Conditions: Pemphigus Vulgaris
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 135
Healthy volunteers: no

Brief summary:
This is a Phase III, randomized, double-blind, double-dummy, active-comparator, parallel-arm, multicenter study to evaluate the efficacy and safety of rituximab compared with MMF in participants with moderate-to-severely active PV requiring 60-120 milligrams per day (mg/day) oral prednisone or equivalent. Participants must have a confirmed diagnosis of PV within the previous 24 months (by skin or mucosal biopsy and immunohistochemistry) and evidence of active disease at screening.

Approximately 135 participants will be enrolled at up to 60 centers worldwide. Participants will be randomized in a 1:1 ratio to receive either rituximab plus MMF placebo or rituximab placebo plus MMF. Randomization will be stratified by duration of illness.

The study will consist of three periods: a screening period of up to 28 days, a 52-week double-blind treatment period, and a 48-week safety follow up period that begins at the time of study treatment completion or discontinuation.

Detailed description:

Arms:
arm 1: Participants will receive MMF orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52. Participants will also receive rituximab matching placebo by intravenous (IV) infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria have been met. arm 2: Participants will receive rituximab by IV infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria have been met. Participants will also receive MMF matching placebo orally twice daily Q12H from Day 1 to Week 52.

Interventions: intervention 1: Mycophenolate Mofetil Placebo intervention 2: Mycophenolate Mofetil intervention 3: Rituximab intervention 4: Rituximab Placebo
Intervention descriptions: intervention 1: MMF matching placebo will be administered orally Q12H. intervention 2: MMF will be administered at a starting dose of 500 milligrams (mg) Q12H and the dose will be titrated to achieve a goal of 1 gram (gm) Q12H. intervention 3: Rituximab will be administered at a dose of 1000 mg via IV infusion. intervention 4: Rituximab matching placebo will be administered via IV infusion.

Protocol document:
Prot_002.pdf: 
 
Official Title: A RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, ACTIVE-
COMPARATOR, MULTICENTER STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF RITUXIMAB VERSUS MMF IN 
PATIENTS WITH PEMPHIGUS VULGARIS 
NCT Number: 
NCT02383589 
Document Date: 
Protocol Version 5: 19-December-2017 
 
 


Clinical Study Report: rituximab - F. Hoffmann-La Roche Ltd
Protocol WA29330     Report Number 1093922
2601
FINAL PROTOCOL APPROVAL 
 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Rituximab—F. Hoffmann-La Roche Ltd 
Protocol WA29330, Version 5 
PROTOCOL 
TITLE: 
A RANDOMIZED, DOUBLE-BLIND, 
DOUBLE-DUMMY, ACTIVE-COMPARATOR, 
MULTICENTER STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF RITUXIMAB VERSUS 
MMF IN PATIENTS WITH PEMPHIGUS VULGARIS 
PROTOCOL 
NUMBER: 
WA29330 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2014-000382-41 
IND NUMBER: 
121595 
TEST PRODUCT: 
Rituximab (RO 0452294) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1:  24 July 2014  
DATE AMENDED: 
Version 2:  6 September 2014 
Version 3:  6 July 2015 
Version 4:  15 January 2016 
Version 5:  See electronic date stamp below. 
 
19-Dec-2017 21:10:57
Title
Approver's Name
Company Signatory
Date and Time (UTC)


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PROTOCOL AMENDMENT, VERSION 5: 
RATIONALE 
Protocol WA29330 has been amended to address a health authority recommendation 
that data obtained via telemedicine (TM) is considered to be exploratory in nature and 
therefore the primary analysis for establishing efficacy is to be based on the 
intent-to-treat (ITT) population for patients who were not recruited via TM.  The following 
changes have been made to the protocol to address this recommendation as follows:  
• 
An additional minimum of 8 non-TM patients will be recruited into this study to 
maintain sufficient statistical power for the primary analysis, thereby increasing the 
overall enrolment from approximately 124 to approximately 132 patients with 
pemphigus vulgaris (Sections 3.1, 4.1, 4.2, and 9.4). 
• 
The Statistical Considerations section (Section 6) has been updated, stipulating that 
all efficacy outcomes will be analyzed using the modified ITT (mITT) population and 
excluding patients who were enrolled via TM.  
• 
The primary efficacy outcome measure has been revised to reflect the exclusion of 
TM patients (Section 3.4.1.1). 
• 
As a result of the increase in enrollment, Section 6.1, Determination of Sample Size, 
has been revised.  
• 
A new primary analysis population has been added, the mITT population, which 
includes patients in the ITT population, excluding the 10 patients enrolled via TM.  
This population will be used in the analyses of efficacy outcomes (Section 6.2.3). 
• 
The analysis of the secondary efficacy endpoints has been updated and changed to 
the mITT population (Section 6.5.2). 
• 
Exploratory analyses (Section 6.9) have been updated to include a statement on 
descriptive statistics for evaluation of the 10 patients recruited via TM. 
 
In addition, the following change has been made: 
• 
An exploratory objective and exploratory outcome measure to evaluate the 
proportion of patients experiencing treatment failure in each treatment arm have 
been added (Sections 2.3 and 3.4.3, respectively). 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 10 
PROTOCOL SYNOPSIS .................................................................................... 11 
1. 
BACKGROUND .......................................................................................... 21 
1.1 
Background on Pemphigus Vulgaris ...................................... 21 
1.2 
Background on Rituximab...................................................... 23 
1.2.1 
Rituximab Mechanism of Action ............................................ 23 
1.2.2 
Rituximab Experience ............................................................ 23 
1.2.3 
Rituximab Drug-Drug Interaction Potential ............................ 23 
1.2.4 
Rituximab Population Pharmacokinetics................................ 24 
1.2.5 
Rituximab Clinical Pharmacodynamics .................................. 24 
1.3 
Background on Mycophenolate Mofetil .................................. 25 
1.3.1 
Mycophenolate Mofetil Mechanism of Action ......................... 25 
1.3.2 
Mycophenolate Mofetil Experience ........................................ 25 
1.4 
Study Rationale and Benefit-Risk Assessment ...................... 25 
1.4.1 
Role of B Cells in Pemphigus Vulgaris .................................. 25 
1.4.2 
Efficacy and Safety of Rituximab in Pemphigus 
Vulgaris .................................................................................. 25 
1.4.3 
Efficacy and Safety of Mycophenolate Mofetil in 
Pemphigus Vulgaris ............................................................... 27 
2. 
OBJECTIVES .............................................................................................. 28 
2.1 
Efficacy Objectives ................................................................ 28 
2.1.1 
Primary Efficacy Objective ..................................................... 28 
2.1.2 
Secondary Efficacy Objectives .............................................. 28 
2.2 
Safety Objectives ................................................................... 29 
2.3 
Exploratory Objectives ........................................................... 29 
3. 
STUDY DESIGN ......................................................................................... 30 
3.1 
Description of Study .............................................................. 30 
3.1.1 
Overview of Study Design ..................................................... 30 
3.1.2 
Corticosteroid Treatment ....................................................... 32 
3.1.3 
Definition of Treatment Failure .............................................. 35 
3.1.4 
Independent Data Monitoring Committee .............................. 35 


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3.2 
End of Study .......................................................................... 36 
3.3 
Rationale for Study Design .................................................... 36 
3.3.1 
Rationale for Rituximab Dose and Schedule ......................... 36 
3.3.2 
Rationale for Active Comparator Arm (MMF) ......................... 37 
3.3.3 
Rationale for Use of the PDAI as the Key 
Assessment of Disease Activity ............................................. 38 
3.3.4 
Rationale for Corticosteroid Treatment 
Guidelines .............................................................................. 38 
3.3.5 
Rationale for Biomarker Assessments, including 
Optional Whole Blood and Serum Samples for 
Storage and Future Research ............................................... 39 
3.4 
Outcome Measures ............................................................... 39 
3.4.1 
Efficacy Outcome Measures .................................................. 39 
3.4.1.1 
Primary Efficacy Outcome Measure ...................................... 39 
3.4.1.2 
Secondary Efficacy Outcome Measures ................................ 40 
3.4.2 
Safety Outcome Measures .................................................... 40 
3.4.3 
Exploratory Outcome Measures ............................................ 40 
4. 
MATERIALS AND METHODS .................................................................... 41 
4.1 
Patients .................................................................................. 41 
4.1.1 
Inclusion Criteria .................................................................... 41 
4.1.2 
Exclusion Criteria ................................................................... 42 
4.2 
Method of Treatment Assignment and Blinding ..................... 44 
4.3 
Study Treatment .................................................................... 45 
4.3.1 
Formulation, Packaging, and Handling .................................. 45 
4.3.1.1 
Rituximab and Placebo .......................................................... 45 
4.3.1.2 
MMF and MMF Placebo ........................................................ 45 
4.3.2 
Dosage, Administration, and Compliance .............................. 45 
4.3.2.1 
Rituximab and Rituximab Placebo ......................................... 45 
4.3.2.2 
MMF and MMF Placebo ........................................................ 46 
4.3.3 
Investigational Medicinal Product Accountability ................... 47 
4.3.4 
Post-Trial Access to Study Drug ............................................ 47 
4.4 
Concomitant Therapy ............................................................ 48 
4.4.1 
Corticosteroids ....................................................................... 48 
4.4.2 
Additional Permitted Therapy and Procedures ...................... 49 


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4.4.3 
Prohibited Therapy ................................................................ 49 
4.5 
Study Assessments ............................................................... 50 
4.5.1 
Informed Consent Forms and Screening 
Assessments ......................................................................... 50 
4.5.1.1 
Screening Examination .......................................................... 50 
4.5.1.2 
Re-Testing:  Laboratory Inclusion/Exclusion 
Criteria ................................................................................... 51 
4.5.1.3 
Re-Screening ......................................................................... 51 
4.5.2 
Medical History and Demographic Data ................................ 51 
4.5.3 
Physical Examinations ........................................................... 51 
4.5.4 
Vital Signs .............................................................................. 51 
4.5.5 
Assessments of Disease Activity ........................................... 52 
4.5.6 
Laboratory, Biomarker, and Other Biological 
Samples ................................................................................. 52 
4.5.7 
Electrocardiogram ................................................................. 53 
4.5.8 
Chest Radiograph .................................................................. 53 
4.5.9 
Patient-Reported and Clinician-Reported 
Outcomes .............................................................................. 54 
4.5.10 
Samples for Roche Clinical Repository.................................. 55 
4.5.10.1 
Overview of the Roche Clinical Repository ............................ 55 
4.5.10.2 
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 55 
4.5.10.3 
Sample Collection .................................................................. 55 
4.5.10.4 
Confidentiality ........................................................................ 56 
4.5.10.5 
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 57 
4.5.10.6 
Withdrawal from the Roche Clinical Repository ..................... 57 
4.5.10.7 
Monitoring and Oversight ....................................................... 57 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation ...................................................................... 58 
4.6.1 
Patient Discontinuation .......................................................... 58 
4.6.2 
Study Treatment Discontinuation ........................................... 58 
4.6.3 
Study and Site Discontinuation .............................................. 59 
4.6.4 
Dose Modification and Treatment Interruption ....................... 59 


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5. 
ASSESSMENT OF SAFETY ....................................................................... 60 
5.1 
Safety Plan ............................................................................ 60 
5.1.1 
Side Effects Known to be Associated with 
Rituximab ............................................................................... 60 
5.1.1.1 
Infusion-Related Reactions .................................................... 60 
5.1.1.2 
Cardiovascular Events ........................................................... 61 
5.1.1.3 
Infection ................................................................................. 61 
5.1.1.4 
Hepatitis B Infection ............................................................... 62 
5.1.1.5 
Progressive Multifocal Leukoencephalopathy ........................ 62 
5.1.1.6 
Skin Reactions ....................................................................... 63 
5.1.1.7 
Immunization ......................................................................... 63 
5.1.1.8 
Pregnancy ............................................................................. 64 
5.1.1.9 
Management of Specific Adverse Events .............................. 64 
5.1.2 
Side Effects Known to Be Associated with MMF ................... 65 
5.1.3 
Side Effects Known to Be Associated with 
Corticosteroids ....................................................................... 66 
5.2 
Safety Parameters and Definitions ........................................ 66 
5.2.1 
Adverse Events ..................................................................... 67 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) ...................................................................... 67 
5.2.3 
Non-Serious Adverse Events (Immediately 
Reportable to the Sponsor) .................................................... 68 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters ................................................ 68 
5.3.1 
Adverse Event Reporting Period ........................................... 68 
5.3.2 
Eliciting Adverse Event Information ....................................... 69 
5.3.3 
Assessment of Severity of Adverse Events ........................... 69 
5.3.4 
Assessment of Causality of Adverse Events ......................... 70 
5.3.5 
Procedures for Recording Adverse Events ............................ 71 
5.3.5.1 
Infusion-Related Reactions .................................................... 71 
5.3.5.2 
Diagnosis versus Signs and Symptoms................................. 71 
5.3.5.3 
Adverse Events That Are Secondary to Other 
Events.................................................................................... 72 
5.3.5.4 
Persistent or Recurrent Adverse Events ................................ 72 
5.3.5.5 
Abnormal Laboratory Values ................................................. 73 


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5.3.5.6 
Abnormal Vital Sign Values ................................................... 73 
5.3.5.7 
Abnormal Liver Function Tests .............................................. 74 
5.3.5.8 
Deaths ................................................................................... 74 
5.3.5.9 
Preexisting Medical Conditions .............................................. 75 
5.3.5.10 
Lack of Efficacy or Worsening of Pemphigus 
Vulgaris .................................................................................. 75 
5.3.5.11 
Hospitalization or Prolonged Hospitalization .......................... 75 
5.3.5.12 
Adverse Events Associated with an Overdose ...................... 76 
5.3.5.13 
Patient-Reported Outcome Data ........................................... 76 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor .......................................................... 76 
5.4.1 
Emergency Medical Contacts ................................................ 77 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Interest................................................................................... 77 
5.4.2.1 
Events That Occur prior to Study Drug Initiation .................... 77 
5.4.2.2 
Events That Occur after Study Drug Initiation ........................ 77 
5.4.3 
Reporting Requirements for Pregnancies .............................. 78 
5.4.3.1 
Pregnancies in Female Patients ............................................ 78 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................. 78 
5.4.3.3 
Abortions ............................................................................... 79 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 79 
5.5 
Follow-Up of Patients after Adverse Events .......................... 79 
5.5.1 
Investigator Follow-Up ........................................................... 79 
5.5.2 
Sponsor Follow-Up ................................................................ 79 
5.6 
Post-Study Adverse Events ................................................... 80 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ................................................................. 80 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................... 81 
6.1 
Determination of Sample Size ............................................... 81 
6.2 
Analysis Populations ............................................................. 82 
6.2.1 
Safety Population .................................................................. 82 
6.2.2 
Intent-to-Treat Population ...................................................... 82 


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6.2.3 
Modified Intent-to-Treat Population ....................................... 82 
6.3 
Summaries of Conduct of Study ............................................ 82 
6.4 
Summaries of Treatment Arm Comparability ......................... 82 
6.5 
Efficacy Analyses .................................................................. 83 
6.5.1 
Primary Efficacy Endpoint ...................................................... 83 
6.5.2 
Secondary Efficacy Endpoints ............................................... 83 
6.6 
Safety Analyses ..................................................................... 83 
6.7 
Pharmacodynamic Analyses ................................................. 84 
6.8 
Pharmacokinetic Analyses ..................................................... 84 
6.9 
Exploratory Analyses ............................................................. 84 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 84 
7.1 
Data Quality Assurance ......................................................... 84 
7.2 
Electronic Case Report Forms ............................................... 85 
7.3 
Telemedicine ......................................................................... 85 
7.4 
Source Data Documentation .................................................. 86 
7.5 
Use of Computerized Systems .............................................. 86 
7.6 
Retention of Records ............................................................. 87 
8. 
ETHICAL CONSIDERATIONS .................................................................... 87 
8.1 
Compliance with Laws and Regulations ................................ 87 
8.2 
Informed Consent .................................................................. 87 
8.3 
Institutional Review Board or Ethics Committee .................... 88 
8.4 
Confidentiality ........................................................................ 88 
8.5 
Financial Disclosure .............................................................. 89 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 89 
9.1 
Study Documentation ............................................................ 89 
9.2 
Protocol Deviations ................................................................ 89 
9.3 
Site Inspections ..................................................................... 89 
9.4 
Administrative Structure......................................................... 90 
9.5 
Publication of Data and Protection of 
Trade Secrets ........................................................................ 90 
9.6 
Protocol Amendments ........................................................... 91 


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10. REFERENCES ........................................................................................... 92 
 
 
LIST OF TABLES 
Table 1 
Corticosteroid Treatment Guideline ............................................ 34 
Table 2 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in the NCI CTCAE ......................................... 70 
Table 3 
Causal Attribution Guidance ....................................................... 71 
 
 
LIST OF FIGURES 
Figure 1 
Overview of Study Design ........................................................... 31 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments ........................................................... 96 
Appendix 2 
Schedule of Assessments for the Safety Follow-Up Period ...... 102 
Appendix 3 
Procedures for the Intravenous Administration of Rituximab .... 104 
Appendix 4 
Pemphigus Disease Area Index (PDAI) .................................... 107 
Appendix 5 
Skindex-29 ................................................................................ 111 
Appendix 6 
Dermatology Quality of Life Index (DLQI) Questionnaire .......... 115 
Appendix 7 
EuroQol 5-Dimension Questionnaire, Three-Level Version 
(EQ-5D-3L) ............................................................................... 116 
Appendix 8 
Patient Global Impression of Change (PGIC) ........................... 120 
Appendix 9 
Clinician Global Impression of Change (CGIC) ......................... 121 
Appendix 10 Uncontrolled Studies and Selected Case Reports of 
Rituximab in Pemphigus Vulgaris ............................................. 122 
Appendix 11 Telemedicine ............................................................................. 130 


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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A RANDOMIZED, DOUBLE-BLIND, 
DOUBLE-DUMMY, ACTIVE-COMPARATOR, 
MULTICENTER STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF RITUXIMAB VERSUS 
MMF IN PATIENTS WITH PEMPHIGUS VULGARIS 
PROTOCOL NUMBER: WA29330 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2014-000382-41 
IND NUMBER: 
121595 
TEST PRODUCT: 
Rituximab (RO 0452294) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please return a copy of this form as instructed by your local study monitor and retain a 
copy for your study files. 
 


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PROTOCOL SYNOPSIS 
TITLE: 
A RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, 
ACTIVE-COMPARATOR, MULTICENTER STUDY TO EVALUATE 
THE EFFICACY AND SAFETY OF RITUXIMAB VERSUS MMF IN 
PATIENTS WITH PEMPHIGUS VULGARIS 
PROTOCOL NUMBER: 
WA29330 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2014-000382-41 
IND NUMBER: 
121595 
TEST PRODUCT: 
Rituximab (RO 0452294) 
PHASE: 
III 
INDICATION: 
Moderate-to-severely active pemphigus vulgaris 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
Efficacy Objectives 
The primary efficacy objective for this study is as follows: 
• 
To evaluate the efficacy of rituximab compared with mycophenolate mofetil (MMF) in 
achieving sustained complete remission, evaluated by the Pemphigus Disease Area Index 
(PDAI; see Section 3.4.1.1), and assessed at Week 52 in patients with 
moderate-to-severely active pemphigus vulgaris (PV) 
The secondary efficacy objectives for this study are as follows: 
• 
To evaluate the efficacy of rituximab compared with MMF, as measured by the time to 
disease flare, the duration of sustained complete remission, the total number of disease 
flares during the treatment period, and the time to initial sustained complete remission 
• 
To assess corticosteroid exposure over 52 weeks  
• 
To assess the effect of rituximab compared with MMF on health-related quality of life 
(HRQoL), as measured by the Dermatology Life Quality Index (DLQI)  
• 
To assess the effect of rituximab compared with MMF on patients’ impression of PV 
symptoms, as measured by the Patient Global Impression of Change (PGIC) questionnaire 
• 
To assess the effect of rituximab compared with MMF on clinician impression of patients’ 
PV symptoms, as measured by the Clinician Global Impression of Change (CGIC) 
questionnaire 
Safety Objectives 
The safety objectives for this study are as follows: 
• 
To evaluate the safety of rituximab compared with MMF, with a focus on adverse events 
and safety laboratory values 
• 
To evaluate corticosteroid-related adverse events in relation to corticosteroid exposure 


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Exploratory Objectives 
The exploratory objectives for this study will include, but are not limited to, the following: 
• 
To evaluate the efficacy of rituximab compared with MMF, as measured by the proportion of 
patients achieving complete or partial remission by 24 weeks and 52 weeks 
• 
To explore the pharmacokinetics and pharmacodynamics of rituximab, and the 
pharmacodynamics of MMF, in patients with PV  
• 
To evaluate the effect of rituximab as compared with MMF on the change in PDAI activity 
score 
• 
To evaluate the effect of rituximab as compared with MMF on anti-desmoglein (anti-Dsg) 
autoantibody titers (anti-Dsg1 and anti-Dsg3) and other mechanistic studies of interest in 
patients with PV 
• 
To assess the effect of rituximab compared with MMF on health utilities as measured by the 
European Quality of Life (EuroQol) 5-Dimension Questionnaire, 3-level version (EQ-5D-3L) 
• 
To assess the effect of rituximab compared with MMF on HRQoL, as measured by the 
Skindex-29 
• 
To evaluate the efficacy of rituximab compared with MMF, as measured by the proportion of patients 
experiencing treatment failure from Week 12 to Week 52 
 
