3), easy bruising (grade 2), 
hirsutism (grade 2), atrophy/striae (grade 2), erosions/tears/ulceration (grade 2). Severe: Acneiform rash (grade 
4), atrophy/striae (grade 3), erosions/tear/laceration (grade 3). 
 


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Table E2. GTI  Composite Index: domains and weights of the 31 unique items in 9 domains. 
Domains 
Score 
1. Change in Body Weight 
(BMI) 
Decrease by ≥ 5 BMI units 
-36 
 
Decrease by > 2 but < 5 BMI units 
-21 
 
No significant change (± 2 BMI units) 
0 
 
Increase of 2 to < 5 BMI units 
21 
 
Increase of 5 or more BMI units 
36 
2. Glucose metabolism 
Improvement in HbA1c AND decrease in 
medication  
-44 
 
Improvement in HbA1c OR decrease in 
medication  
-32 
 
No significant change 
0 
 
Increase in HbA1c OR increase in 
medication 
32 
 
Increase in HbA1c AND increase in 
medication 
44 
3. Blood Pressure 
Improvement in BP AND decrease in 
medication  
-44 
 
Improvement in BP OR decrease in 
medication 
-19 
 
No significant change 
0 
 
Increase in BP OR increase in medication  
19 
 
Increase in BP AND increase in medication 
44 
4. Hyperlipidemia 
Decrease in LDL AND decrease in 
medication  
-30 
 
Decrease in LDL OR decrease in medication 
-10 
 
No significant change 
0 
 
Increase in LDL OR increase in medication 
10 
 
Increase in LDL AND increase in medication 
30 
5. Bone health (BMD) 
Increase in BMD (gain of more than 0.5) 
-29 
 
No significant change in BMD (± 0.5) 
0 
 
Decrease in BMD (loss of more than 0.5) 
29 


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6. Corticosteroid myopathy 
Moderate weakness to none 
-63 
 
Moderate-to-mild weakness 
-54 
 
Mild weakness to none 
-9 
 
No significant change 
0 
 
None-to-mild weakness (without functional 
limitation) 
9 
 
Mild-to-moderate weakness 
54 
 
None-to-moderate weakness (With functional 
limitation) 
63 
7. Skin corticosteroid-related 
toxicity 
Decrease in skin toxicity – moderate to None 
-26 
 
Decrease in skin toxicity – moderate to mild 
-18  
 
Decrease in skin toxicity – mild to none 
-8 
 
No significant change 
0 
 
Increase in skin toxicity – none to mild  
8 
 
Increase in skin toxicity – mild to moderate 
18 
 
Increase in skin toxicity – none to moderate  
26 
8. Neuropsychiatric – 
corticosteroid-related 
symptoms 
Decrease in NP toxicity – moderate to none 
-74 
 
Decrease in NP toxicity – moderate to mild 
-63 
 
Decrease in NP toxicity – mild to none 
-11 
 
No significant change 
0 
 
Increase in NP toxicity – none to mild 
11 
 
Increase in NP toxicity – mild to moderate 
63 
 
Increase in NP toxicity – none to moderate 
74 
9. Infection 
No infection  
0 


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Oral of vaginal candidiasis or uncomplicated 
zoster (<grade 3) 
19 
 
Grade 3, 4 or 5 infection  
93 
BMD, bone mineral density; GTI, Glucocorticoid Toxicity Index; HgbA1c, glycated haemoglobin; 
LDL, low density lipoprotein; NP, neuropsychiatric. 


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Table E3. GTI specific list: 11 domains (9 of which are shared by the Composite Index and 23 unique 
Items 
Description 
At Baseline 
or Before 
New since 
baseline 
Body Mass Index (BMI) 
 
 
• An absolute increase in BMI of more than 8 units (and 
24.9 kg/m² 
 
 
Blood Pressure 
 
 
• Hypertensive emergency  
 
 
• PRES (Posterior reversible encephalopathy syndrome 
 
 
Endocrine 
 
 
• Symptomatic adrenal insufficiency 
 
 
Bone Health 
 
 
• Osteonecrosis of one joint 
 
 
• Osteonecrosis of more than one joint 
 
 
• Bone mineral density decrease >6% 
 
 
• Insufficiency fracture 
 
 
• Insufficiency fracture in more than one bone 
 
 
Muscle and Tendon 
 
 
• Severe glucocorticoid myopathy  
 
 
• Tendon rupture 
 
 
• More than 1 tendon rupture 
 
 
Eye 
 
 
• Central Serous Retinopathy 
 
 
• New-onset or worsened elevation of intraocular pressure 
requiring treatment or change in treatment 
 
 
• Posterior subcapsular cataracts (or history of same) 
 
 
Infection 
 
 
• Grade 4 infection 
 
 


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• Grade 5 infection 
 
 
Glucose tolerance 
 
 
• Diabetic nephropathy 
 
 
• Diabetic neuropathy 
 
 
• Diabetic retinopathy 
 
 
Gastrointestinal Tract 
 
 
• Gastrointestinal perforation (occurring in the absence of 
regular nonsteroidal anti-inflammatory drug use) 
 
 
• Peptic Ulcer disease confirmed by endoscopy (excluding 
Helicobacter pylori) 
 
 
Skin 
 
 
• Sever skin toxicity  
 
 
Neuropsychiatric 
 
 
• Psychosis, defined as hallucinations, delusions, or 
disorganized thought process (occurring in the absence of 
mania, delirium, or depression). 
 
 
• Glucocorticoid-induced violence toward self or others 
 
 
Other Glucocorticoid toxicities 
 
 
 
 
 
GTI, Glucocorticoid Toxicity Index. 
 