Study Design 
Description of Study 
This is a Phase III, randomized, double-blind, double-dummy, active-comparator, parallel-arm, 
multicenter study to evaluate the efficacy and safety of rituximab compared with MMF in 
patients with moderate-to-severely active PV requiring 60120 mg/day oral (PO) prednisone or 
equivalent (1.01.5 mg/kg/day).  Patients must have a confirmed diagnosis of PV within the 
previous 24 months (by skin or mucosal biopsy and immunohistochemistry) and evidence of 
moderate-to-severely active disease at screening (defined as at total PDAI activity score of ≥15). 
This international study will be conducted at investigational sites throughout North America, 
Europe, the Middle East, and Latin America.  It is expected that approximately 60 centers will 
participate.  Approximately 132 patients will be randomized in a 1:1 ratio to receive either 
rituximab plus MMF placebo or rituximab placebo plus MMF.  Randomization will be stratified by 
duration of illness (newly diagnosed [i.e., diagnosed within the 1 year prior to screening] vs. 
diagnosed greater than 1 year) and geographical region (North America [U.S./Canada] vs. rest 
of world).  
The study will consist of three periods:  a screening period of up to 28 days, a 52-week 
double-blind treatment period, and a 48-week safety follow-up (SFU) period that begins at the 
time of study treatment completion or discontinuation.  
Rituximab (1000 mg or matching placebo) will be administered by intravenous (IV) infusion on 
Day 1 and Day 15, with repeat rituximab (or matching placebo) administration on Day 168 and 
Day 182 provided specific safety criteria have been met (see Section 4.6.4).  MMF (500 mg or 
matching placebo) will be administered PO twice daily (every 12 hours [Q12H]), starting with a 
total dose of 1 g/day on Day 1.  The MMF dose will be titrated to achieve a goal of 2 g/day in 
divided doses (1 g Q12H) by Week 2.  Treatment with MMF (or matching placebo) will continue 
through Week 52.   
All patients who withdraw from the treatment period or who complete the total 52-week 
treatment period must return for postWeek 52 SFU assessments at 12, 24, 36, and 48 weeks 
after either the early withdrawal visit or study treatment completion, respectively.  Thus, patients 
will be followed for approximately 1 year in the SFU period.   
Telemedicine  
For a small proportion of patients (approximately 10 patients at one investigational site), the 
Sponsor is proposing the use of telemedicine (TM) consultation visits between the patient and 
the Principal Investigator to make the trial more accessible to this population of patients with a 
rare disease.  The local dermatologist, a research nurse, and other medical personnel in the 
patient’s immediate vicinity will participate throughout the trial as needed.  Data collected via TM 
will be in accordance with the American Telemedicine Association 2012 Guidelines for 


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Teledermatology (ATA 2012).  The software platform to be used in the trial will allow efficient, 
high-quality data collection of all relevant clinical data (including the images of the skin and 
mucosa, prior medical records, notes, and laboratory tests) for easy and reliable review by the 
Principal Investigator.  This type of assessment has become the standard for TM clinical care 
for the diagnosis and treatment of both mild and severe types of skin diseases.  Images will be 
time-stamped and stored in a Health Insurance Portability and Accountability Act 
(HIPAA)-compliant advanced TM platform adapted for this specific trial use.  Other safety and 
efficacy data sets will be transmitted through the TM platform to the Principal Investigator as 
well.  The local dermatologist or other local primary care doctors may still provide 
standard-of-care services that do not require training on the protocol or investigational drug.  All 
clinical trial-related medical decisions will be made by the Principal Investigator and or safety 
assessor. 
Number of Patients 
Approximately 132 patients with active moderate-to-severely active PV will be recruited into 
this study. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Age 1875 years 
• 
Signed Informed Consent Form 
• 
First confirmed diagnosis of PV within the previous 24 months, based on the presence of 
histological features of acantholysis via skin or mucosal biopsy and one of the following:  
tissue-bound immunoglobulin G (IgG) antibodies by direct immunofluorescence on the 
surface of affected epithelium or serological detection of serum Dsg3 autoantibodies 
against epithelial cell surface either by indirect immunofluorescence microscopy or by 
enzyme-linked immunosorbent assay   
• 
Presence of moderate-to-severely active disease, defined as overall PDAI activity score of 
≥15 
• 
Receiving standard-of-care corticosteroids consisting of 60120 mg/day PO prednisone or 
equivalent (1.0  1.5 mg/kg/day) and, in the judgment of the investigator, expected to benefit 
from the addition of immunosuppressive therapy 
• 
For women who are not postmenopausal (≥ 12 months of nontherapy-induced amenorrhea) 
or surgically sterile (absence of ovaries and/or uterus):  agreement to remain abstinent or 
use two effective methods of contraception, including at least one method with a failure rate 
of < 1% per year, during the treatment period and for at least 12 months after the last dose 
of study treatment   
Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
Barrier methods must always be supplemented with the use of a spermicide. 
Examples of contraceptive methods with a failure rate of < 1% per year (highly effective 
contraceptive methods) include tubal ligation, male sterilization, hormonal implants, 
established, proper use of combined oral or injected hormonal contraceptives, and 
certain intrauterine devices. 
• 
For men (including those who have undergone a vasectomy):  agreement to remain 
abstinent or use a condom during the treatment period and for at least 12 months after the 
last dose of study treatment and agreement to refrain from donating sperm during this same 
period 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 


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In addition to male contraception, agreement to advise female partners of childbearing 
potential to use highly effective contraception during the study and for at least 12 months 
after the last dose of study treatment 
• 
Agreement to avoid excessive exposure to sunlight during study participation 
• 
Able to comply with the study protocol, in the investigator’s judgment 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Diagnosis of pemphigus foliaceus or evidence of paraneoplastic pemphigus or other 
non-PV autoimmune blistering disease 
• 
History of a severe allergic or anaphylactic reaction to humanized or murine monoclonal 
antibodies, or known hypersensitivity to any component of rituximab 
• 
Known hypersensitivity or contraindication to MMF, mycophenolic acid, polysorbate, or oral 
corticosteroids 
• 
Lack of peripheral venous access 
• 
Pregnant or lactating, or intending to become pregnant during the study 
Women who are not postmenopausal (≥ 12 months of nontherapy-induced amenorrhea) 
or surgically sterile must have two negative results with a sensitivity of ≥25 mIU/mL:  one 
from a serum pregnancy test at Day 8 to Day 10 of screening and another from a 
urine pregnancy test at Day 1 prior to randomization. 
• 
Participated in another interventional clinical trial within 28 days prior to randomization 
• 
Use of any investigational agent within 28 days or 5 elimination half-lives prior to 
randomization (whichever is the longer) 
• 
Significant cardiovascular or pulmonary disease (including obstructive pulmonary disease) 
• 
Evidence of any new or uncontrolled concomitant disease that, in the investigator’s 
judgment, would preclude patient participation, including but not limited to nervous system, 
renal, hepatic, endocrine, malignant, or gastrointestinal disorders  
• 
Any concomitant condition that required treatment with oral or systemic corticosteroids 
within 12 weeks prior to randomization 
• 
Treatment with IV immunoglobulin (Ig), plasmapheresis, or other similar procedure within 
8 weeks prior to randomization 
• 
Treatment with immunosuppressive medications (e.g., azathioprine, MMF) within 1 week 
prior to randomization 
• 
Treatment with cyclophosphamide within 12 weeks prior to randomization 
• 
History of or currently active primary or secondary immunodeficiency, including known 
history of HIV infection and other severe Immunodeficiency blood disorders  
• 
Known active infection of any kind (excluding fungal infections of nail beds) or any major 
episode of infection requiring hospitalization or treatment with IV anti-infectives within 
4 weeks prior to screening, or completion of oral anti-infectives within 2 weeks prior to 
randomization 
Entry into this study may be reconsidered once the infection has fully resolved. 
• 
History of or current cancer, including solid tumors, hematologic malignancies, and 
carcinoma in situ (except basal cell carcinoma and squamous cell carcinoma of the skin 
that have been excised and cured) 
• 
Currently active alcohol or drug abuse, or history of alcohol or drug abuse within 24 weeks 
prior to screening 
• 
Major surgery within 4 weeks prior to randomization, excluding diagnostic surgery 
• 
Treatment with rituximab or a B celltargeted therapy (e.g., anti-CD20, anti-CD22, or 
anti-BLyS) within 12 months prior to randomization 
• 
Treatment with a live or attenuated vaccine within 28 days prior to randomization 


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It is recommended that a patient’s vaccination record and the need for immunization 
prior to study entry be carefully investigated. 
• 
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or amylase >2.5 × the 
upper limit of normal (ULN) 
• 
Absolute neutrophil count (ANC) <1.5×103/µL  
• 
Hemoglobin <8.0 g/dL 
• 
Positive test results for hepatitis B surface antigen (HBsAg), hepatitis B core antibody 
(HBcAb), or hepatitis C virus (HCV) serology at screening 
 
Length of Study 
Based on study enrollment projections, this study is estimated to take approximately 4 years to 
complete, from first patient in to last patient’s last visit (LPLV), when the final patient completes 
the 48-week SFU period. 
End of Study 
The end of the study is defined as the date when the LPLV occurs.  LPLV is expected to occur 
approximately 2 years after the last patient is enrolled, assuming a 52-week treatment period 
and a 48-week SFU period for the last patient. 
Outcome Measures 
Primary Efficacy Outcome Measure 
The primary efficacy outcome measure for this study is as follows: 
• 
Proportion of patients (excluding TM patients) who achieve a sustained complete remission 
without experiencing an event that constitutes treatment failure (as defined in Section 3.1.3), 
as measured at Week 52 
Sustained complete remission is defined as achieving healing of lesions with no new 
active lesions (i.e., PDAI activity score of 0) while on 0 mg/day prednisone or equivalent, 
and maintaining this response for a total of at least 16 consecutive weeks, during the 
52-week treatment period.  
Patients with transient new lesions for 1 week or less that heal without additional 
systemic corticosteroid therapy will not be considered to have experienced treatment 
failure. 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures are as follows: 
• 
Cumulative oral corticosteroid dose (prednisone or equivalent) over the treatment period 
• 
Total number of disease flares during the treatment period  
• 
Time to sustained complete remission 
• 
Time to disease flare  
Disease flare is defined as the appearance of three or more new lesions a month that do 
not heal spontaneously within 1 week or by the extension of established lesions in a 
patient who has achieved disease control. 
• 
Change in HRQoL, as measured by the DLQI score from baseline to Week 52 
• 
Duration of sustained complete remission 
• 
Patients’ impression of change in PV symptoms, as measured by the PGIC score during the 
treatment period 
• 
Clinician impression of change in patients’ PV symptoms, as measured by the CGIC score 
during the treatment period 
 
Safety Outcome Measures 
The safety outcome measures include, but are not limited to, the following: 
• 
Nature, frequency, and severity of adverse events, including serious adverse events and 
adverse events leading to discontinuation 


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• 
Vital signs and clinical laboratory test results (including complete blood count and blood 
chemistry)  
• 
Incidence of human antichimeric antibody (HACA) 
• 
Circulating B cells, T cells, natural killer (NK) cells, plasma cells, and other leukocytes   
• 
Plasma Ig levels (total Ig, IgG, IgM, and IgA)   
• 
Corticosteroid-related adverse events in relation to corticosteroid exposure 
 
Exploratory Outcome Measures 
The exploratory outcome measures for this study will include, but are not limited to, the 
following: 
• 
Proportion of patients achieving a complete remission by Week 24 and by Week 52 
Complete remission is defined as achieving wound healing with no new active lesions 
(i.e., PDAI activity score of 0) for at least 8 consecutive weeks during the 52-week 
treatment period.   
• 
Proportion of patients achieving a partial remission by Week 24 and by Week 52 
Partial remission is defined as the presence of transient new lesions that heal within 
1 week (while the patient is receiving minimal therapy, including topical corticosteroids).  
Minimal therapy is defined as ≤10 mg/day prednisone (or equivalent) for at least 
8 consecutive weeks during the 52-week treatment period. 
• 
Pharmacokinetics (PK)/pharmacodynamics (PD) of rituximab 
PK/PD parameters include, but are not limited to, serum levels of rituximab, peripheral 
CD19+ B-cell counts, HACA, and autoantibody concentrations.  
• 
To explore the pharmacodynamics of MMF in patients with PV 
• 
Change in total PDAI activity score during the treatment period 
• 
Change from baseline in anti-Dsg1 and anti-Dsg3 autoantibodies 
• 
Change in health utilities as assessed by the EQ-5D-3L score from baseline to Week 52  
• 
Change in HRQoL as measured by the Skindex-29 from baseline to Week 52 
Investigational Medicinal Products 
Test ProductRituximab 
Patients randomized to the rituximab arm will receive treatment with 1000 mg IV rituximab 
(or matching placebo) on Day 1 and Day 15, with repeat rituximab (or matching placebo) 
administration on Day 168 and Day 182 provided specific safety criteria have been met 
(see Section 4.6.4).   
ComparatorMMF 
Patients randomized to the MMF arm will receive treatment with 500 mg MMF (or matching 
placebo) administered orally twice daily (Q12H) starting on Day 1.  MMF dose will then be 
titrated to achieve a maximum dose goal of 2 g/day given as a divided oral dose (1 g Q12H) by 
Week 2.  Slower titration will be allowed on the basis of tolerability.  Treatment with MMF 
(or matching placebo) will continue through Week 52. 
Non-Investigational Medicinal Products 
In order to reduce the frequency and severity of infusion-related reactions, all patients will 
receive methylprednisolone 100 mg or saline solution prior to infusion of rituximab or rituximab 
placebo, respectively.  This premedication will be administered by slow IV infusion, and 
administration should be completed at least 30 minutes prior to infusion of rituximab or rituximab 
placebo.   
All patients should be premedicated with paracetamol/acetaminophen (1 g PO) and an 
antihistamine (diphenhydramine HCl 50 mg PO [or IV equivalent] or equivalent dose of a similar 
agent, or in accordance with local approved labeling) 30 to 60 minutes prior to the start of the 
infusion of rituximab or rituximab placebo. 


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Statistical Methods 
Primary Analysis 
The proportion of patients (excluding TM patients) achieving a sustained complete remission (as 
defined in Section 3.4.1.1) in the rituximab and MMF arms will be compared using a stratified 
Cochran-Mantel-Haenszel test, adjusting for randomization stratification variables.  Results will 
be summarized descriptively by treatment arm and expressed as proportions, corresponding 
adjusted 95% confidence intervals of the difference between response rates, and p-values. 
Patients who meet the pre-specified definitions of treatment failure before entering sustained 
complete remission (as defined in Section 3.1.3) will be deemed non-responders in the primary 
analysis.   
Determination of Sample Size   
The primary efficacy endpoint of this study is the proportion of patients (excluding TM patients) 
achieving a sustained complete remission, as assessed at Week 52, that has been maintained 
for ≥ 16 consecutive weeks during the 52-week treatment period.  With use of limited data 
available in the literature from randomized clinical trials of MMF and investigator-initiated trials 
of rituximab, it is estimated that approximately 40% of patients with PV receiving MMF will 
achieve a sustained complete remission.  It is estimated that patients receiving rituximab will 
induce a sustained complete remission rate of 65%.  On the basis of these assumptions, a total 
of 122 patients randomized to the rituximab arm or the MMF arm in a 1:1 ratio (61 patients in 
the rituximab arm and 61 patients in the MMF arm) will yield approximately 80% power in a 
two-sided test at the 5% significance level.  To account for the 10 TM patients excluded from the 
primary efficacy analysis, approximately 132 patients will be randomized in total. 
No adjustment will be made to account for dropouts.   


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
BUN 
blood urea nitrogen 
CGIC 
Clinician Global Impression of Change 
CL  
clearance 
ClinRO 
clinician-reported outcome 
CLL 
chronic lymphocytic leukemia 
CRP 
C-reactive protein 
DLQI 
Dermatology Life Quality Index 
Dsg1 
desmoglein-1  
Dsg3 
desmoglein-3  
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EQ-5D-3L 
EuroQol 5-Dimension Questionnaire, 3-level version 
EuroQol 
European Quality of Life 
FACS 
fluorescence-activated cell sorting 
FDA 
(U.S.) Food and Drug Administration 
GPA 
granulomatosis polyangiitis 
HACA 
human antichimeric antibody 
HBcAb 
hepatitis B core antibody  
HbsAg 
hepatitis B surface antigen  
HBV 
hepatitis B virus 
HCV 
hepatitis C virus  
HIPAA 
Health Insurance Portability and Accountability Act 
HRQoL 
health-related quality of life 
ICH 
International Council for Harmonisation 
iDMC 
independent Data Monitoring Committee 
Ig 
immunoglobulin  
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
 


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Abbreviation 
Definition 
ITT 
intent to treat 
IV 
intravenous 
IV Ig 
intravenous immunoglobulin 
IxRS 
interactive/web voice response system 
KLH 
keyhole limpet hemocyanin 
LDH 
lactate dehydrogenase 
LPLV 
last patient, last visit 
mITT 
modified intent-to-treat (population) 
MMF 
mycophenolate mofetil 
MPA 
microscopic polyangiitis 
MRI 
magnetic resonance imaging 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria 
for Adverse Events 
NHL 
non-Hodgkin’s lymphoma 
NK 
natural killer (cell) 
PD 
pharmacodynamic 
PDAI 
Pemphigus Disease Area Index 
PGIC 
Patient Global Impression of Change 
PK 
pharmacokinetic 
PML 
progressive multifocal leukoencephalopathy 
PO 
by mouth 
PRCA 
pure red cell aplasia 
PRO 
patient-reported outcome 
PV 
pemphigus vulgaris 
Q12H 
every 12 hours  
RA 
rheumatoid arthritis 
RBC 
red blood cell 
RCR 
Roche Clinical Repository 
SAP 
Statistical Analysis Plan 
SFU 
safety follow-up 
SJS 
Stevens-Johnson syndrome 
SMT 
Study Management Team 
TEN 
toxic epidermal necrolysis 
TM 
telemedicine 
ULN 
upper limit of normal 
VAS 
visual analog scale  
Vc 
central compartment volume of distribution 


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Abbreviation 
Definition 
Vp 
peripheral compartment volume of distribution 
WBC 
white blood cell 
 


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1.
BACKGROUND
1.1
BACKGROUND ON PEMPHIGUS VULGARIS 
Pemphigus is a rare, severe autoimmune diseaseone of a group of unique, related 
blistering disorders that includes pemphigus vulgaris (PV), pemphigus foliaceus, and 
paraneoplastic pemphigus.  They are histologically characterized by suprabasilar 
acantholysis and immunopathologically characterized by autoantibodies to desmosomal 
cadherins.  In PV (characterized by skin and mucosal lesions), the autoantibodies are to 
desmoglein 1 (Dsg1) or desmoglein-3 (Dsg3).  In pemphigus foliaceus (which typically 
does not affect the mucosa), the autoantibody is to Dsg1.  The mechanism that initiates 
the formation of anti-Dsg antibodies is unknown, but is presumed to involve loss of B-cell 
tolerance to these self-antigens.
PV constitutes approximately 80% of pemphigus cases (Tóth and Jonkman 2001).  The 
incidence of PV in the United States is 0.1 to 0.4 in 100,000, with a prevalence of 1 to 
5 in 100,000 (Tóth and Jonkman 2001).  Onset of disease typically occurs after the age 
of 50 years, with the incidence in men and women being equal.  PV occurs in all races.  
There may be a genetic predisposition and link to human leukocyte antigen class II 
alleles, and the disease is more common in people of Eastern European Jewish and 
Mediterranean descent (Hertl et al. 2006; Feldman and Ahmed 2011). 
PV is characterized by fragile and flaccid blisters caused by loss of cohesion between 
the cells in the lower epidermis. Both skin and mucosal lesions are seen in PV.  In 
approximately 50%70% of cases, the disease begins with oral lesions 
(Chryssomallies et al. 1994), which may become painful, rendering patients unable to 
eat or drink, and leading to malnutrition and debilitation.  Left untreated, bullae and 
erosions spread.  As with burns, when these lesions are widespread they can be 
complicated by severe infection and/or metabolic disturbance, leading to death.  Before 
systemic corticosteroids became available, approximately 75% of patients who 
developed PV died within a year (Lever 1953). Following the widespread use of 
systemic corticosteroids to treat pemphigus starting in the 1950s, mortality declined 
drastically to an average of 29% (Bystryn 1984).  
The aim of pharmacologic therapy for PV is to reduce inflammation and enable wound 
healing.  Assessment of disease severity is typically based on clinical presentation 
(i.e., percentage of body surface area involved, duration of lesions [sustained for more 
than a week], and location of lesions [mucosal, skin, scalp]).  Mild disease typically 
refers to patients with few lesions, which are progressing slowly and can be treated 
topically with high-potency corticosteroid ointments or with intralesional injections of 
corticosteroids. Moderate-to-severely active disease has been characterized in the 
literature by numbers of cutaneous and/or mucosal lesions, percentage of body surface 
involvement, or Pemphigus Disease Area Index (PDAI) severity score and the use of 
oral (PO) or intravenous (IV) corticosteroids, such as prednisone or equivalent


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(1.01.5 mg/kg per day) to prevent new blister activity (Mimouni et al. 2003; Bystryn and 
Rudolph 2005; Martin and Murrell 2006; Shimizu et al. 2014).
High doses and prolonged administration of corticosteroids are required, with potentially 
serious side effects, such as an increased susceptibility to infection, accelerated 
osteoporosis, diabetes, capillary fragility, cataracts, Cushingoid habitus, glaucoma, 
gastrointestinal ulceration, hypertension, weight gain, and/or psychiatric symptoms.  
These side effects have led to an alternative approach to treatment that involves a 
combination of corticosteroids with a second immunosuppressive agent, such as 
azathioprine, mycophenolate mofetil (MMF), or cyclophosphamide (Martin et al. 2009; 
Beissert et al. 2010). The goal of combination therapy is to increase efficacy and 
provide a steroid-sparing action to reduce corticosteroid side effects.  In clinical practice, 
once new blisters have stopped forming, the dose of the immunosuppressive drug is 
typically maintained while the dose of corticosteroid is reduced.  The aim is to find the 
lowest dose of corticosteroids needed to control symptoms, and there is significant 
inter-patient variability in response to therapy.  Importantly, care also needs to be taken 
to monitor for systemic toxicity of the steroid-sparing agents themselves, including the 
increased risks of bone marrow suppression or hepatotoxicity.
The use of high-dose, long-term systemic corticosteroids, with or without other 
immunosuppressive agents, has improved outcomes and reduced 1-year mortality to 
approximately 5%15% (Baibergenova et al. 2012).  However, patients with PV often 
have a poor quality of life, and many experience severe side effects from 
immunosuppression and long-term use of corticosteroids, including death 
(Lester et al. 1998; Tóth and Jonkman 2001; Feldman and Ahmed 2011).  Currently, a 
significant cause of death in treated PV patients is opportunistic infections secondary to 
prolonged immunosuppression.  In addition, many PV patients become refractory to 
standard therapies and require more aggressive treatments, such as plasmapheresis or 
intravenous immunoglobulin (IV Ig).  Clearly, a major unmet need exists for new 
treatment options for patients with PV (Feldman and Ahmed 2011).
In the past 17 years, monoclonal antibodies designed to selectively deplete B cells have 
been developed and used in the treatment of non-Hodgkin’s lymphoma (NHL), chronic 
lymphocytic leukemia (CLL), and autoimmune diseases, such as rheumatoid arthritis 
(RA), granulomatosis polyangiitis (GPA; Wegener’s), and microscopic polyangiitis
(MPA).  Owing to its ability to deplete pathogenic B cells, rituximab has been used 
off-label for multiple autoimmune conditions, including PV.  As described in the literature, 
therapy with rituximab has additionally aimed to reduce anti-Dsg1 and anti-Dsg3 
autoantibody production.
Both rituximab (Rituxan®/MabThera®) and MMF (CellCept®) have been available 
worldwide for over 15 years to treat other diseases; however, neither of them has been 
approved for the treatment of PV.


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1.2
BACKGROUND ON RITUXIMAB
1.2.1
Rituximab Mechanism of Action
Rituximab is a glycosylated immunoglobulin G1 (IgG1) chimeric murine/human 
monoclonal antibody that binds specifically to the transmembrane antigen CD20, which 
is located on pre-B and mature B lymphocytes, but not on hematopoietic stem cells, 
pro-B cells, normal plasma cells, or other normal tissue.  Following antibody binding, 
CD20 is not internalized or shed from the cell membrane into the environment. CD20 
does not circulate in the plasma as a free antigen and thus does not compete for 
antibody binding. Rituximab is believed to exert its therapeutic effect by promoting B-cell 
lysis, inducing a rapid and sustained depletion of peripheral CD20B cells.  Possible 
mechanisms of cell lysis include complement-dependent cytotoxicity, 
antibody-dependent cellular cytotoxicity, and induction of apoptosis.  Following cessation 
of treatment, a normal B-cell pool can be reconstituted from hematopoietic stem cells 
and CD20precursor B cells, which are not affected by treatment with rituximab.
1.2.2
Rituximab Experience
Rituximab is currently approved for the treatment of relapsed or refractory NHL, CLL, 
and, in combination with methotrexate, for the treatment of RA patients with an 
inadequate response to one or more anti-tumor necrosis factor therapies.  Rituximab is 
also approved for the treatment of two forms of anti-neutrophil cytoplasmic 
autoantibody-associated vasculitis, GPA, and MPA. Rituximab is under investigation in 
this study as an experimental drug in PV and is currently not approved for the treatment 
of patients with PV.
Clinical studies have investigated the use of rituximab in other populations of patients 
with RA and several other autoimmune disorders, including multiple sclerosis and 
systemic lupus erythematosus.
See the Rituximab Investigator’s Brochure for additional details on nonclinical and 
clinical studies.
1.2.3
Rituximab Drug-Drug Interaction Potential
The elimination of rituximab is mediated by both the specific CD20 receptor-mediated
pathway and the nonspecific IgG clearance pathways.  Data suggest that rituximab 
would not be expected to have many of the common mechanisms of drug-drug 
interactions with small molecules, including changes in protein binding, P450 activity, 
and transporters.  Although no specific drug interaction studies have been performed, 
based on pharmacokinetic (PK) data from Phase II/III RA clinical studies, 
cyclophosphamide, methotrexate, and corticosteroids seemed to have little or no effect 
on the pharmacokinetics of rituximab.


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1.2.4
Rituximab Population Pharmacokinetics
A population PK analysis, based on RA clinical trial data from two Phase II and four 
Phase III studies, demonstrated that weight, sex, and C-reactive protein (CRP) were the 
most influential covariates on clearance (CL), central compartment volume of distribution 
(Vc), and peripheral compartment volume of distribution (Vp).  However, the covariates 
explained only a small portion of the variability in PK parameters.  Of note, development 
of human antichimeric antibody (HACA) response was not a significant covariate for PK 
parameters.  The typical population estimates of rituximab CL and Vc from 2005 patients 
with RA who received two rituximab IV doses (of either 21 g or 20.5 g) on Days 1 
and 15 were 0.335 L/day and 3.10 L/day, respectively, and the mean terminal half-life of 
rituximab was calculated as 18.0 days (range, 5.1777.5 days).  Co-administration of 
cyclophosphamide, methotrexate, and corticosteroids seemed to have little or no effect 
on the pharmacokinetics of rituximab.
Rituximab Vc and the Vp proportionally increased with body weight.  However, body 
weight, sex, and CRP explained a small magnitude of the overall inter-individual 
variability of the respective physiologically relevant parameters.  Therefore, results from 
the RA analysis suggested that dosing of rituximab should not be adjusted according to 
demographic or physiologic variables.
1.2.5
Rituximab Clinical Pharmacodynamics
RA patients showed near-complete depletion of peripheral CD19B cells by 2 weeks 
after the first dose, with no differences observed between the 21.0 g and 20.5 g doses 
of rituximab.  In the majority of patients, peripheral B-cell depletion was maintained over 
the 24 weeks, with only a small proportion of patients showing signs of peripheral B-cell 
recovery by Week 24, when serum rituximab concentrations fell below 110 g/mL.  The 
extent and duration of B-cell depletion were similar for each treatment course.  Repeat 
treatments were given on the basis of clinical symptoms and not on patients’ CD19cell 
counts, which may or may not have returned to the lower limit of normal or baseline 
value. 
Levels of total Ig, IgA, IgG, and IgM decreased in patients who received rituximab 
compared with those who received placebo.  Mean immunoglobulin levels generally
remained within the normal range.
T-cell counts remained stable after a transient decrease, likely because of concomitant 
RA treatment with corticosteroids.  Treatment with rituximab did not appear to have an 
effect on serum complement, antinuclear antibody titer, or protective immunity to 
common infectious agents in patients with RA.


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1.3
BACKGROUND ON MYCOPHENOLATE MOFETIL
1.3.1
Mycophenolate Mofetil Mechanism of Action
Mycophenolate mofetil (MMF) is the 2-morpholinoethyl ester of mycophenolic acid 
(MPA). MPA is a potent, selective, noncompetitive, and reversible inhibitor of inosine 
monophosphate dehydrogenase (IMPDH) and therefore inhibits the de novo pathway of 
guanosine nucleotide synthesis.  The mechanism by which MPA inhibits the enzymatic 
activity of IMPDH appears to be related to the ability of MPA to structurally mimic both 
nicotinamide adenine dinucleotide cofactor and a catalytic water molecule. This 
prevents the oxidation of IMP to xanthose-5’-monophosphate, which is the committed 
step in de novo guanosine nucleotide biosynthesis. MPA has more potent cytostatic 
effects on lymphocytes than on other cells because T and B lymphocytes are critically 
dependent for their proliferation on de novo synthesis of purines, whereas other cell 
types can utilize salvage pathways.
1.3.2
Mycophenolate Mofetil Experience
MMF is approved worldwide to prevent organ rejection in patients who receive kidney, 
heart, or liver transplants. MMF has been studied in lung transplant and in autoimmune 
diseases; however, it is not approved for these diseases. MMF is an experimental drug, 
which has not been approved by health authorities for the treatment of patients with PV.
Several small clinical studies have shown that treatment with MMF may benefit patients 
with PV by stopping antibody production by B cells.
1.4
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
1.4.1
Role of B Cells in Pemphigus Vulgaris
PV is characterized by the deposition of autoantibodies on the keratinocyte cell surface,
resulting in suprabasal acantholysis.  These autoantibodies are produced by circulating 
B cells and target Dsg1 and Dsg3. They bind to keratinocytes, inhibit cell-cell adhesion, 
and cause blister formation and inflammation in the skin and mucous membrane 
(Feldman and Ahmed 2011).  In addition to the role of autoantibodies in PV, 
dysregulated B cells may further worsen disease by secreting cytokines, co-stimulating 
T cells, and differentiating into memory B cells and plasma cells, which contribute to 
persistent autoantibody production and relapsing disease.
1.4.2
Efficacy and Safety of Rituximab in Pemphigus Vulgaris
Owing to its ability to deplete pathogenic B cells, rituximab has been used off-label for
multiple autoimmune conditions, and there is increasing evidence for the successful use 
of rituximab in severe and refractory PV.  A review of the literature shows that over 
400 PV patients have been treated with rituximab; 44% of them have received the 
rituximab 21000 mg IV (Days 1 and 15) dose, with repeat administration in some 
cases.  Several small, investigator-initiated, uncontrolled clinical studies investigating the 
use of rituximab in PV with variable definitions of response have demonstrated overall 
complete remission rates of approximately 30%90%, as determined by the 


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investigators (Feldman and Ahmed 2011).  The high variability in complete remission 
rates may be due to differences in concomitant therapy, duration of disease, number of 
cycles of rituximab administered, follow-up periods, and the definition of complete 
remission (e.g., complete remission on or off corticosteroid treatment by Months 36 
following rituximab treatment).  All patients had active disease, despite 
immunosuppressant therapy, and had variable durations of disease onset.  The results 
of several uncontrolled studies and selected case reports of rituximab in PV (see 
Appendix 10) provide supportive data that rituximab has provided significant benefit to 
PV patients when standard therapies have inadequately controlled their disease.
A summary of the key publications reporting the efficacy of the rituximab 21000 mg IV 
(Days 1 and 15) dose in PV patients is provided below:  

Heelan et al. (2014) concluded that rituximab 21000 mg IV (Days 1 and 15) 
appeared to be an effective therapeutic option, with minimal serious adverse events,
for patients with severe or refractory pemphigus (N92; PV84).  After a single 
cycle of rituximab, 74 patients (80%) achieved complete remission while off 
systemic therapy. The study reported that patients who did not achieve remission 
after one cycle and those who experienced relapse benefited from further rituximab 
cycles, which were typically 21000 mg IV doses repeated at 6 months (
, 
personal communication).

Leshem et al. (2014) reported that treatment with rituximab 21000 mg IV (Days 1 
and 15) resulted in a 90% remission rate 6 months after treatment.  Patients
enrolled (N10) were previously part of a larger study (Leshem et al. 2013) 
evaluating the clinical efficacy of rituximab 21000 mg IV (Days 1 and 15).  The 
limitations of this study included the small number of patients and the lack of a 
control group.  Nevertheless, it was a prospective study using rituximab 21000 mg 
IV (Days 1 and 15) in patients with severe PV with favorable efficacy and safety 
results.  

Leshem et al. (2013) also reported, in a study of 47 patients, that rituximab
21000 mg IV (Days 1 and 15), used typically with concurrent immunosuppressive 
medications, demonstrated a 76% remission rate in severe PV patients at a median 
of 4 months after the first treatment cycle. Repeating treatment with rituximab 
21000 mg IV at 6 months increased the remission rate to 91%.  The limitations of 
this study included its retrospective nature and lack of immunologic evaluation of 
response to therapy.  Nevertheless, this was one of the largest published series on 
rituximab in pemphigus and provides data on the efficacy and safety of both a single 
cycle and repeated cycles of rituximab 21000 mg IV.

Kanwar et al. (2013) concluded that rituximab may be an important treatment 
modality for PV patients because of the efficacy observed in patients with resistant 
and extensive disease. Thirty percent of patients in the study (N9) achieved a 
complete remission and were off all treatment, 40% achieved complete remission 
and were on low-dose oral prednisolone, and 20% had partial remission and were 
on low-dose prednisolone.  Mean time to disease control was 8 weeks (range, 
512 weeks). 


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
Cianchini et al. (2012) (N37) demonstrated the efficacy of rituximab 21000 mg IV 
(Days 1 and 15) in combination with prednisone, with 86% of patients with severe 
PV in complete remission and off corticosteroids within 6 months of induction 
therapy. Six patients with a partial remission experienced a complete remission 
after an additional single 500-mg infusion of rituximab.

An ongoing investigator-sponsored study in France has completed enrollment 
(N90), and final results are anticipated in 2015 (ClinicalTrials.gov, Joly P).  This 
randomized, open-label, multicenter trial is comparing rituximab plus low-dose 
prednisone with standard-dose prednisone in patients with moderate-to-severe PV.
Administration of rituximab in PV patients was associated most commonly with 
infusion-related events, which occurred primarily with the first infusion and included 
fever, chills, nausea, and headache (Feldman and Ahmed 2011). Serious adverse 
events were consistent with the known safety profile of rituximab 
(Kasperkiewicz et al. 2012a, 2012b; Lunardon et al. 2012; Balighi et al. 2013;
Colliou et al. 2013; Leshem et al. 2013).  Overall, the adverse events reported in the 
literature for rituximab use in PV were consistent with those reported in patients with 
severe PV treated with other immunosuppressants and with the known adverse event 
profile of rituximab in autoimmune and other indications.
Given the significant data generated to date from multiple case reports and small 
uncontrolled clinical studies (as outlined above), the Sponsor believes that treatment 
with rituximab offers a potential benefit for PV patients and that it is becoming an 
unapproved standard of care, especially in PV patients for whom conventional therapy 
has failed.  In addition to the extensive safety database available from the use of 
rituximab across multiple indications, demonstration of efficacy and safety in this single 
pivotal Phase III trial, to be conducted in patients with moderate-to-severely active PV, 
would enable a benefit-risk assessment in this rare disease.
1.4.3
Efficacy and Safety of Mycophenolate Mofetil in 
Pemphigus Vulgaris
There have been multiple publications describing the efficacy and safety of MMF in the 
treatment of PV.  Most of these were uncontrolled studies and involved small numbers of 
patients. Doses ranged from 13.5 g/day, and duration of treatment from 1 month to 
4 years. These studies showed that MMF was well tolerated in most patients and had a 
favorable safety profile when prescribed at 23 g/day given in divided doses.  MMF is 
associated with dose-limiting toxicity, particularly gastrointestinal and hematologic 
toxicities, and doses above 3 g/day are not typically used in PV (Beissert et al. 2010).  
Published studies have also demonstrated that, when combined with prednisone, MMF 
is very effective in achieving remission (Marzano et al. 2006; Sarma and Ghosh 2007; 
Zwerner and Fiorentino 2007; Doukaki et al. 2011; Strowd et al. 2011; Eskin-Schwartz et 
al. 2011, 2012; Ioannides et al. 2012; Almugairen et al. 2013; Vyas et al. 2013). 


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The International Pemphigus and Pemphigoid Society endorses published treatment 
guidelines (Harman et al. 2003), and the European Dermatology Forum, in cooperation 
with the European Academy of Dermatology and Venereology, developed treatment 
guidelines generated by expert consensus, which support the use of either MMF or 
azathioprine as immunosuppressive adjuvants (European Dermatology Forum 2013).  
A comparison of these two therapies concluded that MMF was slightly better at inducing 
remission and was associated with fewer adverse events (Beissert et al. 2006).  
A pivotal, prospective trial sponsored by Vifor Pharma, Ltd. (Beissert et al. 2010) 
examined the use of MMF versus placebo in PV patients with mild-to-moderate disease 
receiving prednisone. While this study did not meet its primary endpoint of complete 
remission (i.e., absence of new, persistent oral or cutaneous lesions, and prednisone 
dose 10 mg/day from Weeks 4852), it identified that a dose of 2 g/day is considered 
to be equally effective to 3 g/day when evaluating secondary endpoints, including time to 
response and duration of response.  In addition, MMF was well tolerated in this study 
over a treatment period of up to 52 weeks, with the majority of adverse events being mild 
or moderate and most frequently involving infections and infestations, which appeared to 
be treatment and dose dependent.  In the MMF 3 g/day treatment group, frequently 
reported adverse events included oral candidiasis, headache, and upper respiratory tract 
infection, which occurred with a higher frequency than in the placebo or MMF 2 g/day 
groups. The MMF 2 g/day group had the highest incidence of nasopharyngitis, pyrexia, 
cough, hypertension, and arthralgia. While laboratory values generally remained normal 
over the course of the study, one subject in the MMF 3 g/day group experienced severe 
lymphopenia and severe neutropenia and was subsequently withdrawn from the study.  
Based on this information, MMF has been selected to be the active comparator in this 
study at a proposed dose of 2 g/day orally.
2.
OBJECTIVES
2.1
EFFICACY OBJECTIVES
2.1.1
Primary Efficacy Objective
The primary efficacy objective for this study is as follows:

To evaluate the efficacy of rituximab compared with MMF in achieving sustained 
complete remission, evaluated by the PDAI (see Section 3.4.1.1), and assessed at 
Week 52 in patients with moderate-to-severely active PV
2.1.2
Secondary Efficacy Objectives
The secondary efficacy objectives for this study are as follows:

To evaluate the efficacy of rituximab compared with MMF, as measured by the time 
to disease flare, the duration of sustained complete remission, the total number of 
disease flares during the treatment period, and the time to initial sustained complete 
remission


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
To assess corticosteroid exposure over 52 weeks 

To assess the effect of rituximab compared with MMF on health-related quality of 
life (HRQoL), as measured by the Dermatology Life Quality Index (DLQI) 

To assess the effect of rituximab compared with MMF on patients’ impression of PV 
symptoms, as measured by the Patient Global Impression of Change (PGIC) 
questionnaire

To assess the effect of rituximab compared with MMF on clinician impression of 
patients’ PV symptoms, as measured by the Clinician Global Impression of Change 
(CGIC) questionnaire
2.2
SAFETY OBJECTIVES
The safety objectives for this study are as follows:

To evaluate the safety of rituximab compared with MMF, with a focus on adverse 
events and safety laboratory values

To evaluate corticosteroid-related adverse events in relation to corticosteroid 
exposure
2.3
EXPLORATORY OBJECTIVES
The exploratory objectives for this study will include, but are not limited to, the following:

To evaluate the efficacy of rituximab compared with MMF, as measured by the 
proportion of patients achieving complete or partial remission by 24 weeks and 
52 weeks

To explore the pharmacokinetics and pharmacodynamics of rituximab, and the 
pharmacodynamics of MMF, in patients with PV

To evaluate the effect of rituximab as compared with MMF on the change in PDAI 
activity score

To evaluate the effect of rituximab as compared with MMF on anti-Dsg autoantibody 
titers (anti-Dsg1 and anti-Dsg3) and other mechanistic studies of interest in patients 
with PV

To assess the effect of rituximab compared with MMF on health utilities as 
measured by the European Quality of Life (EuroQol) 5-Dimension Questionnaire, 
3-level version (EQ-5D-3L)

To assess the effect of rituximab compared with MMF on HRQoL, as measured by 
the Skindex-29 

To evaluate the efficacy of rituximab compared with MMF, as measured by the
proportion of patients experiencing treatment failure from Week 12 to Week 52


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3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
3.1.1
Overview of Study Design
This is a Phase III, randomized, double-blind, double-dummy, active-comparator, 
parallel-arm, multicenter study to evaluate the efficacy and safety of rituximab compared 
with MMF in patients with moderate-to-severely active PV requiring 60120 mg/day PO
prednisone or equivalent (1.01.5 mg/kg/day).  Patients must have a confirmed 
diagnosis of PV within the previous 24 months (by skin or mucosal biopsy and 
immunohistochemistry) and evidence of moderate-to-severely active disease at 
screening (defined as a total PDAI activity score of 15).
This international study will be conducted at investigational sites throughout North 
America, Europe, the Middle East, and Latin America.  It is expected that approximately 
60 centers will participate.  Approximately 132 patients will be randomized in a 1:1 ratio
to receive either rituximab plus MMF placebo or rituximab placebo plus MMF.  
Randomization will be stratified by duration of illness (newly diagnosed [i.e., diagnosed 
within the 1 year prior to screening] vs. diagnosed greater than 1 year) and geographical 
region (North America [U.S./Canada] vs. rest of world).  
The study will consist of three periods:  a screening period of up to 28 days, a 52-week 
double-blind treatment period, and a 48-week safety follow-up (SFU) period that begins 
at the time of study treatment completion or discontinuation.
Rituximab (1000 mg or matching placebo) will be administered by IV infusion on Day 1 
and Day 15, with repeat rituximab (or matching placebo) administration on Day 168 and 
Day 182 provided specific safety criteria have been met (see Section 4.6.4).  MMF
(500 mg or matching placebo) will be administered PO twice daily (every 12 hours
[Q12H]), starting with a total dose of 1 g/day on Day 1.  The MMF dose will be titrated to 
achieve a goal of 2 g/day in divided doses (1 g Q12H) by Week 2.  Treatment with MMF 
(or matching placebo) will continue through Week 52.
In order to reduce the frequency and severity of infusion-related reactions, all patients 
will receive methylprednisolone 100 mg or saline solution prior to infusion of rituximab or 
rituximab placebo, respectively.  This premedication will be administered by slow IV 
infusion, and administration should be completed at least 30 minutes prior to infusion of 
rituximab or rituximab placebo.  
All patients should be premedicated with paracetamol/acetaminophen (1 g PO) and an 
antihistamine (diphenhydramine HCl 50 mg PO, or IV equivalent, or equivalent dose of a 
similar agent or in accordance with local approved labeling) 3060 minutes prior to the 
start of the infusion of rituximab or rituximab placebo.




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during a scheduled or unscheduled visit, the visit should proceed as the withdrawal visit, 
that is, only the withdrawal visit assessments should be conducted.  After the withdrawal 
visit, the patient will be asked to enter the SFU period of the study.
All patients who withdraw from the treatment period or who complete the total 52-week 
treatment period must return for postWeek 52 SFU assessments at 12, 24, 36, and 
48 weeks after either the early withdrawal visit or study treatment completion, 
respectively. Thus, patients will be followed for approximately 1 year in the SFU period. 
A schedule of assessments during the SFU period is provided in Appendix 2.
Before Week 12, patients who experience treatment failure (as defined in Section 3.1.3)
will require an early withdrawal visit and will be followed in the SFU period to receive 
standard-of-care treatment per the investigator’s best medical judgment.
From Week 12 through Week 52, patients who experience treatment failure (as defined 
in Section 3.1.3) are eligible to receive rescue therapy during the treatment period with 
another immunosuppressive medication, IV Ig, plasmapheresis, or another treatment or 
procedure as per the investigator’s best medical judgment.  An early withdrawal visit is 
not required for a patient to receive rescue therapy, and patients should continue to be 
followed in the study per the 52-week treatment period (see Appendix 1).
If a patient receives rescue therapy with rituximab, the number and timing of infusions 
will be at the discretion of the investigator. Every effort will be made to maintain the 
study blind, but the patient may be unblinded at the discretion of the Principal 
Investigator’s safety assessment. Patients who receive rescue infusions with rituximab 
from Week 12 through Week 24 will not receive the scheduled rituximab or matching 
placebo infusions on Days 168 and 182. Careful consideration should also be given as 
to whether MMF/matching placebo are continued following rescue therapy with any 
immunosuppressive medication.
Evaluation of the primary endpoint will occur at Week 52.  To prevent potential 
unblinding due to observed efficacy or laboratory changes, a dual-assessor approach 
will be used to evaluate efficacy and safety.  
3.1.2
Corticosteroid Treatment
Patients eligible for this study will be receiving 60120 mg/day background oral 
prednisone or equivalent (1.01.5 mg/kg/day) at study entry.  During the screening
period (up to 28 days), the daily corticosteroid dose may be tapered, as directed by the 
investigator on the basis of disease activity and tolerability to reach a dosage of 
60 or 80 mg/day by Day 1.  Thereafter, corticosteroid treatment should then be tapered 
according to the treatment guideline in Table 1, which provides recommended doses 
based on the presence of disease activity, defined as the appearance of new lesions or 
the extension of established lesions.  The decision to taper the corticosteroid dose can 
be affected by physician preferences, patient tolerability, and local practices, among 


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other considerations.  The oral corticosteroid dose may be increased during the study as 
needed as the primary intervention for control of disease activity.  Prednisone (or 
equivalent) will be sourced locally.
The goal of study treatment is to maintain disease control and ultimately achieve disease 
remission.  Oral corticosteroids will be tapered to the target prednisone (or equivalent) 
dosage of 0 mg/day by Week 24 (or sooner, if appropriate).  From Week 24 to Week 52, 
the corticosteroid dosage should be maintained at 0 mg/day.  However, patients who 
experience a disease flare (as defined in Section 3.4.1.2) at 0 mg/day should restart at 
Step 5 of Table 1 (20 mg/day).  Patients whose disease is not controlled after increasing 
the corticosteroid dose up to an allowable maximum dose of 240 mg/day will be 
considered to have experienced treatment failure and may receive standard-of-care 
treatment per the investigator’s best medical judgment.  Use of minimal concomitant
topical corticosteroids will be permitted at the investigator’s discretion but will be tracked 
carefully during the course of the study.