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REFERENCES 
E1. Miloslavsky EM, Naden RP, Bijlsma JWJ, Brogan PA, Brown ES, Brunetta P, et al. 
Development of a Glucocorticoid Toxicity Index (GTI) using multicriteria decision analysis. 
Ann Rheum Dis 2017;76:543-6. 
E2. Hansen P, Ombler F. A new method for scoring additive multi-attribute value models using 
pairwise rankings of alternatives. J Multi-Criteria Decis Anal 2008;15:87-107. 
E3. Neogi T, Jansen TLTA, Dalbeth N, Fransen J, Schumacher HR, Berendsen D, et al. 2015 
Gout classiﬁcation criteria: an American College of Rheumatology/ European League Against 
Rheumatism collaborative initiative. Ann Rheum Dis 2015;74:1789-98. 
E4. Johnson SR, Naden RP, Fransen J, Van Den Hoogen F, Pope JE, Baron M, et al. Multicriteria 
decision analysis methods with 1000Minds for developing systemic sclerosis classiﬁcation 
criteria. J Clin Epidemiol 2014;67:706-14. 
E5. Aringer M, Costenbader K, Daikh D, Brinks R, Mosca M, Ramsey-Goldman R, et al. 2019 
European League Against Rheumatism/American College of Rheu- matology Classiﬁcation 
Criteria for systemic lupus erythematosus. Arthritis Rheumatol 2019;71:1400-12. 
E6. Neogi T, Aletaha D, Silman AJ, Naden RL, Felson DT, Aggarwal R, et al. The 2010 
American College of Rheumatology/European League against Rheuma- tism classiﬁcation 
criteria for rheumatoid arthritis: phase 2 methodological report. Arthritis Rheum 
2010;62:2582-91. 
 
 


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Appendix 10 
Clinical Trial Management Systems (CTMS) 
CTMS is the Mayo Clinic Research Committee-endorsed institutional resource for clinical data 
management. CTMS is a robust institutional effort initiated in 2010 to address emerging changes 
within the data and statistical coordinating centers affiliated with NCI-funded cooperative groups. 
In 2010, NCI selected Medidata Rave® 
) as the required data collection 
tool for all cooperative studies. To capitalize on Mayo Clinic and the NCI’s investment in 
Medidata Rave®, Mayo Clinic formalized a three-tier data management infrastructure with the 
Medidata Rave® product as the premier system.  
Medidata Rave® is a product for multi-center clinical trials conducted under 21 CFR Part 11 
requirements. This web-based system provides ease of use coupled with an integrated 
randomization module (Medidata Balance™), custom reporting, robust data validation routines, 
and straightforward integration with SAS. • 
Electronic Data Capture: Medidata Rave® allows for data collection in multisite studies. 
During the course of the data entry into Medidata Rave®, the system provides real-time 
within-case report form (CRF) and inter-CRF data consistency verification. Medidata 
Rave® is flexible in nature so that all data can be entered even if “required” fields and or 
other consistency checks requirements are not satisfied. The system uses an internal 
“flagging” or “query” system to distinguish the valid from the invalid data thereby 
ensuring compliance with the FDA guidance document “Computerized Systems Used in 
Clinical Trials.” All data discrepancy issues are tracked and audited by the system to 
ensure the highest quality data is available for analysis and study reporting.  
Contained within the CTMS initiative at Mayo Clinic is a diverse set of administrative 
and technical personnel to support the development and implementation of clinical trials 
in Medidata Rave®. While the time necessary to program Rave’s electronic case report 
forms (eCRFs) has been directly budgeted, the CTMS initiative supports protocol 
independent activities such as software/server maintenance, data standards, institutional 
system integrations, SAS data, and training of study personnel through institutional 
resources.  
The dedicated VPN connection between Mayo Clinic and Medidata provides the conduit 
for data connectivity. Clinical trial data hosted in Medidata is accessible when needed for 
SAS using the SAS On Demand Connection, in combination with Mayo Clinic’s SAS 
Pipeline program, which creates a common and direct combination of the metadata 
(labels, formats, etc.) and data (raw values) into SAS datasets on a scheduled (nightly) 
basis. This process removes the need to separately label and format the entire clinical trial 
database separately in SAS 
 
Appendix 11 
Principal Investigator Signatures 
Study Title: 
A Randomized, Double-Blind, Active Comparator-Controlled Study 
to Evaluate the Effect of Obinutuzumab versus Rituximab in PR3-


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Patients with Anti-Neutrophil Cytoplasmic Antibody (ANCA)-
Associated Vasculitis 
Study Number: 
21-012197 
Final Date: 
Version 3.0 17OCT2023 
 
This clinical study protocol was subject to critical review and has been approved by the sponsor.  
 
Signed: 
 
 
Date:  
 
Ulrich Specks, M.D. 
 
Division of Pulmonary and Critical Care Medicine 
 
Mayo Clinic College of Medicine and Science 
 
Signed: 
 
 
Date:  
 
, M.D., M.P.H. 
Principal Investigator 
Professor of Medicine 
Harvard Medical School 
Massachusetts General Hospital 
 
 
 
 
 
 
 


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Appendix 12 
Clinical Investigator’s Signature 
 
Study Title: 
 
A Randomized, Double-Blind, Active Comparator-Controlled Study 
to Evaluate the Effect of Obinutuzumab versus Rituximab in PR3-
Patients with Anti-Neutrophil Cytoplasmic Antibody (ANCA)-
Associated Vasculitis 
Study Number: 
21-012197 
Final Date: 
Version 3.0 17OCT2023 
 
I have read the protocol described above. I agree to comply with all applicable regulations and to 
conduct the study as described in the protocol.  
 
 
 
 
 
Signed: 
 
 
Date:  
 
Clinical Investigator