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Table 1
Corticosteroid Treatment Guideline
Step
No. of Weeks
Daily Dose of 
Prednisone or 
Equivalent
Presence of Disease Activity a
No
Yes
1 (start) b
1 week
80 mg
Go to Step 2
Go to Step A
A
1 week
120 mg
Go to Step 2
Go to Step B
B
1 week
240 mg
Go to Step A
Discontinue taper c
2 (start) b
1 week
60 mg
Go 1 step forward
Go to Step 1
3
1 week
40 mg
Go 1 step back
4
2 weeks
30 mg
5
2 weeks
20 mg
Go 2 steps back
6
2 weeks
15 mg
7
2 weeks
12.5 mg
8
2 weeks
10 mg
9
2 weeks
7.5 mg
10
2 weeks
5 mg
11
2 weeks
2.5 mg
Stop corticosteroid
12
During complete 
remission
0 mg
Restart at Step 5
Notes:  On Day 1, start the oral corticosteroid regimen with an initial dosage of 60 or 
80 mg/day prednisone (or equivalent), as outlined in the schedule.  Increase the dose if 
disease activity is present after 1 week.  If necessary, increase the dose again (to 240 mg/day) 
if disease activity is still present after the second week.
a Disease activity is defined as the appearance of new lesions or the extension of established 
lesions.
b Patients on 80 mg/d on Day 1 will start at Step 1.  Patients on 60 mg/d on Day 1 will start at 
Step 2.
c Patients whose disease is not controlled after increasing the corticosteroid dose to 
240 mg/day will be considered to have experienced treatment failure and may receive 
standard-of-care treatment per the investigator’s best medical judgment.
Source:  Modified from Mentink LF, Mackenzie MW, Tóth GG, et al. Randomized controlled 
trial of adjuvant oral dexamethasone pulse therapy in pemphigus vulgaris (PEMPULS Trial). 
Arch Dermatol 2006;142:5706.


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3.1.3
Definition of Treatment Failure
Treatment failure is the occurrence of any one of the following events:

After disease control has been achieved, a two-step increase in prednisone (or 
equivalent) dose to 20 mg/day for more than 2 weeks to treat increased disease
activity during the corticosteroid taper 

Failure to achieve disease control after receiving 240 mg/day PO prednisone (or 
equivalent) for 1 week
Disease control is defined as the time at which new lesions cease to form and 
established lesions begin to heal (beginning of the consolidation phase).

Increase in MMF/matching placebo dosage above 2 g/day

Initiation of any rescue therapy (addition of another immunosuppressive medication,
additional rituximab open-label doses, IV Ig, plasmapheresis, or another treatment 
or procedure) as determined by the investigator’s best medical judgment
Patients experiencing treatment failure prior to achieving sustained complete remission 
will be categorized as non-responders in the primary analysis, but will continue to be 
followed in the study per the schedule of assessments. Patients who achieve sustained 
complete remission without experiencing an event constituting treatment failure 
beforehand will not be categorized as non-responders, regardless of whether they 
subsequently meet the criteria during the remaining treatment period.
3.1.4
Independent Data Monitoring Committee
Safety data will be reviewed by an independent Data Monitoring Committee (iDMC) as 
specified in the iDMC Charter and at the following times, whichever occurs first: 

After the first 10 patients have completed at least 3 months of study treatment or 
have withdrawn early from the study 

After the first 5 telemedicine (TM) patients have completed at least 3 months of 
study treatment or have withdrawn early
Thereafter, meetings will be held approximately every 4 to 6 months (frequency may be 
adjusted during the recruitment period), after 10 TM patients have completed at least 
3 months of study treatment or withdrawn early from the study, or as requested by the 
iDMC.  
The safety evaluations will be detailed in the iDMC Charter and will include review of 
conventional safety variables, such as serious adverse events, infusion-related reactions,
and infections.  Any safety event that requires unblinding will be immediately reported to 
the iDMC and to the U.S. Food and Drug Administration (FDA) in a U.S. Investigational 
New Drug (IND) safety report.  The iDMC may request and review any additional reports 
outside of the planned analyses at any time if deemed necessary to ensure the safety of 
patients.  The iDMC will also review the TM data (see Section 7.3).  After reviewing 
safety data, the iDMC will make recommendations regarding continuation, termination, 


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or modification of the study.  The details of the iDMC roles and responsibilities and the 
logistics of the iDMC activities will be outlined in an iDMC Charter.  
3.2
END OF STUDY
The end of the study is defined as the date when the last patient, last visit (LPLV) occurs.  
LPLV is expected to occur approximately 2 years after the last patient is enrolled, 
assuming a 52-week treatment period and a 48-week SFU period for the last patient.
3.3
RATIONALE FOR STUDY DESIGN  
3.3.1
Rationale for Rituximab Dose and Schedule
In 2006, rituximab was approved by the FDA for use in RA at a dosing schedule in adults 
that is irrespective of body weight (i.e., 21000 mg IV [Days 1 and 15 with repeated 
infusions between Months 4 and 6]).  Rituximab is under investigation in this study as an 
experimental drug in PV and is currently not approved for the treatment of patients with 
PV.
In previous studies of rituximab in PV, investigators have used the proposed 21000 mg 
IV dose in the initial cycle (Days 1 and 15) as well as 4375 mg/m2 IV dose (Days 1, 8, 
15, and 22).  If a 70-kg person of average height were to be treated with the 375 mg/m2
approach, the total dose for their initial cycle would be approximately 2.8 g, versus 2 g if 
the 21000 mg IV approach were used.  PV (like RA) is an autoimmune disease, and an 
effective treatment does not require depletion of malignant B-cell clones, as in 
lymphoma (Leshem et al. 2013).  Given the experience with 21000 mg IV dose in 
autoimmune indications, the literature supporting this dose in PV patients, and the fact 
that this dose results in a lower total exposure and fewer infusions, the Sponsor has 
selected this dose and schedule for this trial. 
In RA, the rituximab dose 21000 mg IV (Days 1 and 15) has been demonstrated to be 
an effective dose, sufficient to sustain B-cell depletion for 69 months. Achieving other 
therapeutic outcomes in PV, such as complete removal of autoantibodies via sustained 
B-cell depletion in both the periphery and secondary lymphoid organs, is also a target in 
the management of PV. Sustained complete remission is the ultimate therapeutic goal. 
A single cycle of rituximab, although generally effective for at least 6 months (24 weeks),
is not considered a cure in this autoimmune-relapsing disease.  In RA, it is 
recommended that, until the desired treatment target is reached, drug therapy should be 
repeated at least every 6 months (Smolen et al. 2010).  Additionally, a recent clinical trial 
investigating the use of rituximab in patients with severe and/or refractory pemphigus 
(84 PV patients; 8 pemphigus foliaceus patients) showed that patients who do not 
achieve remission after 1 cycle and those who experience relapse benefit from further 
cycles of rituximab.  This recent study suggested that the majority of PV patients 
receiving a single cycle of rituximab will experience a disease flare, further supporting 
the rationale for an additional treatment cycle at 6 months (Heelan et al. 2014).  


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3.3.2
Rationale for Active Comparator Arm (MMF)
Corticosteroids are felt to be the mainstay of initial therapy for PV patients, and 64% of 
patients with mild-to-moderate disease achieved a complete remission with initial 
corticosteroid infusion and prednisone taper without the use of additional 
immunosuppressants (Beissert et al. 2010).  Patients who have persistent disease that 
is not fully responsive to corticosteroid treatment and those who have a higher risk of 
prednisone-related complications require additional immunosuppressive therapy (i.e., 
typically with azathioprine [2 mg/kg PO] or MMF [2 g/day PO]) 
(Grundmann-Kollmann et al. 1999; Nousari et al. 1999; Powell et al. 2003; 
Marzano et al. 2006; Sarma and Ghosh 2007; Zwerner and Fiorentino 2007; 
Doukaki et al. 2011; Strowd et al. 2011; Eskin-Schwartz et al. 2011, 2012; 
Ioannides et al. 2012; Almugairen et al. 2013; Vyas et al. 2013).  A comparison of these 
two therapies concluded that MMF was slightly better at inducing remission and was 
associated with fewer adverse events (Beissert et al. 2006).  
MMF (CellCept®) is marketed in oral and intravenous dosage forms and is currently 
approved for the prophylaxis of organ rejection in patients receiving allogeneic renal, 
cardiac, or hepatic transplants. For these approved uses, concomitant treatment with 
cyclosporine and corticosteroids is recommended. 
Clinical studies have investigated the use of MMF in other populations, and MMF is 
currently used to treat other conditions, including PV; however, it is not approved for 
indications unrelated to organ transplant. As such, MMF is under investigation in this 
study as an experimental drug in PV and is currently not approved for the treatment of 
patients with PV.  For additional information on the approved indications and relevant 
safety information, see the local prescribing information for MMF.
The International Pemphigus and Pemphigoid Society has published treatment 
recommendations that were generated by consensus, and these support the use of 
either MMF or azathioprine. Internal marketing data from the Sponsor on U.S. practice 
has determined that a higher proportion of U.S. dermatologists use MMF versus 
azathioprine (33% vs. 25%, respectively [internal data]), further confirming that MMF is a 
significant part of the standard-of-care treatment for PV patients.  Multiple publications 
have assessed the efficacy and safety of MMF in the treatment of PV 
(Eskin-Schwartz et al. 2011).
MMF has typically been prescribed at 2 to 3 g/day given in divided doses in immunologic 
(non-transplant) indications.  A pivotal, prospective, company-sponsored study was 
conducted that examined the use of MMF for the treatment of PV patients with 
mild-to-moderate disease. While this study did not meet its primary endpoint of 
complete remission (i.e., absence of new, persistent oral or cutaneous lesions, and 
prednisone dose 10 mg/day from Weeks 4852), it identified that a dose of 2 g/day is 
considered to be equally effective to 3 g/day when evaluating secondary endpoints, 
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dose-limiting toxicity, particularly gastrointestinal and hematologic toxicities, and doses 
above 3 g/day are not typically used in PV (Beissert et al. 2010).  Dose adjustments 
above 2 g/day are not recommended.
For these reasons, MMF has been selected to be the active comparator in this study. 
The proposed MMF dosing of 2 g/day PO is consistent with the CellCept® U.S. Package 
Insert, publications, and guidelines, and represents a strong clinical comparator in the 
proposed study. 
3.3.3
Rationale for Use of the PDAI as the Key Assessment of 
Disease Activity
Several different instruments assessing clinical disease activity have been developed to 
capture distribution, activity, and severity of pemphigus. The most commonly used 
instrument is the PDAI, developed by the International Pemphigus Committee 
(Murrell et al. 2008; Rosenbach et al. 2009; Daniel et al. 2012).  Rahbar et al. (2014) 
evaluated the PDAI and a number of other validated instruments in a large number of 
patients with PV.  Inter-rater reliability and convergent validity according to anti-Dsg titers 
(which correlate with pemphigus disease activity) were evaluated, and the authors 
concluded that the PDAI had the highest reliability and validity.  It is recommended for 
use in multicenter studies of rare diseases, such as PV.  The PDAI can be completed in 
less than 5 minutes.  The PDAI will provide a reliable and validated measurement of 
disease activity and severity in this study.  
3.3.4
Rationale for Corticosteroid Treatment Guidelines 
There is no uniformly accepted taper regimen for oral corticosteroids.  The initial use of 
high-dose systemic corticosteroids, typically 60120 mg/day PO prednisone or 
equivalent (1.01.5 mg/kg/day) is frequently used in the treatment of 
moderate-to-severely active disease.  Recent studies employed a similar regimen and 
suggest that a dose of 1.01.5 mg/kg per day PO prednisone (or equivalent) tapered 
over 36 months is a standard regimen (Beissert et al. 2006, 2010).  The decision to 
taper can be affected by various considerations, including physician preferences, patient 
tolerability, and local practices.
The rate at which corticosteroids are tapered in this study is based on the clinical 
manifestations of the disease, and tapering too rapidly increases the chances of a
disease flare.  The suggested taper and initial dose were discussed with expert advisors 
in an advisory board and deemed desirable (Advisory Board Meeting 12 February 2014).  
Patients who experience disease flare will receive an increase in prednisone up to 
240 mg/day at the investigator’s discretion.  Patients who require prednisone 
240 mg/day for 1 week and are still not controlled and patients who require a two-step 
increase in prednisone dose to 20 mg/day for more than 2 weeks to treat increased 
disease activity during the corticosteroid taper will be considered non-responders in the 
primary efficacy analysis.  There are additional treatment failure criteria that lead to 
protocol-defined non-response, outlined in Section 3.1.3.


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3.3.5
Rationale for Biomarker Assessments, including Optional 
Whole Blood and Serum Samples for Storage and Future 
Research
PV is a heterogeneous disease, and anti-Dsg1 and anti-Dsg3 autoantibodies expression 
has been shown to vary among patients (Harman et al. 2001).  Autoantibody titers may 
influence responses to rituximab or MMF.  Predictive biomarker samples collected 
during the study will be assessed in an effort to identify those patients with 
autoantibody-driven pathogenesis and, potentially, those who are most likely to respond 
to rituximab. 
Identification of proteins targeted by autoantibodies in PV is a subject of intense 
research.  There is evidence that keratinocyte antigens other than Dsg1 and Dsg3 are 
pathophysiologically relevant (Nguyen et al. 1998). Current understanding, however, 
does not adequately explain the mechanism of acantholysis in patients lacking anti-Dsg1 
and anti-Dsg3 antibodies.  Results of a recent study indicate that autoreactivity in PV 
relies on somatic mutations generated in response to an antigen unrelated to Dsg3 
(Di Zenzo et al. 2012).  Taken together, these observations justify a search for novel 
targets of pemphigus autoimmunity via collection of additional optional blood samples for 
the Roche Clinical Repository (RCR) for storage and future research in PV.  These 
samples include serum for biomarker analysis and whole blood samples for RNA and 
DNA analysis.
Other pharmacodynamic (PD) biomarkers, including CD19, will be assessed to 
demonstrate evidence of biologic activity of rituximab in patients and to inform potential 
revisions to the PK sample collection schedule.  As these biomarkers may also have 
prognostic value, their potential association with disease progression will also be 
explored.
3.4
OUTCOME MEASURES 
3.4.1
Efficacy Outcome Measures
3.4.1.1
Primary Efficacy Outcome Measure
The primary efficacy outcome measure is as follows:

Proportion of patients (excluding TM patients) who achieve a sustained complete 
remission without experiencing an event that constitutes treatment failure (as
defined in Section 3.1.3), as measured at Week 52
Sustained complete remission is defined as achieving healing of lesions with no 
new active lesions (i.e., PDAI activity score of 0) while on 0 mg/day prednisone 
or equivalent, and maintaining this response for a total of at least 
16 consecutive weeks, during the 52-week treatment period. 
Patients with transient new lesions for 1 week or less that heal without 
additional systemic corticosteroid therapy will not be considered to have 
experienced treatment failure.


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3.4.1.2
Secondary Efficacy Outcome Measures
The secondary efficacy outcome measures are as follows:

Cumulative oral corticosteroid dose (prednisone or equivalent) over the 
treatment period

Total number of disease flares during the treatment period

Time to sustained complete remission

Time to disease flare
Disease flare is defined as appearance of three or more new lesions a month
that do not heal spontaneously within 1 week or by the extension of established 
lesions in a patient who has achieved disease control.

Change in HRQoL, as measured by the DLQI score from baseline to Week 52

Duration of sustained complete remission

Patients’ impression of change in PV symptoms, as measured by the PGIC score
during the treatment period

Clinician impression of change in patients’ PV symptoms, as measured by the CGIC 
score during the treatment period
3.4.2
Safety Outcome Measures
The safety outcome measures include, but are not limited to, the following:

Nature, frequency, and severity of adverse events, including serious adverse events 
and adverse events leading to discontinuation

Vital signs and clinical laboratory test results (including complete blood count and 
blood chemistry) 

Incidence of HACA

Circulating B cells, T cells, natural killer (NK) cells, plasma cells, and other 
leukocytes  

Plasma Ig levels (total Ig, IgG, IgM, and IgA)  

Corticosteroid-related adverse events in relation to corticosteroid exposure
3.4.3
Exploratory Outcome Measures
The exploratory outcome measures for this study will include, but are not limited to, 
the following:

Proportion of patients achieving a complete remission by Week 24 and by Week 52
Complete remission is defined as achieving wound healing with no new active 
lesions (i.e., PDAI activity score of 0) for at least 8 consecutive weeks during 
the 52-week treatment period.  

Proportion of patients achieving a partial remission by Week 24 and by Week 52
Partial remission is defined as the presence of transient new lesions that heal 
within 1 week (while the patient is receiving minimal therapy, including topical 


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corticosteroids).  Minimal therapy is defined as 10 mg/day prednisone (or 
equivalent) for at least 8 consecutive weeks during the 52-week treatment 
period.

Pharmacokinetics/pharmacodynamics of rituximab
PK/PD parameters include, but are not limited to, serum levels of rituximab, 
peripheral CD19B-cell counts, HACA, and autoantibody concentrations.

To explore the pharmacodynamics of MMF in patients with PV

Change in total PDAI activity score during the treatment period

Change from baseline in anti-Dsg1 and anti-Dsg3 autoantibodies

Change in health utilities as assessed by the EQ-5D-3L score from baseline to 
Week 52 

Change in HRQoL, as measured by the Skindex-29 from baseline to Week 52

Proportion of patients who experience treatment failure from Week 12 to Week 52
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 132 patients with active moderate-to-severely active PV will be recruited 
into this study.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Age 1875 years

Signed Informed Consent Form

First confirmed diagnosis of PV within the previous 24 months, based on the 
presence of histological features of acantholysis via skin or mucosal biopsy and one 
of the following:  tissue-bound IgG antibodies by direct immunofluorescence on the 
surface of affected epithelium or serological detection of serum Dsg3 autoantibodies 
against epithelial cell surface either by indirect immunofluorescence microscopy or
by enzyme-linked immunosorbent assay  

Presence of moderate-to-severely active disease, defined as overall PDAI activity 
score of 15

Receiving standard-of-care corticosteroids consisting of 60120 mg/day PO
prednisone or equivalent (1.01.5 mg/kg/day) and, in the judgment of the 
investigator, expected to benefit from the addition of immunosuppressive therapy

For women who are not postmenopausal (12 months of nontherapy-induced 
amenorrhea) or surgically sterile (absence of ovaries and/or uterus):  agreement to 
remain abstinent or use two effective methods of contraception, including at least 
one method with a failure rate of 1% per year, during the treatment period and for 
at least 12 months after the last dose of study treatment  


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Abstinence is acceptable only if it is in line with the preferred and usual lifestyle 
of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception.
Barrier methods must always be supplemented with the use of a spermicide.
Examples of contraceptive methods with a failure rate of 1% per year (highly 
effective contraceptive methods) include tubal ligation, male sterilization, 
hormonal implants, established, proper use of combined oral or injected 
hormonal contraceptives, and certain intrauterine devices.

For men (including those who have undergone a vasectomy):  agreement to remain 
abstinent or use a condom during the treatment period and for at least 12 months 
after the last dose of study treatment and agreement to refrain from donating sperm 
during this same period
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle 
of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception.
In addition to male contraception, agreement to advise female partners of 
childbearing potential to use highly effective contraception during the study and 
for at least 12 months after the last dose of study treatment

Agreement to avoid excessive exposure to sunlight during study participation

Able to comply with the study protocol, in the investigator’s judgment
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Diagnosis of pemphigus foliaceus or evidence of paraneoplastic pemphigus or other 
non-PV autoimmune blistering disease

History of a severe allergic or anaphylactic reaction to humanized or murine 
monoclonal antibodies, or known hypersensitivity to any component of rituximab

Known hypersensitivity or contraindication to MMF, mycophenolic acid, polysorbate, 
or oral corticosteroids

Lack of peripheral venous access

Pregnant or lactating, or intending to become pregnant during the study
Women who are not postmenopausal (12 months of nontherapy-induced 
amenorrhea) or surgically sterile must have two negative results with a 
sensitivity of 25 mIU/mL:  one from a serum pregnancy test at Day 8 to 
Day10 of screening and another from a urine pregnancy test at Day 1 prior to 
randomization.

Participated in another interventional clinical trial within 28 days prior to 
randomization


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
Use of any investigational agent within 28 days or 5 elimination half-lives prior to 
randomization (whichever is the longer)

Significant cardiovascular or pulmonary disease (including obstructive pulmonary 
disease)

Evidence of any new or uncontrolled concomitant disease that, in the investigator’s 
judgment, would preclude patient participation, including but not limited to nervous 
system, renal, hepatic, endocrine, malignant, or gastrointestinal disorders 

Any concomitant condition that required treatment with oral or systemic 
corticosteroids within 12 weeks prior to randomization

Treatment with IV Ig, plasmapheresis, or other similar procedure within 8 weeks 
prior to randomization

Treatment with immunosuppressive medications (e.g., azathioprine, MMF) within 
1 week prior to randomization

Treatment with cyclophosphamide within 12 weeks prior to randomization

History of or currently active primary or secondary immunodeficiency, including 
known history of HIV infection and other severe Immunodeficiency blood disorders

Known active infection of any kind (excluding fungal infections of nail beds) or any 
major episode of infection requiring hospitalization or treatment with IV
anti-infectives within 4 weeks prior to screening, or completion of oral anti-infectives 
within 2 weeks prior to randomization
Entry into this study may be reconsidered once the infection has fully resolved.

History of or current cancer, including solid tumors, hematologic malignancies, and 
carcinoma in situ (except basal cell carcinoma and squamous cell carcinoma of the 
skin that have been excised and cured)

Currently active alcohol or drug abuse, or history of alcohol or drug abuse within 
24 weeks prior to screening

Major surgery within 4 weeks prior to randomization, excluding diagnostic surgery

Treatment with rituximab or a B celltargeted therapy (e.g., anti-CD20, anti-CD22, 
or anti-BLyS) within 12 months prior to randomization

Treatment with a live or attenuated vaccine within 28 days prior to randomization
It is recommended that a patient’s vaccination record and the need for 
immunization prior to study entry be carefully investigated.

Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or amylase 
2.5the upper limit of normal (ULN)

Absolute neutrophil count (ANC) 1.5103/L 

Hemoglobin 8.0 g/dL

Positive test results for hepatitis B surface antigen (HBsAg), hepatitis B core 
antibody (HBcAb), or hepatitis C virus (HCV) serology at screening


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4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
A total of approximately 132 patients will be recruited into this study and will be 
randomized in a 1:1 ratio to two treatment arms using an interactive/web voice response 
system (IxRS).  Patient randomization numbers will be generated by the IxRS vendor.  
A unique randomization number will be linked to the patient’s identification number 
(electronic Case Report Form [eCRF] number) via the IxRS.  Patients may not be dosed 
at any visit prior to receiving the IxRS-assigned medication numbers.  Patients who 
enroll in this study and who have completed treatment as specified are not permitted to 
be re-randomized to this study; however, re-screening is allowed as described in 
Section 4.5.1.3.
Randomization will be stratified by duration of illness (newly diagnosed [diagnosed within 
1 year prior to screening] vs. diagnosed greater than 1 year from screening) and 
geographical region (North America [U.S./Canada] vs. rest of world).  Patients
prematurely discontinued from the study will not be replaced.
The randomization list will not be available at the study center, to the Sponsor monitors, 
or the Sponsor’s project team, including the project statisticians.  The medication 
allocation will only be known to the unblinded drug accountability monitors and an 
unblinded on-site pharmacist who will prepare locally sourced methylprednisolone for 
patients receiving rituximab and a saline solution for patients receiving rituximab 
placebo, to be administered prior to the infusion. 
Every effort will be made to maintain the blind; for example, opaque infusion bags and IV 
lines will be used if local methylprednisolone has noticeable coloring compared with the 
saline solution.  To maintain the blind, investigational sites will not receive data related to
CD19B-cell counts, PK results, or HACA results. CD19B-cell counts will be made 
available to the investigator at the end of SFU period.  In addition, to prevent potential 
unblinding, there will be an efficacy assessor and a safety assessor for observed 
efficacy and safety evaluations.  Only the safety assessor will have access to adverse 
event reports and laboratory test results, and will determine dose adjustments and 
treatment decisions.
While PK samples must be collected from patients assigned to the comparator arm to 
maintain the blind, PK assay results for these patients are generally not needed for the 
safe conduct or proper interpretation of this trial.  Sponsor personnel responsible for 
performing PK assays will be unblinded to patients’ treatment assignments to identify 
appropriate PK samples to be analyzed.  Samples from patients assigned to the 
comparator MMF arm will not be analyzed for rituximab PK except by request (i.e., to 
evaluate a possible error in dosing). 
If the identity of the test medication is necessary for either patient management (in the 
case of a serious adverse event) or independent pharmacologic analysis of biologic 
samples, adequate procedures will be in place to maintain the integrity of the data.  


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Treatment codes should not be broken except in emergency situations, i.e., when 
knowledge of the treatment is essential for the immediate further management of the 
patient.  For emergency unblinding, the Principal Investigator or designee will contact 
IxRS prior to unblinding a patient’s treatment assignment. IxRS will provide the site with 
the patient’s unblinding treatment code.  The Medical Monitor will be notified of this 
event.
The Principal Investigator should make every attempt to contact the Sponsor before 
unblinding any patient’s treatment assignment, but in any case must do so within 
1 working day after the event and, if appropriate, complete an adverse event form.  The 
investigator should document and provide an explanation for any premature unblinding 
(e.g., accidental unblinding, unblinding due to a serious adverse event).  Unblinding 
does not in itself necessitate patient withdrawal from study, which would be determined 
at the discretion of the investigator.
In case of accidental unblinding, all the above procedures should be followed, except an 
adverse event form should not be completed.
For regulatory reporting purposes, and if required by local health authorities, the 
Sponsor will break the treatment code for all suspected, unexpected, and serious 
adverse reactions (see Section 5.7) that are considered by the investigator or Sponsor to 
be related to study drug.
4.3
STUDY TREATMENT 
Patients will be randomized in a 1:1 ratio to receive either rituximab plus MMF placebo 
or rituximab placebo plus MMF.
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Rituximab and Placebo
Rituximab (500-mg vials) and matching placebo will be supplied by the Sponsor.  For 
information on the formulation, packaging, and handling of rituximab, see the pharmacy 
manual and the Rituximab Investigator's Brochure.
4.3.1.2
MMF and MMF Placebo
MMF (500-mg tablets; 140 tablets per bottle) and matching placebo will be supplied by 
Sponsor.  For information on the formulation, packaging, and handling of MMF, see the 
local prescribing information for MMF.
4.3.2
Dosage, Administration, and Compliance
4.3.2.1
Rituximab and Rituximab Placebo
Rituximab at a dose of 1000 mg (or matching placebo) will be administered by IV 
infusion on Day 1 and Day 15, with repeat rituximab (or matching placebo) 
administration on Day 168 and Day 182 provided specific safety criteria have been met 
(see Section 4.6.4).  Rituximab (and matching placebo) should be administered in a 


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hospital, clinic, or healthcare-related environment where full resuscitation facilities are 
immediately available and under the close supervision of an experienced healthcare 
professional.  
After the end of the infusion, the IV line should remain in place for at least 1 hour to 
enable administration of drugs intravenously, if necessary.  If no adverse events occur 
during this period of time, the IV line may be removed.  Rituximab should not be 
administered in the setting of an active infection.  
All patients will receive 100-mg IV methylprednisolone (patients in the rituximab arm) or 
a saline solution (patients in the rituximab placebo arm) by slow infusion, to be 
completed at least 30 minutes prior to each infusion of rituximab or rituximab placebo, 
respectively.  All patients should be premedicated with paracetamol/acetaminophen 
(1 g PO) and an antihistamine (diphenhydramine HCl 50 mg PO [or IV equivalent] or 
equivalent dose of a similar agent, or in accordance with local approved labeling) 30 to 
60 minutes prior to the start of a rituximab infusion.
Detailed guidance for the administration of rituximab, including the rates of infusions and 
the actions to be taken in the event of an infusion-related reaction, is provided in
Appendix 3.
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 4.6.4, Section 5.1.1.9, and Appendix 3.
Any overdose or incorrect administration of rituximab should be noted on the Study Drug 
Administration eCRF.  Adverse events associated with an overdose or incorrect 
administration of rituximab should be recorded on the Adverse Event eCRF.
4.3.2.2
MMF and MMF Placebo
MMF (500 mg or matching placebo) will be administered orally twice daily (Q12H) 
starting on Day 1.  Patients will be initiated on 1 g/day MMF or matching placebo given 
as a divided oral dose. MMF dose will then be titrated to achieve a maximum dose goal 
of 2 g/day given as a divided oral dose (1 g Q12H) by Week 2.  Slower titration will be 
allowed on the basis of tolerability.  Treatment with MMF (or matching placebo) will 
continue through Week 52.
During the 52-week treatment period, the MMF (or matching placebo) dose should 
remain as stable as possible.  If reductions in dose are necessary because of tolerability, 
decreases will be allowed in 500-mg decrements and must be recorded on the 
appropriate eCRF.  If neutropenia develops (ANC 1.3103/L), dosing with MMF should 
be interrupted or the dose should be reduced.  Guidelines for dosage modification and 
treatment interruption or discontinuation of MMF are provided in the MMF prescribing 
information.


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In cases where MMF is introduced as a standard-of-care therapy, it should always be 
initiated on 1 g/day as a divided oral dose for 2 weeks.
Dose adjustments of MMF/matching placebo above 2 g/day are not recommended in 
this study.
Any overdose or incorrect administration of MMF should be noted on the appropriate
eCRF.  Adverse events associated with an overdose or incorrect administration of MMF 
should be recorded on the Adverse Event eCRF.
4.3.3
Investigational Medicinal Product Accountability
All investigational medicinal products (IMPs) required for completion of this study will be 
provided by the Sponsor where required by local health authority regulations.  The study 
site will acknowledge receipt of IMP, using the IxRS to confirm the shipment condition 
and content.  Any damaged shipments will be replaced.
IMP will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.
Accurate records of all IMP received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Post-Trial Access to Study Drug
The Sponsor will offer post-trial access to the study drug (rituximab/MMF) free of charge 
to eligible patients in accordance with the Roche group Global Policy on Continued 
Access to Investigational Medicinal Product, as outlined below.
A patient may be eligible, upon the investigator’s request, to receive post-trial access to study 
drug after the end of the study (i.e., end of SFU), if all of the following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being 

There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any country-specific legal or 
local regulatory requirements that apply to them
A patient will not be eligible to receive study drug after the end of the study if any of the 
following conditions are met:

The study drug is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or would not
otherwise create a financial hardship for the patient)


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
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for PV

The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for PV

Provision of study drug is not permitted under the laws and regulations of the 
patient's country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Internet site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy includes any background drug or substance (e.g., prescription 
drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) 
used by a patient from the time the patient is screened in the study until study 
completion.  This includes any preventative vaccines (e.g., tetanus or flu vaccines) that 
the patient may receive during the course of this study. All such medications should be 
reported to the investigator and recorded on the Concomitant Medications eCRF.  It 
should be noted that live or attenuated vaccines (e.g., certain formulations of influenza 
vaccines) are not permitted. Additional use of immunosuppressive medications, 
cell-depleting agents, or other standard-of-care therapies per best medical judgment 
must be reported as concomitant medications.
4.4.1
Corticosteroids
Oral prednisone (or equivalent) dose adjustments will be the main approach to treat 
either new or worsened disease activity.  Patients who experience disease flare (defined 
as appearance of three or more new lesions a month that do not heal spontaneously 
within 1 week or by the extension of established lesions in a patient who has achieved 
disease control) or who are unable to adhere to the protocol-defined prednisone tapering 
regimen (see Table 1) prior to Week 52 because of ongoing disease activity should
interrupt the protocol-defined prednisone taper and be given therapy with prednisone (up 
to 240 mg/day) at the discretion of the investigator, according to the guideline in Table 1.  
The patient should continue to receive blinded study treatment (rituximab, MMF, or 
matching placebo) and should continue with all study assessments as per Appendix 1
for the duration of the 52-week, double-blind treatment period.  Ongoing prednisone use 
will be at the discretion of the investigator during the treatment period.
Patients who require a two-step increase in corticosteroid dose to 20 mg/day for more 
than 2 weeks to treat increased disease activity will be deemed non-responders in the 
primary analysis.
All prednisone (or equivalent) doses and adjustments should be recorded on the
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4.4.2
Additional Permitted Therapy and Procedures
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use.  
Patients not already taking vitamin D (400 IU/day) and calcium supplements 
(1200 mg/day calcium citrate or 1500 mg/day calcium carbonate) may start these 
supplements at study initiation.  Pneumocystis jirovecii pneumonia prophylaxis may be 
performed according to local clinical practice guidelines and investigator judgment.
From Week 12 through Week 52, an additional provision is made for patients who would 
otherwise be withdrawn from the study because of lack of efficacy.  Specifically, patients 
who experience treatment failure between Week 12 through Week 52 are eligible to 
receive rescue therapy with another immunosuppressive medication, IV Ig, 
plasmapheresis, rituximab, or another treatment or procedure as per the investigator’s
best medical judgment and continue to be followed in the 52-week treatment period per 
the treatment period schedule of assessments (see Appendix 1).  Details of additional
therapies for PV should be reported as concomitant medications.
If a patient receives rescue therapy with any medication, dose and dosing schedule will 
be at the discretion of the investigator.  Every effort will be made to maintain the study 
blind, but the patient may be unblinded at the discretion of the Principal Investigator’s 
safety assessment.  Patients who receive rescue infusions with rituximab from Week 12 
through Week 24 will not receive the scheduled rituximab or matching placebo infusions 
on Days 168 and 182.  Careful consideration should also be given as to whether 
MMF/matching placebo are continued following rescue therapy with any 
immunosuppressive medication.
4.4.3
Prohibited Therapy
Use of the following therapies is prohibited during the study and for at least 28 days or 
5 elimination half-lives prior to initiation of study treatment, unless otherwise specified 
below, with prior approval of the Sponsor, or required for a medical emergency:

Investigational therapy

Live or attenuated vaccines (i.e., measles, mumps, rubella, oral polio, bacillus 
Calmette-Guérin, typhoid, yellow fever, vaccinia, some forms of influenza 
[e.g., FluMist®], or any other live vaccines not yet licensed but belonging to this 
category) are prohibited during the study and while the patient’s peripheral CD19
B cells are depleted below the central laboratory lower limit of normal.
– Non-live or inactivated vaccine (e.g., some forms of influenza) is not prohibited 
during the study; however, the efficacy of certain vaccines during or following 
periods of B-cell depletion has not been studied.
– Patients who are eligible for yearly influenza vaccine or who require other 
non-live booster vaccinations can receive vaccination with killed/toxoid vaccines 
consistent with normal clinical practice.


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Although not prohibited, caution should be especially used with the following:

Immunosuppressants/immunomodulators, antacids containing aluminum and/or 
magnesium, antivirals (e.g., acyclovir, ganciclovir, valganciclovir), calcium-free 
phosphate binders (e.g., aluminum products, lanthanum, sevelamer), rifampin, 
H2 blockers, and proton-pump inhibitors 
If concomitant medications (including prescription and over-the-counter medications, 
dietary and herbal supplements, vitamins, and nutritional supplements) are required, the 
investigator should use caution and monitoring when considering concomitant use with 
rituximab or MMF.  
4.5
STUDY ASSESSMENTS 
To prevent potential unblinding due to observed efficacy or changes in laboratory test 
results, a dual-assessor approach will be used to evaluate efficacy and safety.  The 
efficacy assessor should be a dermatologist or skilled physician PV assessor. To 
ensure consistency, wherever possible it is required that the same efficacy assessor 
continues to assess all efficacy parameters throughout the study for any particular 
patient.  The efficacy assessor will have access only to the efficacy data.  The safety 
assessor should be a dermatologist.  The safety assessor will have access to both 
safety and efficacy data and will make all treatment decisions based on the patient’s 
clinical response and laboratory test results.
It is essential that assessments by the patient (e.g., patient-reported outcomes [PROs]) 
and efficacy assessor are made before those of the safety assessor. Consequently,
assessments should be made in the following order:
1. Patient-reported outcomes:  DLQI, PGIC, EQ-5D-3L, and Skindex-29
2. Clinician-reported outcome (efficacy assessor): CGIC
3. Efficacy assessor:  PDAI (activity scale), lesion count, flare assessment
4. Safety assessor:  adverse event and laboratory assessments, corticosteroid dose 
assessment, and all treatment decisions
Please see Appendix 1 for the schedule of assessments performed during the study.
4.5.1
Informed Consent Forms and Screening Assessments
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site.
4.5.1.1
Screening Examination
The screening visit can occur up to 28 days prior to the first dose of study treatment.  
The timing of the pregnancy test during the screening period (8 to 10 days prior to the 
planned pregnancy test on Day 1) may require the patient to return to the clinic for an 


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additional visit.  All screening evaluations must be completed and reviewed to confirm 
that patients meet all eligibility criteria before randomization on Day 1 (see Section 4.1.1
and Section 4.1.2).  Screening assessments will be performed in accordance with the 
schedule of assessments (see Appendix 1).  The investigator will maintain a screening
log to record details of all patients screened and to confirm eligibility or record reasons 
for screening failure, as applicable.
4.5.1.2
Re-Testing:  Laboratory Inclusion/Exclusion Criteria
If a patient does not meet the laboratory eligibility criteria at screening (see Section 4.1.1
and Section 4.1.2), the investigator may repeat the test twice within the screening 
period.  If the patient does not meet the laboratory criteria for a third time, the patient will 
be considered a screen failure.  It is possible to re-screen a patient (see Section 4.5.1.3).
It will not be considered re-testing if blood samples have to be redrawn owing to sample 
handling problems, breakage, or sample integrity.
4.5.1.3
Re-Screening
Re-screening refers to repeating the entire screening process if a patient has not met all 
the eligibility criteria within 28 days of the original screening visit.
Patients are allowed to be re-screened only once. Each patient must be re-consented 
before re-screening occurs.
It will not be considered re-screening if blood samples have to be redrawn owing to
sample handling problems, breakage, or sample integrity.
4.5.2
Medical History and Demographic Data
Medical history includes clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
use of alcohol and drugs of abuse, and all previous medications (e.g., prescription drugs, 
over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used 
by the patient within 6 months prior to the screening visit.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.3
Physical Examinations
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurologic systems.  Any abnormality identified at 
baseline should be recorded on the eCRF.
4.5.4
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, temperature, and 
systolic and diastolic blood pressure while the patient is in a seated position.


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4.5.5
Assessments of Disease Activity
Disease status and activity will be evaluated using the PDAI and the CGIC at the 
timepoints specified in Appendix 1.  
The PDAI integrates cutaneous with mucosal disease in well-defined anatomical 
locations, assesses number and sizes of lesions, and scores post-inflammatory 
hyperpigmentation of resolving lesions (Murrell et al. 2008).  It is a validated instrument 
with a high inter-rater reliability.
The CGIC is a measure of perceived change in PV symptoms as assessed by the 
clinician using a 7-item categorical scale ranging from “very much improved” to “very 
much worse.”
4.5.6
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be sent to one or several central 
laboratories for analysis:

Pregnancy test
All women who are not postmenopausal (12 months of nontherapy-induced 
amenorrhea) or surgically sterile will have a serum pregnancy test at screening.  
Urine pregnancy tests will be performed at specified subsequent visits.  
If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy 
test.  Prior to starting study drug, female patients of childbearing potential must 
have two negative pregnancy tests.  The second test on Day 1 prior to 
randomization should be performed 8 to10 days after the first test during the 
screening period.

Safety laboratory assessments
Hematology (white blood cell [WBC] count, red blood cell [RBC] count, 
hemoglobin, hematocrit, platelet count, differential [neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, and other cells])
Serum chemistry (sodium, potassium, chloride, bicarbonate, glucose, blood 
urea nitrogen [BUN] or urea, creatinine, total protein, albumin, phosphorus, 
calcium, total and direct bilirubin, alkaline phosphatase, ALT, AST, uric acid, 
and lactate dehydrogenase [LDH])
Viral serology
–
HBsAg
–
HBcAb
–
HCV antibody
Urinalysis dipstick (glucose, protein, blood); if abnormal findings are present, a 
microscopic examination should be performed (sediment, RBCs, WBCs, casts, 
crystals, epithelial cells, and bacteria)


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
Immunology and other laboratory assessments
Lymphocyte subtypes and FACS analysis
–
Determination of NK-, T-, and B-cell populations will be performed via 
FACS analysis; lymphocyte subtypes of interest may include but are not 
limited to CD56NK cells;CD3, CD4, CD8, and NK T cells; CD19and 
CD27B cells; CD19CD27-naive B cells; CD19CD27memory B cells;
and CD24highCD38high transitional B cells.  
Quantitative Ig levels:  total Ig, IgA, IgG, and IgM
Autoantibodies:  anti-Dsg1 and anti-Dsg3 antibodies
HACA 
Rituximab PK analysis (see Appendix 1 and Appendix 2 for timepoints)
Optional whole blood sample for DNA, whole blood sample for RNA, and serum 
biomarker sample (for patients who sign the Optional Research Informed 
Consent Form [see Section 4.5.10])
Instruction manuals and supply kits will be provided for all central laboratory 
assessments.
4.5.7
Electrocardiogram
An electrocardiogram (ECG) should be taken at the time indicated in Appendix 1 and 
reviewed by the investigator or designee.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours 
after any meal.  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation), should be avoided 
during the pre-ECG resting period and during ECG recording.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Any abnormality identified at baseline should be recorded on the eCRF.  
Paper copies of ECG tracings will be kept as part of the patient's permanent study file at 
the site.  
4.5.8
Chest Radiograph
Posterior-anterior (P/A) and lateral chest radiographs (or chest radiographs in 
accordance with local requirements) should be obtained at screening and reviewed by 
the investigator or designee.  Any abnormality identified at baseline should be recorded 
on the eCRF.  At screening, if chest radiographs have been taken within the past 
3 months that show no clinically significant abnormality, and there are no signs or 


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symptoms suggestive of pulmonary disease that would exclude the patient, then chest 
radiograph does not need to be repeated.
4.5.9
Patient-Reported and Clinician-Reported Outcomes 
PRO and clinician-reported outcomes (ClinRO) data will be collected via questionnaires 
to more fully characterize the clinical profile of rituximab.  The questionnaires will be 
translated as required in the local language.  To ensure instrument validity and that data 
standards meet health authority requirements, questionnaires scheduled for 
administration during a clinic visit should be completed prior to the performance of 
non-PRO and ClinRO assessments and the administration of study treatment.
The DLQI is a 10-item, validated questionnaire used routinely in clinical practice to 
evaluate the impact of dermatologic diseases on patients' lives.  The DLQI questionnaire 
refers to the previous 7 days and questions are categorized into 6 domains: symptoms 
and feelings (2 items), daily activities (2 items), leisure (2 items), work and school 
(1 item), personal relationships (2 items), and treatment (1 item).  A total DLQI score is 
calculated on a scale of 0 to 30, where higher scores mean greater impairment of the 
patient’s HRQoL.  A copy of the DLQI is provided in Appendix 6.
The PGIC is a measure of perceived change in PV symptoms as assessed by the 
patient using a 7-item categorical scale ranging from “very much improved” to “very 
much worse.”  The PGIC asks patients to rate the change of their PV symptoms.  The 
recall period of the PGIC is from the start of treatment.  A copy of the PGIC is provided 
in Appendix 8.
The EQ-5D-3L is a generic, preference-based, health-utility measure including questions 
about mobility, self-care, usual activities, pain/discomfort, and anxiety/depression that 
are used to build a composite of the patient’s health status.  It is accompanied by a 
visual analog scale (VAS) on which the patient provides a self-assessment of their own 
health in a range from 0 (worst imaginable health state) to 100 (best imaginable health 
state) (Gusi et al. 2010).  The EQ-5D-3L will be used in this study for economic modeling.  
A copy of the EQ-5D-3L is provided in Appendix 7.
The Skindex-29 is a 30-item questionnaire used to assess the impact of dermatologic 
diseases on patients' health-related quality of life (Chren et al. 1996).  The Skindex-29 
refers to the previous 4 weeks, and questions are categorized into four domains:  
emotions (10 items), symptoms (7 items), functioning (12 items), and treatment (1 item)
and ask patients to think back over the previous 4 weeks.  The questions are assessed 
on a 5-point Likert-like scale.  A total Skindex-29 score is calculated on a scale of 0 to 
100, where a higher score indicates a higher impact of the patient’s skin disease.  
A copy of the Skindex-29 is provided in Appendix 5.
The CGIC is a measure of perceived change in PV symptoms as assessed by the 
clinician using a 7-item categorical scale ranging from “very much improved” to “very 


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much worse.”  The CGIC asks clinicians to rate the change of patients’ PV symptoms.  
The recall period of the CGIC is start of treatment. A copy of the CGIC is provided in 
Appendix 9.
4.5.10
Samples for Roche Clinical Repository 
4.5.10.1
Overview of the Roche Clinical Repository
The RCR is a centrally administered group of facilities used for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection and analysis of RCR specimens will 
facilitate the rational design of new pharmaceutical agents and the development of 
diagnostic tests, which may allow for individualized drug therapy for patients in the future.
Specimens for the RCR will be collected from patients who give specific consent to 
participate in this optional research.  RCR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.10.2
Approval by the Institutional Review Board or 
Ethics Committee
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site's Institutional Review Board or Ethics Committee (IRB/EC) 
and, if applicable, an appropriate regulatory body.  If a site has not been granted 
approval for RCR sampling, this section of the protocol (Section 4.5.10) will not be
applicable at that site.
4.5.10.3
Sample Collection
The following samples will be collected for research purposes, including but not limited 
to research on dynamic (non-inherited) biomarkers related to rituximab, pemphigus, or 
autoimmune-related diseases:

Whole blood for RNA extraction
The following samples will be collected for research purposes, including but not limited 
to research on genetic (inherited) biomarkers related to rituximab, pemphigus, or 
autoimmune-related diseases:

Whole blood for DNA extraction


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The following samples will be collected for research purposes, including but not limited 
to research on dynamic (non-inherited) biomarkers related to rituximab, pemphigus, or 
autoimmune-related diseases:

Serum for biomarker analysis
For all samples, dates of consent and specimen collection should be recorded on the 
associated RCR page of the eCRF.  For sampling procedures, storage conditions, and 
shipment instructions, see the laboratory manual.  
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below.  
4.5.10.4
Confidentiality
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is "double-coded" by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A "linking key" between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche's Legal Department, as applicable.
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate.
Patient medical information associated with RCR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication.


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Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise.
4.5.10.5
Consent to Participate in the Roche Clinical Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RCR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate by completing the RCR eCRF.
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research.
4.5.10.6
Withdrawal from the Roche Clinical Repository
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the RCR Subject Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the RCR Research 
Sample Withdrawal of Informed Consent eCRF.  The patient will be provided with 
instructions on how to withdraw consent after the trial is closed.  A patient's withdrawal 
from Study WA29330 does not, by itself, constitute withdrawal of specimens from the 
RCR.  Likewise, a patient's withdrawal from the RCR does not constitute withdrawal from 
Study WA29330.
4.5.10.7
Monitoring and Oversight
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the RCR samples.


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4.6
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient

Patient non-compliance with protocol procedures
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced.
4.6.2
Study Treatment Discontinuation
Patients must discontinue study treatment and not receive repeat treatment if they 
experience any of the following:

Pregnancy

Progressive multifocal leukoencephalopathy (PML)

Malignant events (except basal cell carcinoma and squamous cell carcinoma of the 
skin that have been excised and cured)

Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN)

Severe allergic or anaphylactic study drug treatment-related reaction

National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) Grade 4 (life-threatening) event during or within 24 hours of an 
infusion

Pure red cell aplasia
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.
In the event that the patient develops a medically significant NCI CTCAE Grade 3 or 4 
infection, see Section 4.6.4.


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4.6.3
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.

Patient enrollment is unsatisfactory.
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for
Good Clinical Practice

No study activity (i.e., all patients have completed and all obligations have been 
fulfilled)
4.6.4
Dose Modification and Treatment Interruption
In the event that the patient develops a medically significant NCI CTCAE Grade 3 or 4 
infection, no further doses of rituximab/placebo or MMF/placebo study drug treatment 
should be provided until the infection has resolved.
Rituximab and matching placebo:  Prolonged B-cell depletion is the expected outcome of 
rituximab treatment and is not considered a toxicity. 
Patients who experience a Grade 4 (life-threatening) event during an infusion of 
rituximab (or matching placebo) should have their infusion stopped.  Additional infusions 
of rituximab (or matching placebo) should not be given.
MMF and matching placebo:  During the 52-week treatment period, the MMF (or 
matching placebo) dose should remain as stable as possible.  If reductions in dose are 
necessary because of tolerability, decreases will be allowed in 500-mg decrements and 
must be recorded on the appropriate eCRF.  If neutropenia develops (ANC 1.3103/L), 
dosing with MMF (or matching placebo) should be interrupted or the dose should be 
reduced. 
Guidelines for dosage modification and treatment interruption or discontinuation of MMF 
are provided in the MMF prescribing information.


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In addition to the above, the following safety criteria must be met prior to resuming either 
rituximab/placebo or MMF/placebo study drug treatment:

ANC 1.3103/L at the last blood sample analysis

The patient has not developed any of the following:
–
Primary or secondary immunodeficiency, including HIV infection
–
Known active infection of any kind (excluding fungal infections of nail beds), or 
any major episode of infection requiring hospitalization or treatment with IV 
anti-infectives within 4 weeks prior to infusion or within 2 weeks prior to oral 
MMF (matching placebo) and completion of oral anti-infectives within 2 weeks 
prior to infusion or within 1 week prior to oral MMF (matching placebo)
–
The patient has not developed any conditions that, in the investigator’s opinion, 
would preclude the patient from receiving further courses of treatment, such as:  
any new or uncontrolled disease including, but not limited to, cardiovascular 
disease; nervous system, pulmonary, renal, hepatic, endocrine, or 
gastrointestinal disorders; or malignancies

Patient is not pregnant or breastfeeding
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Patient safety will be monitored through physical examination, regular assessment of 
vital signs, hematologic laboratory tests, and incidence and severity of adverse events
potentially due to any of the study medications.  Infections will be treated according to 
local standard of care.  Corticosteroid-related adverse events will also be assessed.  An 
iDMC will review all safety data during the course of the study (see Section 3.1.4).  
Given the known side effects of both rituximab and MMF, abnormalities in hematologic 
tests, specifically leukocyte count, hemoglobin, and platelet count will be monitored 
closely.  If the patient becomes leukopenic or thrombocytopenic, or experiences 
intolerable gastrointestinal adverse effects, the dose of MMF or dosing schedule of 
rituximab will be altered at the investigator’s discretion.
5.1.1
Side Effects Known to be Associated with Rituximab
5.1.1.1
Infusion-Related Reactions
Rituximab is associated with infusion-related reactions, which may be related to release 
of cytokines and/or other chemical mediators.
For RA patients, most infusion-related events reported in clinical trials were mild to
moderate in severity. Severe infusion-related reactions with fatal outcomes have been
rarely reported in the postmarketing setting. Closely monitor patients with preexisting 
cardiac conditions and those who experienced prior cardiopulmonary adverse reactions.  
The most common symptoms were headache, pruritus, throat irritation, flushing, rash,
urticaria, hypertension, and pyrexia. In general, the proportion of patients experiencing
any infusion-related reaction was higher following the first infusion of any treatment 


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course than following the second infusion. Subsequent rituximab infusions were better
tolerated by patients than the initial infusion. Fewer than 1% of patients experienced
serious infusion-related reactions, with most of these reported during the first infusion of 
the first course.  The reactions reported were usually reversible with a reduction in rate 
or interruption of rituximab infusion, and administration of an anti-pyretic, an 
antihistamine, and, occasionally, oxygen, IV saline, bronchodilators, or glucocorticoids,
as required.  
Anaphylactic and other hypersensitivity reactions have been reported following the IV 
administration of proteins to patients. Medicinal products for the treatment of 
hypersensitivity reactions, e.g., epinephrine, antihistamines, and glucocorticoids, should 
be available for immediate use in the event of an allergic reaction during administration
of rituximab.
Infusion-related reactions in patients with GPA and MPA were similar to those seen in 
RA patients in clinical trials.  For patients with GPA and MPA, rituximab was given in 
combination with high doses of glucocorticoids, which may reduce the incidence and 
severity of these events.
Patients with a history of a severe allergic or anaphylactic reaction to humanized or 
murine monoclonal antibodies, or known hypersensitivity to any component of rituximab,
will be excluded from study participation.
On rituximab infusion days, vital signs will be collected immediately prior to infusion and 
then every 30 minutes until the end of the infusion.  To reduce the frequency and 
severity of infusion-related reactions, patients will receive premedication prior to the start 
of each infusion of rituximab or rituximab placebo (see Section 4.3.2.1 and Appendix 3).  
5.1.1.2
Cardiovascular Events
Since hypotension may occur during rituximab infusion, consideration should be given to 
withholding anti-hypertensive medications 12 hours prior to the rituximab/matching 
placebo infusion.  Angina pectoris, cardiac arrhythmias such as atrial flutter and 
fibrillation, heart failure, or myocardial infarction have occurred in patients treated with 
rituximab.  Therefore, patients with a history of cardiac disease should be monitored 
closely, especially during infusions (see Section 5.1.1.1).
5.1.1.3
Infection
Patients may have an increased risk of infection following rituximab therapy.  Rituximab 
should not be administered to patients with an active infection or to patients who are 
severely immunocompromised (e.g., where levels of CD4or CD8cell counts are very 
low).  
Physicians should exercise caution when considering the use of rituximab in patients 
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further predispose patients to serious infection.  Patients with a history of or currently 
active primary or secondary immunodeficiency, including known history of HIV infection, 
will be excluded from study participation.  Patients with a known active infection of any 
kind (excluding fungal infections of nail beds) or any major episode of infection requiring 
hospitalization or treatment with IV anti-infectives within 4 weeks prior to screening, or 
completion of oral anti-infectives within 2 weeks prior to randomization, will also be 
excluded.
Patients who develop infection following rituximab therapy should be promptly evaluated 
and treated appropriately.  Repeat infusions of rituximab (or matching placebo) should 
only be considered once any infection has fully resolved (see Section 4.6.4).
5.1.1.4
Hepatitis B Infection
Cases of hepatitis B virus (HBV) reactivation, including those with a fatal outcome, have 
been reported in RA, GPA, and MPA patients receiving rituximab. HBV screening 
should always be performed in high-risk patients before initiation of treatment with 
rituximab.  Carriers of hepatitis B and patients with a history of hepatitis B should be 
closely monitored for clinical and laboratory signs of active HBV infection during and for 
several months following rituximab therapy. 
Patients will be tested for HBsAg, HBcAb, and HCV serology at screening.  Those 
testing positive will be excluded from study participation.  
5.1.1.5
Progressive Multifocal Leukoencephalopathy
Very rare cases of fatal PML have been reported following use of rituximab for the 
treatment of autoimmune diseases, including RA.  Several, but not all, of the reported 
cases had potential risk factors for PML, including the underlying disease, long-term 
immunosuppressive therapy, or chemotherapy. PML has also been reported in patients 
with autoimmune disease not treated with rituximab. Physicians treating patients with 
autoimmune diseases should consider PML in the differential diagnosis of patients 
reporting neurological symptoms, and consultation with a neurologist should be 
considered as clinically indicated, including further evaluation with magnetic resonance 
imaging (MRI; preferably with contrast), cerebrospinal fluid testing for JC viral DNA, and 
repeat neurological assessments.
If PML is diagnosed in a patient receiving rituximab, no additional infusions of rituximab 
should be administered; reductions in concomitant immunosuppressive therapy and 
appropriate treatment, including antiviral therapy, should be considered.  There are no 
known interventions that can reliably prevent PML or adequately treat PML, should it 
occur.
At the time of initiation of this protocol, there were no reports in the literature or in the 
Sponsor’s global safety database of PML in PV patients who have received rituximab.


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5.1.1.6
Skin Reactions
Severe skin reactions, such as SJS and TEN, some with fatal outcome, have been 
reported.  In case of such an event with a suspected relationship to rituximab, treatment 
should be permanently discontinued.
Additional information on side effects associated with rituximab is provided in the 
Investigator’s Brochure.
5.1.1.7
Immunization
The safety of immunization with live viral vaccines following rituximab therapy has not 
been studied.  Therefore, vaccination with live viral vaccines is not recommended while 
on rituximab or while peripheral B cells are depleted.  It is recommended that a patient’s 
vaccination status be reviewed and current immunization guidelines followed prior to 
study entry.  Should non-live vaccinations be required, immunization should be 
completed at least 4 weeks prior to the first administration of study medication.  
Patients treated with rituximab may receive non-live vaccinations.  However, response 
rates to non-live vaccines may be reduced.  In a randomized study of immunization 
responses, patients with RA, treated with rituximab and methotrexate, had comparable 
response rates to tetanus recall antigen (39% vs. 42%), reduced rates to pneumococcal 
polysaccharide vaccine (43% vs. 82% to at least two pneumococcal antibody serotypes), 
and keyhole limpet hemocyanin (KLH) neoantigen (47% vs. 93%), when given at least 
6 months after rituximab, compared with patients receiving only methotrexate 
(Bingham et al. 2010).  
In the overall experience of rituximab repeat treatment in RA patients over 1 year, the 
proportions of patients with positive antibody titers against S. pneumoniae, influenza, 
mumps, rubella, varicella, and tetanus toxoid were generally similar to the proportions at 
baseline.
Patients who have been treated with a live or attenuated vaccine within 28 days prior to 
randomization will be excluded from study participation.  
The use of live or attenuated vaccines (i.e., measles, mumps, rubella, oral polio, BCG, 
typhoid, yellow fever, vaccinia, some forms of influenza [e.g., FluMist], or any other live 
vaccines not yet licensed but belonging to this category) are specifically prohibited 
during the study and while the patient’s peripheral B cells are depleted.
The use of killed or inactivated vaccine (e.g., some forms of influenza) is not prohibited 
during the study; however, the efficacy of certain vaccines during or following periods of 
B-cell depletion has not been studied.
Patients who are eligible for yearly influenza vaccine or who require other non-live 
booster vaccinations can receive vaccination with killed/toxoid vaccines consistent with 
normal clinical practice.


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5.1.1.8
Pregnancy
A reproductive toxicology study was conducted in cynomolgus monkeys to investigate 
the effects of rituximab on embryo-fetal development.  Doses up to 100 mg/kg were 
administered weekly during the period of organogenesis.  There were no findings of 
toxicity to the dams or the developing fetuses, and the only effect noted was the 
dose-dependent pharmacologic depletion of peripheral CD19B cells in the lymphoid 
organs of the fetuses.
Studies of the human reproduction have not been performed.  It is not known whether 
rituximab can cause fetal harm when administered to pregnant women or whether it can 
affect reproductive capacity.  However, since IgG molecules such as rituximab are 
known to cross the placenta, rituximab may cause fetal CD19B-cell depletion.  
Transient B-cell depletion and lymphocytopenia have been reported in some infants born 
to mothers exposed to rituximab during pregnancy.  It is not known whether rituximab is 
excreted in breast milk and what effect this might have on the breast-feeding infant. 
However, since immunoglobulins are found in breast milk, breast-feeding mothers are 
excluded from participation in the study.
Well-controlled reproductive studies with glucocorticoids have not been performed in 
humans, but high doses of glucocorticoids given during pregnancy have caused 
hypoadrenalism in newborns.
Female patients should avoid becoming pregnant during this study, including the SFU 
period.  As such, women of childbearing potential should use two effective methods of 
contraception, including at least one method with a failure rate of 1% per year, for the 
duration of the study and for 1 year after receiving rituximab.  Regular pregnancy tests 
will be performed per the schedule of assessments (Appendix 1).
Patients who become pregnant will not receive additional doses of rituximab or MMF 
while pregnant or breast-feeding.  Pregnancies occurring during the entire study 
(including the SFU period) must also be reported to the investigator.  The investigator 
should counsel the patient, and discuss the risks of continuing with the pregnancy and 
the possible effects on the fetus.  Monitoring of the patient should continue until 
conclusion of the pregnancy.
Effects on pregnancies in partners of male patients whose peripheral CD19B cells are 
depleted have not been studied.  Therefore, it is strongly advised that male patients also 
use reliable contraception while receiving rituximab in this trial and for 1 year after 
receiving rituximab.
5.1.1.9
Management of Specific Adverse Events
Infusion-Related Reactions
In the event of a mild infusion-related reaction, the infusion rate should be reduced to 
half the current rate (e.g., from 100 mg/hr to 50 mg/hr).  Once the adverse event has 


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resolved, the infusion must continue at the reduced rate for an additional 30 minutes.  
If tolerated, the infusion rate may be increased to the next highest rate on the infusion 
schedule.  Patients who experience a moderate to severe infusion-related reaction 
(e.g., fever 38.5C, chills, mucosal swelling, or systolic blood pressure decrease of 
30 mmHg) should have their infusion interrupted immediately and should receive 
aggressive symptomatic treatment.  After all symptoms have resolved, the infusion may 
be restarted at half the previous rate.  If the patient tolerates the reduced rate for 
30 minutes, the infusion rate may be increased to the next highest rate following the 
infusion schedule.  Patients who experience a Grade 4 (life-threatening) event during an 
infusion should have their infusion stopped.  Additional infusions should not be given.
Additional instructions pertaining to the rituximab infusion are provided in Appendix 3.
Infections
Rituximab (or matching placebo) should not be administered in the setting of an active 
infection.  If a patient experiences a new infection between the Day 1 and Day 15 
infusions of any course, the Day 15 infusion should be delayed (up to a maximum of 
28 days from the scheduled Day 1 date) until the infection has completely resolved 
and treatment with any anti-infective medications has been completed. This will not 
affect the patient’s eligibility to receive additional courses of treatment as required.  
However, repeat infusions of rituximab (or matching placebo) should only be considered 
once any infection, experienced at any time during the study, has fully resolved.
5.1.2
Side Effects Known to Be Associated with MMF
MMF has been associated with gastrointestinal intolerance (diarrhea, nausea, vomiting); 
gastrointestinal disorders (colitis, pancreatitis); fetal malformations (facial malformations 
such as cleft lip, cleft palate, micrognathia, and hypertelorism of the orbits; abnormalities 
of the ear (e.g., abnormally formed or absent external/middle ear) and eye (e.g., 
coloboma, microphthalmos); malformations of the fingers (e.g., polydactyly, syndactyly, 
brachydactyly); cardiac abnormalities such as atrial and ventricular septal defects; 
esophageal malformations (e.g., esophageal atresia); and nervous system 
malformations such as spina bifida); spontaneous abortions; leukopenia; anemia 
(leading to tiredness, lethargy, or lack of energy), which could be severe and necessitate 
transfusion of blood; and increased risk of certain types of infections, including PML,
reactivation of hepatitis B, tuberculosis, and atypical mycobacterial infection.  Cases of 
pure red cell aplasia (PRCA) have been reported in patients treated with MMF in 
combination with other immunosuppressive agents. Patients receiving MMF should be 
monitored for neutropenia.  If neutropenia develops (ANC 1.3103/L), dosing with
MMF should be interrupted or the dose reduced and the patient should be carefully 
observed (see Section 4.6.4).  Immunomodulatory drugs such as MMF have the ability 
to alter or regulate one or more immune functions and reduce the body’s immunity. 
Possible development of lymphoma and other cancers, particularly of the skin, may 
result from the reduction of the body’s immunity.  As with all patients at an increased risk 


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for skin cancer, exposure to sunlight and UV light should be limited by wearing protective 
clothing and using a sunscreen with a high sun protection factor.
Females of childbearing potential must have two negative pregnancy tests, with the 
second test on Day 1 performed 8 to 10 days after the first test, before receiving MMF 
and must use two effective method of contraception, including at least one method with 
a failure rate of 1% per year, for the time period as stated in Section 4.1.1.  
Patients should not donate blood during therapy and for at least 6 weeks following 
discontinuation of MMF.  
Drug interactions with other drugs have been reported with MMF (see the MMF 
Investigator’s Brochure for more information).  
Side effects reported in more than 1 out of 10 patients treated with MMF after an organ 
transplant include, but are not limited to, hypertension asthenia constipation, nausea, 
vomiting, cough, acne, dizziness, insomnia, and tremors. 
Oral fungal infection, headache, nasopharyngitis fever, cough, hypertension, and upper 
respiratory tract infection were reported in more than 1 out of 10 patients treated with 
MMF for PV in a clinical trial (Beissert et al. 2010). 
At the time of this protocol, there were no reports in the literature or in the Sponsor’s 
global MMF safety database of PML in PV patients who received MMF.
Further information on side effects associated with MMF is provided in the Investigator’s 
Brochure. 
5.1.3
Side Effects Known to Be Associated with Corticosteroids
Corticosteroids may have many potential side effects, including increased blood 
pressure, mood changes, and increased risk for infections.  Long-term use or high doses 
of corticosteroids may also have side effects such as diabetes or changes in bones such 
as osteoporosis.
Further information on side effects associated with corticosteroids is provided in the local 
package insert.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and non-serious adverse events of special interest; 
measurement of protocol-specified safety laboratory assessments; measurement of 
protocol-specified vital signs; and other protocol-specified tests that are deemed critical 
to the safety evaluation of the study.


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Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to 
the Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Fatal (i.e., the adverse event actually causes or leads to death)

Life-threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)


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The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] criteria; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Non-Serious Adverse Events (Immediately Reportable to 
the Sponsor)
Non-serious adverse events of special interest are required to be reported by the 
investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2 for reporting instructions).  Adverse events of special interest 
for this study include the following:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 5.3.5.7)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section, and in Sections 5.4, 5.5, and 5.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.


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After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).  In addition, any 
adverse events occurring during any corticosteroid dose adjustment during the 
screening period should be reported.
After initiation of study drug, all adverse events, regardless of relationship to study 
drug, including corticosteroid-related adverse events, will be reported during the 
treatment period.  During the SFU period, serious adverse events and all infectious 
adverse events, irrespective of causality, will be reported.  After this period, the 
investigator is not required to actively monitor patients for adverse events; however, the 
Sponsor should be notified if the investigator becomes aware of any post-study serious 
adverse events (see Section 5.6).
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 2 will be used for assessing severity for
adverse events that are not specifically listed in the NCI CTCAE.


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Table 2
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in the NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not an adverse event is considered to be related to the study drug, indicating "yes" or 
"no" accordingly.  The following guidance should be taken into consideration (see also 
Table 3):

Temporal relationship of event onset to the initiation of study drug

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the PV disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non–treatment-related factors that are known to be associated with the 
occurrence of the event


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Table 3
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
For patients receiving other/background therapies (e.g., oral corticosteroids), causality 
will be assessed individually for each protocol-mandated therapy.  All adverse events 
attributed to corticosteroids should also be reported in the Adverse Event eCRF.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion should be captured as a diagnosis 
(e.g., "infusion-related reaction" [or] "anaphylactic reaction") on the Adverse Event eCRF.  
If possible, avoid ambiguous terms such as "systemic reaction."  Associated signs and 
symptoms should be recorded on the dedicated Infusion-Related Reaction eCRF.  If a 
patient experiences both a local and systemic reaction to the same dose of study drug, 
each reaction should be recorded separately on the Adverse Event eCRF, with signs 
and symptoms also recorded separately on the dedicated Infusion-Related Reaction
eCRF.
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than infusion-related reactions (see Section 5.3.5.1), a 
diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 


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at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  The initial severity (intensity) of the event will be recorded 
at the time the event is first reported.  If a persistent adverse event becomes more 
severe, the most extreme intensity should also be recorded on the Adverse Event eCRF.  
If the event becomes serious, it should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning that the event became serious; see Section 5.4.2 for 
reporting instructions).  The Adverse Event eCRF should be updated by changing the 
event from "non-serious" to "serious," providing the date that the event became serious, 
and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.


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5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Clinically significant in the investigator’s judgment 
Note:  For oncology trials, certain abnormal values may not qualify as 
adverse events.
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Clinically significant in the investigator’s judgment 


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It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury.  
Therefore, investigators must report as an adverse event the occurrence of either of the 
following:

Treatment-emergent ALT or AST (3ULN) in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST (3ULN) in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or a non-serious adverse event of special 
interest (see Section 5.4.2).
5.3.5.8
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of PV.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  The term "sudden death" should be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without preexisting heart disease, within 1 hour after the onset of acute symptoms or, in 
the case of an unwitnessed death, within 24 hours after the patient was last seen alive 
and stable.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 


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cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.
If the death is attributed to progression of PV, "pemphigus vulgaris progression" should 
be recorded on the Adverse Event eCRF.  
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study (i.e., changes 
from screening).  When recording such events on the Adverse Event eCRF, it is 
important to convey the concept that the preexisting condition has changed by including 
applicable descriptors (e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of Pemphigus Vulgaris
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease, worsening, disease flare, or treatment failure should not be recorded 
as an adverse event or serious adverse event.  These data will be captured as efficacy 
assessment data only.  In most cases, the expected pattern of progression, worsening, 
disease flare, or treatment failure will be based on the criteria described in 
Sections 3.1.3, 3.4.1.2, and 4.5.5.  In rare cases, the determination of clinical 
progression will be based on symptomatic deterioration.  However, every effort should 
be made to document progression, worsening, disease flare, or treatment failure using 
objective criteria.  If there is any uncertainty as to whether an event is due to disease 
progression, it should be reported as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
The following hospitalization scenarios are not considered to be adverse events:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration) 


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
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event
The following hospitalization scenarios are not considered to be serious adverse events, 
but should be reported as adverse events instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours

Hospitalization for elective surgery or procedure
5.3.5.12
Adverse Events Associated with an Overdose
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills serious 
criteria, the event should be reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event; see Section 5.4.2).
No safety data related to overdosing of rituximab are available.
5.3.5.13
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  However, if any PRO responses 
suggestive of a possible adverse event are identified during site review of the PRO data, 
the investigator will determine whether the criteria for an adverse event have been met 
and, if so, will report the event on the Adverse Event eCRF.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events

Non-serious adverse events of special interest

Pregnancies


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The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information for All Sites
Medical Monitor:
, M.D.
Telephone No.:
Mobile Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls.  The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk and 
Medical Monitor contact information will be distributed to all investigators (see "Protocol 
Administrative and Contact Information & List of Investigators"). 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
A paper Serious Adverse Event Reporting Form and fax cover sheet should be 
completed and faxed to Roche Safety Risk Management or its designee immediately 
(i.e., no more than 24 hours after learning of the event), using the fax numbers provided 
to investigators (see "Protocol Administrative and Contact Information & List of 
Investigators").
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, all adverse events, including serious adverse events and 
non-serious adverse events, will be reported during the treatment period.  During the 
SFU period, serious adverse events and all infectious adverse events, irrespective of 
causality, will be reported. Investigators should record all case details that can be 


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gathered immediately (i.e., within 24 hours after learning of the event) on the 
Adverse Event eCRF and submit the report via the electronic data capture (EDC) system.  
A report will be generated and sent to Roche Safety Risk Management by the EDC 
system.
In the event that the EDC system is unavailable, a paper Serious Adverse Event 
Reporting Form and fax cover sheet should be completed and faxed to Roche Safety 
Risk Management or its designee immediately (i.e., no more than 24 hours after learning 
of the event), using the fax numbers provided to investigators (see "Protocol 
Administrative and Contact Information & List of Investigators").  Once the EDC system 
is available, all information will need to be entered and submitted via the EDC system.  
Instructions for reporting post-trial adverse events are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study (including the 48-week SFU 
period).  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  A pregnancy report will automatically be generated and sent to 
Roche Safety Risk Management.  Pregnancy should not be recorded on the Adverse 
Event eCRF.  The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any serious adverse 
events associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF.
In the event that the EDC system is unavailable, a paper Clinical Trial Pregnancy 
Reporting Form and fax cover sheet should be completed and faxed to Roche Safety 
Risk Management or its designee immediately (i.e., no more than 24 hours after learning 
of the pregnancy), using the fax numbers provided to investigators (see "Protocol 
Administrative and Contact Information & List of Investigators").  Once the EDC system 
is available, all information will need to be entered and submitted via the EDC system.
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study (including the 
48-week SFU period).  A Pregnancy Report eCRF should be completed by the 
investigator immediately (i.e., no more than 24 hours after learning of the pregnancy) 
and submitted via the EDC system.  Attempts should be made to collect and report 
details of the course and outcome of any pregnancy in the partner of a male patient 
exposed to study drug.  The pregnant partner will need to sign an Authorization for Use 


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and Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
Once the authorization has been signed, the investigator will update the Pregnancy 
Report eCRF with additional information on the course and outcome of the pregnancy.  
An investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician.
In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.4.3.1.
5.4.3.3
Abortions
Any abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).  
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.  If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF. 
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1.
5.5.2
Sponsor Follow-Up
For serious adverse events, non-serious adverse events of special interest, and 
pregnancies, the Sponsor or a designee may follow up by telephone, fax, electronic mail, 


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and/or a monitoring visit to obtain additional case details and outcome information 
(e.g., from hospital discharge summaries, consultant reports, autopsy reports) in order to 
perform an independent medical assessment of the reported case.
5.6
POST-STUDY ADVERSE EVENTS
The investigator is not required to actively monitor patients for adverse events after the 
end of the adverse event reporting period (defined as 12 months [see Section 5.3.1]
after the last dose of study drug).  However, the Sponsor should be notified if the 
investigator becomes aware of any death or other serious adverse event that occurs
after the end of the adverse event reporting period, regardless of causality.
The investigator should report these events directly to Roche Safety Risk Management 
via telephone or via fax machine using the Serious Adverse Event Reporting Form and 
fax cover sheet (see "Protocol Administrative and Contact Information & List of 
Investigators").
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and non-serious adverse 
events of special interest against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to investigators, IRBs, ECs, and 
applicable health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents:

Rituximab Investigator's Brochure

MMF Investigator’s Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
An iDMC will monitor the incidence of the above-listed anticipated events during the 
study.  An aggregate report of any clinically relevant imbalances that do not favor the 
test product will be submitted to health authorities.


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6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
Full details of all statistical methods and planned statistical analyses will be specified in 
the Statistical Analysis Plan (SAP), which will be finalized prior to locking and unblinding 
of the database.  All efficacy outcomes will be analyzed according to the modified
intent-to-treat (mITT) population and will include all randomized patients, with exception 
of TM patients, who have received any amount of study drug. 
Treatment period data will be locked after all patients have completed the Week 52 visit.  
The primary efficacy (excluding TM patients) and safety analyses will be performed on 
data for patients through the Week 52 assessments or early discontinuation. A final 
database lock will occur after all patients have completed the trial, including the SFU
period.
Safety assessments will be performed on patients who are evaluable for safety.  In all 
safety analyses, patients will be grouped according to the treatment received rather than 
the treatment assigned.
Every effort will be made to obtain all scheduled efficacy and safety assessments for 
each patient.  Patients who miss any scheduled doses or assessments will continue 
participation in the study and will continue to receive study drug.  
Primary imputation methods for missing data will be specified in the SAP.
As part of a sensitivity analysis, the inclusion of TM patients, missing data patterns and 
associated missing data mechanisms will be further explored and analyzed as 
appropriate.  The assumptions and methodology will be specified in SAP.
6.1
DETERMINATION OF SAMPLE SIZE
The primary efficacy endpoint of this study is the proportion of patients (excluding TM 
patients) achieving a sustained complete remission, as assessed at Week 52, that has 
been maintained for 16 consecutive weeks during the 52-week treatment period.  With
use of limited data available in the literature from randomized clinical trials of MMF and 
investigator-initiated trials of rituximab, it is estimated that approximately 40% of patients 
with PV receiving MMF will achieve a sustained complete remission.  It is estimated that 
patients receiving rituximab will induce a sustained complete remission rate of 65%. On 
the basis of these assumptions, a total of 122 patients randomized to the rituximab arm 
or the MMF arm in a 1:1 ratio (61 patients in the rituximab arm and 61 patients in the 
MMF arm) will yield approximately 80% power in a two-sided test at the 5% significance 
level. To account for the 10 TM patients excluded from the primary efficacy analysis, 
approximately 132 patients will be randomized in total.
No adjustment will be made to account for dropouts.  


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6.2
ANALYSIS POPULATIONS
All patient populations for the analysis of the 52-week, double-blind treatment period will 
be defined, agreed to, and documented prior to unblinding the data collected up to 
Week 52.
6.2.1
Safety Population
This population will be used for all summaries of safety data (i.e., adverse events, 
previous and concomitant medications, previous and concomitant diseases, laboratory 
data, and compliance with study treatment).  The safety population will include all 
patients who were randomized and received any part of an infusion of study drug.  
Patients who receive the incorrect therapy from that intended will be summarized 
according to the therapy actually received.  Patients who were not randomized but who 
receive study drug will be included in the safety population and summarized according to 
the therapy actually received.
In the unlikely event of a patient commencing one study therapy and crossing over to the 
other, data for that patient will be included in summaries and analyses for the original 
treatment arm.
6.2.2
Intent-to-Treat Population
All randomized patients who received any part of an infusion of study drug will be 
included in the ITT population. Sensitivity analyses of the efficacy outcomes will be 
performed using the ITT population.
Patients who prematurely withdraw from the study for any reason and for whom an 
assessment is not performed for whatever reason will still be included in the ITT 
analysis.  Patients who received an incorrect therapy (i.e., different from that to which 
they were randomized) will be summarized in the treatment arm to which they were 
randomized.
Patients who were not randomized but who received study drug will be excluded from 
the ITT population and subsequent analyses.
6.2.3
Modified Intent-to-Treat Population 
The mITT population includes patients in the ITT population, excluding the 10 TM 
patients.  This population will be used in the analyses of efficacy outcomes.
6.3
SUMMARIES OF CONDUCT OF STUDY
Eligibility deviations and major protocol violations will be summarized.
6.4
SUMMARIES OF TREATMENT ARM COMPARABILITY
Patient demographics and baseline characteristics will be listed and summarized for the 
safety population. 


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6.5
EFFICACY ANALYSES
6.5.1
Primary Efficacy Endpoint
The proportion of patients (excluding TM patients) achieving a sustained complete 
remission (as defined in Section 3.4.1.1) in the rituximab and MMF arms will be 
compared using a stratified Cochran-Mantel-Haenszel test, adjusting for randomization 
stratification variables.  Results will be summarized descriptively by treatment arm and 
expressed as proportions, corresponding adjusted 95% confidence intervals of the 
difference between response rates, and p-values.
Patients who meet the pre-specified definitions of treatment failure before entering 
sustained complete remission (as defined in Section 3.1.3) will be deemed 
non-responders in the primary analysis.  Further analysis will be described in full in the 
SAP.
6.5.2
Secondary Efficacy Endpoints
All secondary efficacy parameters will be listed or summarized and presented in tables 
or graphs based on the mITT population.  
The secondary efficacy outcome measures are as follows:

Cumulative oral corticosteroid dose (prednisone or equivalent) over the treatment 
period 

Total number of disease flares during the treatment period

Time to initial sustained complete remission

Time to disease flare (as defined in Section 3.4.1.2)

Change in HRQoL, as measured by the DLQI score from baseline to Week 52

Duration of sustained complete remission

Patients’ impression of change in PV symptoms, as measured by the PGIC score
during the treatment period

Clinician impression of change in patients’ PV symptoms, as measured by the CGIC 
score during the treatment period
Details on the analysis of secondary endpoints will be provided in the SAP. 
Given the multiple endpoints, the statistical hypotheses related to the secondary 
objectives will be tested using a sequential testing procedure to control for the type I 
error (i.e., probability of a falsepositive statistical inference).  Full details on 
methodology to control for the type I error will be provided in the SAP.
6.6
SAFETY ANALYSES
The safety and tolerability of rituximab and MMF will be evaluated from adverse events, 
clinical laboratory tests, vital signs, and other safety parameters as defined by the 
protocol.  Corticosteroid-related adverse events will also be analysed in relation to 


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corticosteroid exposure.  Safety parameters will be summarized or listed for the safety 
population.
6.7
PHARMACODYNAMIC ANALYSES 
Graphical and statistical techniques, including linear, nonlinear, and logistic regression,
may be used to explore potential relationships between treatment regimen, 
pharmacokinetics, pharmacodynamics, safety, and efficacy.
6.8
PHARMACOKINETIC ANALYSES
Population PK analysis will be performed to describe the time course of serum 
concentrations of rituximab, if necessary and deemed appropriate.  The influence of 
covariates (e.g., body weight, age, sex, race, and concomitant medications) on PK 
parameters will be investigated, if necessary and appropriate.  If necessary, the data 
may be pooled with data from previous studies.
Individual and mean serum concentrations at each sampling timepoint for rituximab will 
be listed, as appropriate. 
Summary statistics (e.g., means, standard deviation, coefficient of variation, geometric 
means, medians, and ranges) for serum concentrations for rituximab will be presented 
by nominal collection times, as appropriate. 
Additional exploratory PK and/or PK/PD modeling may be applied to the data, as 
appropriate. 
Results of PK and/or any population PK or PK/PD analyses may be reported outside the 
clinical study report.
6.9
EXPLORATORY ANALYSES
All exploratory efficacy parameters will be listed or summarized and presented in tables 
or graphs. 
Descriptive statistics will be provided for the 10 patients recruited via TM.
Further details of the derivation of the endpoints will be provided in the SAP.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.


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The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data. Other electronic data will be sent directly 
to the Sponsor, using the Sponsor’s standard procedures to handle and process the 
electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
Data from paper PRO questionnaires will be entered into the EDC system by site staff.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
TELEMEDICINE
For a small proportion of patients (approximately 10 patients at one investigational site), 
the Sponsor is proposing the use of TM consultation visits between the patient and the
Principal Investigator to make the trial more accessible to this population of patients with 
a rare disease.  The local dermatologist, a research nurse, and other medical personnel 
in the patient’s immediate vicinity will participate throughout the trial as needed.  Data 
collected via TM will be in accordance with the American Telemedicine Association 2012 
Guidelines for Teledermatology (ATA 2012).  The software platform to be used in the 
trial will allow efficient, high-quality data collection of all relevant clinical data (including 
the images of the skin and mucosa, prior medical records, notes, and laboratory tests) 
for easy and reliable review by the Principal Investigator.  This type of assessment has 
become the standard for TM clinical care for the diagnosis and treatment of both mild 
and severe types of skin diseases.  Images will be time-stamped and stored in a Health 
Insurance Portability and Accountability Act (HIPAA)-compliant advanced TM platform 
adapted for this specific trial use.  Other safety and efficacy data sets will be transmitted 
through the TM platform to the Principal Investigator as well.  The local dermatologist or 
other local primary care doctors may still provide standard-of-care services that do not 
require training on the protocol or investigational drug.  All clinical trial-related medical 
decisions will be made by the Principal Investigator and/or safety assessor. 


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Appendix 11 provides additional details and procedures related to TM, which will be
effective only for TM site(s), as identified by the Sponsor. Based on the iDMC review of 
the safety data, health authority interactions, and the Sponsor’s review of the TM data 
quality, the Sponsor may elect to increase or limit the number of patients and/or sites 
participating in TM.
7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities.
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.


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7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for at least 15 years 
after completion or discontinuation of the study, or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of time, 
the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. IND
Application will comply with U.S. FDA regulations and applicable local, state, and federal 
laws.  Studies conducted in the European Union or European Economic Area will comply 
with the E.U. Clinical Trial Directive (2001/20/EC), as amended.
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Caregiver's Informed Consent Form, if applicable) will be provided to 
each site.  If applicable, it will be provided in a certified translation of the local language.  
The Sponsor or its designee must review and approve any proposed deviations from the 
Sponsor's sample Informed Consent Forms or any alternate consent forms proposed by 
the site (collectively, the "Consent Forms") before IRB/EC submission.  The final 
IRB/EC-approved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.


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Patients must be re-consented to the most current version of the Informed Consent 
Forms (or to a significant new information/findings addendum in accordance with 
applicable laws and IRB/EC policy) during their participation in the study.  For any 
updated or revised Informed Consent Forms, the case history or clinical records for each 
patient shall document the informed consent process and that written informed consent 
was obtained using the updated/revised Informed Consent Forms for continued 
participation in the study.
A copy of each signed Informed Consent Form must be provided to the patient or the 
patient’s legally authorized representative.  All signed and dated Informed Consent 
Forms must remain in each patient’s study file or in the site file and must be available for 
verification by study monitors at any time.
For sites in the United States, each Informed Consent Form may also include patient 
authorization to allow use and disclosure of personal health information in compliance 
with the U.S. HIPAA of 1996.  If the site utilizes a separate Authorization Form for patient 
authorization for use and disclosure of personal health information under the HIPAA 
regulations, the review, approval, and other processes outlined above apply except that 
IRB review and approval may not be required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.


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Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local health authorities, Sponsor
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.


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9.4
ADMINISTRATIVE STRUCTURE
The overall procedures for quality assurance of clinical study data are described in the 
Roche Standard Operational Procedures.
This multicenter, international study will be sponsored by F. Hoffmann-La Roche Ltd and 
managed in partnership with a clinical research organization. Approximately 60 sites in 
North America, Europe, the Middle East, and Latin America are expected to participate 
in the study and will enroll approximately 132 patients.
Patients will be randomized to one of the two treatment arms through a centralized 
computerized IxRS (see Section 4.2).
All samples collected per the schedule of assessments (see Appendix 1 and 
Appendix 2) will be shipped to a central laboratory.  
Data for this study will be recorded via an EDC system using eCRFs (see Section 7.2).
The study will be overseen by the Study Management Team (SMT). During the study, 
the SMT will review study data according to the Data Quality Plan.
Safety data will be reviewed by an iDMC as specified in the iDMC Charter and as 
outlined in Section 3.1.4.  The safety evaluations will be specified in the iDMC Charter 
and will include review of conventional safety variables, such as serious adverse events, 
infusion-related reactions, and infections.  Any safety event that requires unblinding will 
be immediately reported to the iDMC.  The iDMC may request and review any additional 
reports outside of the planned analyses at any time if deemed necessary to ensure the 
safety of patients.  After reviewing the safety data, the iDMC will make recommendations 
regarding continuation, termination, or modification of the study.  The details of the iDMC 
roles and responsibilities and the logistics of the iDMC activities will be outlined in an 
iDMC Charter.  
9.5
PUBLICATION OF DATA AND PROTECTION OF 
TRADE SECRETS
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor
prior to submission.  This allows the Sponsor to protect proprietary information and to 
provide comments based on information from other studies that may not yet be available 
to the investigator.
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.


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Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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pemphigus disease area index. J Dermatol 2014;41:96973.
Smolen JS, Aletaha D, Bijlsma JWJ, et al. Treating rheumatoid arthritis to target: 
recommendations of an international task force Ann Rheum Dis 2010;69:6317.
Strowd LC, Taylor SL, Jorizzo JL, et al. Therapeutic ladder for pemphigus vulgaris: 
emphasis on achieving complete remission. J Am Acad Dermatol 2011;64:4904.
Toth GG, Jonkman MF. Therapy of pemphigus. Clin Dermatol 2001;19:7617. 
Vyas N, Patel NS, Cohen GF. Mycophenolate mofetil as a first-line steroid-sparing agent 
in the treatment of pemphigus vulgaris. J Drugs Dermatol 2013;12:2106.
Zwerner J, Fiorentino D. Mycophenolate mofetil. Dermatol Ther 2007;20:22938. 


Clinical Study Report: rituximab - F. Hoffmann-La Roche Ltd
Protocol WA29330     Report Number 1093922
2696
Rituximab—F. Hoffmann-La Roche Ltd
96/Protocol WA29330, Version 5
Appendix 1
Schedule of Assessments
Week
Screen
(28 to 
1)
1
2
4
8
12
16
20
24
26
32
40
48
52
WD a
SFU b
Day
1 (BL 
and Rz)
15
1
28
3
56
3
84
3
112
3
140
3
168
3
182
1
224
3
280
3
336
3
364
3
Informed consent
x
Medical history, c
previous 
medications, and 
baseline conditions
x
Pregnancy test 
(serum) d
x
Pregnancy test 
(urine) d
x
x
x
x
x
x
x
x
x
x
x
x
Complete physical 
examination e
x
Body weight
x
x
x
x
Height
x
Vital signs f
x
x g
x g
x g
x g
x
x
ECG
x
CXR h
x
Efficacy and PRO/ClinRO
Disease activity 
(PDAI)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Flare assessment
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


Clinical Study Report: rituximab - F. Hoffmann-La Roche Ltd
Protocol WA29330     Report Number 1093922
2697
Appendix 1
Schedule of Assessments (cont.)
Rituximab—F. Hoffmann-La Roche Ltd
97/Protocol WA29330, Version 5
Week
Screen
(28 to 
1)
1
2
4
8
12
16
20
24
26
32
40
48
52
WD a
SFU b
Day
1 (BL 
and Rz)
15
1
28
3
56
3
84
3
112
3
140
3
168
3
182
1
224
3
280
3
336
3
364
3
DLQI i
x
x
x
x
x
x
x
PGIC i
x
x
x
x
x
x
CGIC i
x
x
x
x
x
x
EQ-5D-3L i
x
x
x
x
x
x
Skindex-29 i
x
x
x
x
x
x
x
Prednisone (or 
equivalent) dose 
assessment/ 
adjustment j
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Safety and Routine Laboratory Assessments
Adverse events k
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x l
Concomitant 
medications
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x l
Hematology m
x
x n
x n
x
x
x
x n
x n
x
x
x
x
x
Blood chemistry o
x
x n
x n
x
x
x
x n
x n
x
x
x
x
x
HBsAg, HBcAb, and 
HCV antibody
x
Urinalysis p
x
x
x
x
x
x
x
x


Clinical Study Report: rituximab - F. Hoffmann-La Roche Ltd
Protocol WA29330     Report Number 1093922
2698
Appendix 1
Schedule of Assessments (cont.)
Rituximab—F. Hoffmann-La Roche Ltd
98/Protocol WA29330, Version 5
Week
Screen
(28 to 
1)
1
2
4
8
12
16
20
24
26
32
40
48
52
WD a
SFU b
Day
1 (BL 
and Rz)
15
1
28
3
56
3
84
3
112
3
140
3
168
3
182
1
224
3
280
3
336
3
364
3
Immunology and Other Labs
Lymphocyte 
subtypes and FACS 
panel q
x n
x n
x
x
x
x n
x n
x
x
x
x
Quantitative Ig r
x
x
x
x
x
x
Autoantibodies s
x
x
x
x
x
x
x
HACA
x
x
x
x
x
PK samples 
x t
x t
x
x
x
x t
x t
x
x
x
x
x
Optional serum
biomarker sample 
for RCR
x u
x
x
x
x u
x u
x
x
Optional whole 
blood sample (RNA) 
for RCR
x u
x
x
x
x u
x u
x
x
Optional whole 
blood sample (DNA) 
for RCR v
x


Clinical Study Report: rituximab - F. Hoffmann-La Roche Ltd
Protocol WA29330     Report Number 1093922
2699
Appendix 1
Schedule of Assessments (cont.)
Rituximab—F. Hoffmann-La Roche Ltd
99/Protocol WA29330, Version 5
Week
Screen
(28 to 
1)
1
2
4
8
12
16
20
24
26
32
40
48
52
WD a
SFU b
Day
1 (BL 
and Rz)
15
1
28
3
56
3
84
3
112
3
140
3
168
3
182
1
224
3
280
3
336
3
364
3
Study Treatment Dispensed
Methylprednisolone/ 
saline solution
premedication w
x
x
x
x
Rituximab/matching 
placebo x
x y
x
x
x
MMF/matching 
placebo z
x
x
x
x
x
x
x
x
x
x
x
ALT alanine aminotransferase; AST aspartate aminotransferase; BLbaseline; BUNblood urea nitrogen; CGICClinician Global Impression 
of Change; ClinRO clinician-reported outcomes; CXRchest X-ray; DLQIDermatology Life Quality Index; Dsg1desmoglein 1; 
Dsg3desmoglein 3; ECG electrocardiogram; eCRF electronic Case Report Form; EQ-5D-3LEuroQol 5-Dimension Questionnaire, 
three-level version; FACSfluorescence-activated cell sorting; HACAhuman anti-chimeric antibodies; HBcAghepatitis B core antibody; 
HBsAghepatitis B surface antigen; HCVhepatitis C virus; Igimmunoglobulin; IVintravenous; LDHlactate dehydrogenase; 
MMFmycophenolate mofetil; PDAIPemphigus Disease Area Index; PGICPatient Global Impression of Change; PKpharmacokinetic;
PROpatient-reported outcome; Q12Hevery 12 hours; RBCred blood cell; RCRRoche Clinical Repository; Rzrandomization; SFU safety 
follow-up; WBCwhite blood cell; WDwithdrawal visit.
Notes:  All assessments and laboratory sampling should be performed within 3 days of the scheduled visit, unless otherwise specified.  On 
treatment days, all assessments should be performed prior to dosing, unless otherwise specified.
a Patients who discontinue both study treatments early, and patients who experience treatment failure (as defined in Section 3.1.3) before 
Week 12, will be asked to return to the clinic for a treatment WD visit.  If a patient withdraws at or during a scheduled or unscheduled visit, the 
visit should proceed as the withdrawal visit, that is, only the withdrawal visit assessments should be conducted.  After the withdrawal visit, the 
patient will be asked to enter the SFU period of the study.  An early withdrawal visit is not required for a patient to receive rescue therapy
between Week 12 through Week 52, and patients should continue to be followed in the 52-week treatment period.
b Safety follow-up required at 12, 24, 36, and 48 weeks (1 week) after withdrawal from or completion of treatment (see Appendix 2). Required 
follow-up information will be collected every 3 months or until death, loss to follow-up, or study termination by the Sponsor.
c Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, smoking history, use of alcohol and drugs of abuse, and all previous medications (e.g., prescription drugs, over-the-counter drugs, 
herbal or homeopathic remedies, nutritional supplements) used by the patient within 6 months prior to the screening visit.


Clinical Study Report: rituximab - F. Hoffmann-La Roche Ltd
Protocol WA29330     Report Number 1093922
2700
Appendix 1
Schedule of Assessments (cont.)
Rituximab—F. Hoffmann-La Roche Ltd
100/Protocol WA29330, Version 5
d All women who are not postmenopausal (12 months of nontherapy-induced amenorrhea) or surgically sterile will have a serum pregnancy 
test at screening.  Urine pregnancy tests will be performed at specified subsequent visits.  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test.  Prior to starting study drug, female patients of childbearing potential must have two negative pregnancy 
tests.  The second test on Day 1 prior to randomization should be performed 8 to 10 days after the first test during the screening period.
e Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurologic systems.  Record abnormalities observed at baseline on the eCRF.  Record new or worsened 
clinically significant abnormalities on the Adverse Event eCRF.
f
Includes respiratory rate, pulse rate, temperature, and systolic and diastolic blood pressure while the patient is in a seated position.
g Vital signs should be taken immediately prior to infusion and then every 30 minutes until completion of the rituximab or rituximab placebo 
infusion.
h If screening chest radiographs taken within the past 3 months show no clinically significant abnormality, further radiographic assessment is not 
required.
i
The DLQI, PGIC, EQ-5D-3L, and Skindex-29 will be completed by the patient before any other non-PRO assessments and before the patient 
receives any disease-status information or study drug during that visit. The CGIC, where possible, will be completed prior to the completion of 
other non-PRO assessments.
j
To be captured on the eCRF.
k After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  In addition, any adverse events occurring during any corticosteroid dose adjustment during the screening 
period should be reported. 
l
See Appendix 2.
m Includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, and other cells).
n Samples to be collected prior to administration of IV methylprednisolone or saline solution and 30 minutes following completion of rituximab or 
rituximab placebo infusion, respectively.
o Includes sodium, potassium, chloride, bicarbonate, glucose (except at 30 minutes following completion of study drug infusion at Weeks 1, 2, 24, 
and 26), BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total and direct bilirubin, alkaline phosphatase, ALT, AST, uric 
acid, and LDH.
p Dipstick for blood, protein, and glucose (microscopic examination at central laboratory if abnormal and applicable).
q See Section 4.5.6 for T- and B-cell assessments.
r
Total Ig, IgG, IgA, and IgM.
s Anti-Dsg1 and anti-Dsg3 antibodies.
t
On infusion days, PK samples will be collected prior to administration of IV methylprednisolone or saline solution and 30 minutes following 


Clinical Study Report: rituximab - F. Hoffmann-La Roche Ltd
Protocol WA29330     Report Number 1093922
2701
Appendix 1
Schedule of Assessments (cont.)
Rituximab—F. Hoffmann-La Roche Ltd
101/Protocol WA29330, Version 5
completion of rituximab or rituximab placebo infusion, respectively.
u Samples to be collected prior to administration of IV methylprednisolone or saline solution for patients in the rituximab or rituximab placebo 
arms, respectively. 
v The optional DNA sample can be collected prior to or after study drug administration.
w Methylprednisolone or saline solution should be administered by slow IV infusion to be completed at least 30 minutes prior to each infusion of 
rituximab or rituximab placebo, respectively.
x Rituximab at a dose of 1000 mg (or matching placebo) will be administered by IV infusion on Day 1 and Day 15, with repeat rituximab (or 
matching placebo) administration on Day 168 and Day 182 provided specific safety criteria have been met (see Section 4.6.4).  See Appendix 3
for administration instructions.
y Administration of the first dose of study treatment (Day 1) should occur within 24 hours following the baseline assessments; however, 
administration up to 72 hours will be allowed when necessary.  The second infusion should occur on Day 151 day.
z MMF (500 mg or matching placebo) will be administered orally twice daily (Q12H) starting on Day 1.  Patients will be initiated on MMF at 
1 g/day or matching placebo in divided oral doses (Q12H).  The MMF dose will be titrated to achieve a goal of 2 g/day in divided oral doses 
(1 g Q12H) by Week 2.


Clinical Study Report: rituximab - F. Hoffmann-La Roche Ltd
Protocol WA29330     Report Number 1093922
2702
Rituximab—F. Hoffmann-La Roche Ltd
102/Protocol WA29330, Version 5
Appendix 2
Schedule of Assessments for the Safety Follow-Up Period
All patients who withdraw from both study treatments or complete the study will enter the 
safety follow-up period to receive standard-of-care treatment per the investigator’s best medical 
judgment.  Please note that for patients whose peripheral CD19B cells remain depleted 
(below the lower limit of normal or pre-rituximab baseline level, whichever is lower), 
safety follow-up will not be extended beyond the standard protocol-defined 48 weeks 
after treatment withdrawal or completion.  CD19B-cell counts and other blinded 
laboratory values will be provided to the investigator at the end of the safety follow-up
period.
Assessment
Week
12
(1 
week)
24
(1 
week)
36
(1 
week)
48
(1 
week)
Safety Assessments to Be Performed for All Patients
Adverse events a
x
x
x
x
Concomitant medications b
x
x
x
x
HACA
x
Autoantibody testing c
x
x
Immunology and Other Labs
Lymphocyte subtypes and FACS panel d
x
x
x
x
Quantitative Ig e
x
x
x
x
PK sample f
x
x
x
x
Disease Status and Activity Limitation Questions
Disease activity (PDAI) and flare assessment
x
x
x
x
DLQI g
x
x
PGIC g
x
x
CGIC g
x
x
Skindex-29 g
x
x
Prednisone (or equivalent) dose assessment/adjustment h
x
x
x
x


Clinical Study Report: rituximab - F. Hoffmann-La Roche Ltd
Protocol WA29330     Report Number 1093922
2703
Appendix 2  
Schedule of Assessments for the Safety Follow-Up Period 
(cont.) 
Rituximab—F. Hoffmann-La Roche Ltd 
103/Protocol WA29330, Version 5 
CGIC  Clinician Global Impression of Change; DLQI  Dermatology Life Quality Index; 
Dsg1  desmoglein 1; Dsg3  desmoglein 3; eCRF  electronic Case Report Form; 
FACS  fluorescence-activated cell sorting; HACA  human antichimeric antibodies; 
Ig  immunoglobulin; PDAI  Pemphigus Disease Area Index; PGIC  Patient Global Impression of 
Change; PK  pharmacokinetic; PV  pemphigus vulgaris; SFU  safety follow-up. 
a Only serious adverse events and all infectious adverse events, irrespective of causality, will be 
reported in the SFU period.  For all serious infectious adverse events reported, quantitative Ig, 
and CD19+ cells counts should be determined within 1 week of the adverse event becoming 
serious.  Pregnancy information will be reported for the duration of the SFU period. 
b During the SFU period, reporting of concomitant medications should be limited to subsequent 
PV treatments, use of biologics, immunosuppressive medications, and cell-depleting agents. 
c Anti-Dsg1 and anti-Dsg3 antibodies. 
d See Section 4.5.6 for T- and B-cell assessments. 
e Total Ig, IgG, IgA, and IgM.  
f PK samples will be collected only in patients who withdraw early from study treatment. 
g The DLQI, PGIC, and Skindex-29 should be completed before all other assessments during 
the study visit and prior to providing patient with any disease status information. The CGIC, 
where possible, should be completed prior to the completion of other non-PRO study 
assessments. 
h To be captured on the eCRF. 


Clinical Study Report: rituximab - F. Hoffmann-La Roche Ltd
Protocol WA29330     Report Number 1093922
2704
Rituximab—F. Hoffmann-La Roche Ltd
104/Protocol WA29330, Version 5
Appendix 3
Procedures for the Intravenous Administration of Rituximab
PROCEDURES FOR ALL INFUSIONS
Although rituximab and matching placebo (for simplicity, referred to as rituximab in the 
remainder of the appendix) may be administered on an outpatient basis, patients may be 
hospitalized for observation at the discretion of the investigator.  Irrespective, rituximab 
(and matching placebo) should be administered in a hospital, clinic, or healthcare-related 
environment where full resuscitation facilities are immediately available and under the 
close supervision of an experienced healthcare professional.
Rituximab should be given as a slow intravenous (IV) infusion through a dedicated line. 
It should not be administered as an IV push or bolus.
To reduce the frequency and severity of infusion-related reactions, methylprednisolone 
(100 mg) or a saline solution will be administered by slow IV infusion 3060 minutes
prior to the start of each infusion of rituximab or rituximab placebo, respectively.  
Patients should also receive prophylactic treatment with acetaminophen or paracetamol
(1 g by mouth) and diphenhydramine HCl (50 mg by mouth or IV equivalent, or 
equivalent dose of a similar agent) 3060 minutes prior to the start of each infusion of 
rituximab.
In the event of a mild infusion-related reaction, the infusion rate should be reduced to 
half the current rate (e.g., from 100 mg/hr to 50 mg/hr).  Once the adverse event has 
resolved, the infusion must continue at the reduced rate for an additional 30 minutes.  
If tolerated, the infusion rate may be increased to the next highest rate on the infusion 
schedule.  Patients who experience a moderate to severe infusion-related reaction 
(e.g., fever 38.5C, chills, mucosal swelling, or systolic blood pressure decrease of 
30 mmHg) should have their infusion interrupted immediately and should receive 
aggressive symptomatic treatment.  After all symptoms have resolved, the infusion may 
be restarted at half the previous rate.  If the patient tolerates the reduced rate for 30 
minutes, the infusion rate may be increased to the next highest rate following the 
infusion schedule.  Patients who experience a Grade 4 (life-threatening) event during an 
infusion should have their infusion stopped.  Additional infusions should not be given.
After the end of each infusion, the IV line should remain in place for at least 1 hour to 
allow for administration of IV drugs, if necessary.  If no adverse events occur during this 
time, the IV line may be removed.
Rituximab infusions must be administered according to the infusion schedules provided 
below.


Clinical Study Report: rituximab - F. Hoffmann-La Roche Ltd
Protocol WA29330     Report Number 1093922
2705
Appendix 3
Procedures for the Intravenous Administration of Rituximab 
(cont.)
Rituximab—F. Hoffmann-La Roche Ltd
105/Protocol WA29330, Version 5
FIRST INFUSION (DAY 1)
The first rituximab infusion (4 mg/mL concentration) should commence at a rate of 
50 mg/hr.  This may be escalated in 50 mg/hr increments every 30 minutes to a 
maximum of 400 mg/hr.  Such an infusion schedule is presented below.
Table 1
Schedule for First Infusion (Day 1)
Time (Minutes)
Infusion Rate 
(mg/hr)
Infusion Rate 
(mL/hr)
Dose in
30 Minutes (mg)
Cumulative Dose
(mg)
030
50
12.5 a
25
25
3160
100
25
50
75
6190
150
37.5 a
75
150
91120
200
50
100
250
121150
250
62.5 a
125
375
151180
300
75
150
525
181210
350
87.5 a
175
700
212240
400
100
200
900
241255 b
400
100
100
1000
a For countries not able to set the infusion pump to an accuracy of 0.5 mL/hr, the rate is to 
be rounded down to the nearest whole number.
b Should complete total dose of 1000 mg at 255 minutes (4 hr, 15 min).
SECOND INFUSION (DAY 15)
The second rituximab infusion (4 mg/mL concentration) should commence at a rate of 
100 mg/hr.  This may be escalated in 100 mg/hr increments every 30 minutes to a 
maximum of 400 mg/hr.  Such an infusion schedule is presented below.


Clinical Study Report: rituximab - F. Hoffmann-La Roche Ltd
Protocol WA29330     Report Number 1093922
2706
Appendix 3
Procedures for the Intravenous Administration of Rituximab 
(cont.)
Rituximab—F. Hoffmann-La Roche Ltd
106/Protocol WA29330, Version 5
Table 2
Schedule for Second Infusion (Day 15)
Time (Minutes)
Infusion Rate 
(mg/hr)
Infusion Rate 
(mL/hr)
Dose in
30 Minutes (mg)
Cumulative Dose
(mg)
030
100
25
50
50
3160
200
,50
100
150
6190
300
75
150
300
91120
400
100
200
500
121150
400
100
200
700
151180
400
100
200
900
181195a
400
100
100
1000
a Should complete total dose of 1000 mg at 195 minutes (3 hr, 15 min).
THIRD INFUSION (DAY 168) AND FOURTH INFUSION (DAY 182)
The Day 168 and Day 182 infusions should be administered according to the schedules 
for the Day 1 and Day 15 infusions, respectively.


Clinical Study Report: rituximab - F. Hoffmann-La Roche Ltd
Protocol WA29330     Report Number 1093922
2707
Rituximab—F. Hoffmann-La Roche Ltd
107/Protocol WA29330, Version 5
Appendix 4
Pemphigus Disease Area Index (PDAI)


Clinical Study Report: rituximab - F. Hoffmann-La Roche Ltd
Protocol WA29330     Report Number 1093922
2708
Appendix 4
Pemphigus Disease Area Index (PDAI) (cont.)
Rituximab—F. Hoffmann-La Roche Ltd
108/Protocol WA29330, Version 5


Clinical Study Report: rituximab - F. Hoffmann-La Roche Ltd
Protocol WA29330     Report Number 1093922
2709
Appendix 4
Pemphigus Disease Area Index (PDAI) (cont.)
Rituximab—F. Hoffmann-La Roche Ltd
109/Protocol WA29330, Version 5
The PDAI lesion counts (number of lesions3) for the Skin and Mucous membrane are 
assigned a score used in calculating the Total Skin and Total Mucosa Activity scores, 
respectively, when the anatomical location activity score is 1 or 2.
Skin
When an anatomical location is scored a 1 (13 lesions, up to one2 cm in any 
diameter, none6 cm), record the number of lesions at that site, ranging from 
13 lesions.  Incorporate the lesion count into the scoring by giving each location a 
score of 1 if 1 lesion is present, a score of 1.3 if 2 lesions are present, and a score of 
1.6 if 3 lesions are present.
When an anatomical location is scored a 2 (23 lesions, at least two2 cm diameter, 
none6 cm), record the number of lesions at that site, ranging from 23 lesions.  
Incorporate the lesion count into the scoring by giving each location a score of 2 if 
2 lesions are present and a score of 2.3 if 3 lesions are present.
Skin 
anatomical location activity score
Number of lesions if3
Final score
1
(13 lesions, up to one2 cm in any 
diameter, none6 cm)
1
1
2
1.3
3
1.6
2
(23 lesions, at least two2 cm diameter, 
none6 cm)
2
2
3
2.3
Mucous Membrane
When an anatomical location is scored a 1 (1 lesion), record the number one for number 
of lesions at that site.  Incorporate the lesion count into the scoring by giving each 
location a score of 1 when 1 lesion is present.
When an anatomical location is scored a 2 (23 lesions), record the number of lesions 
at that site, ranging from 23 lesions.  Incorporate the lesion count into the scoring by 
giving each location a score of 2 if 2 lesions are present and a score of 2.3 if 3 lesions 
are present.


Clinical Study Report: rituximab - F. Hoffmann-La Roche Ltd
Protocol WA29330     Report Number 1093922
2710
Appendix 4
Pemphigus Disease Area Index (PDAI) (cont.)
Rituximab—F. Hoffmann-La Roche Ltd
110/Protocol WA29330, Version 5
Mucous membrane 
anatomical location activity score
Number of lesions if3
Final score
1
(1 lesion)
1
1
2
(23 lesions)
2
2
3
2.3
Source:  Rosenbach M, Murrell DF, Bystryn JC, et al. Reliability and convergent validity of two 
outcome instruments for pemphigus. J Invest Dermatol 2009;129:240410; Victoria Werth, 
personal communication.


Clinical Study Report: rituximab - F. Hoffmann-La Roche Ltd
Protocol WA29330     Report Number 1093922
2711
Rituximab—F. Hoffmann-La Roche Ltd
111/Protocol WA29330, Version 5
Appendix 5
Skindex-29


Clinical Study Report: rituximab - F. Hoffmann-La Roche Ltd
Protocol WA29330     Report Number 1093922
2712
Rituximab—F. Hoffmann-La Roche Ltd 
2/Protocol WA29330, Version 5 


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Appendix 6
Dermatology Quality of Life Index (DLQI) Questionnaire


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Appendix 7
EuroQol 5-Dimension Questionnaire, Three-Level Version 
(EQ-5D-3L)
         
US (English) © 1998 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group
Health Questionnaire
English version for the US


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Appendix 7
EuroQol 5-Dimension Questionnaire, Three-Level Version (EQ-5D-3L)
(cont.)


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Appendix 7
EuroQol 5-Dimension Questionnaire, Three-Level Version (EQ-5D-3L)
(cont.)




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Appendix 8
Patient Global Impression of Change (PGIC)
How would you rate the change of your pemphigus vulgaris symptoms since you 
started taking the study drug?
1  Very much improved
2  Much improved
3  Minimally improved
4  No change
5  Minimally worse
6  Much worse
7  Very much worse


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Appendix 9
Clinician Global Impression of Change (CGIC)
How would you rate the change in the patient’s pemphigus vulgaris symptoms 
since the patient started taking the study drug? 
1  Very much improved
2  Much improved
3  Minimally improved
4  No change
5  Minimally worse
6  Much worse
7  Very much worse


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Appendix 10
Uncontrolled Studies and Selected Case Reports of Rituximab in Pemphigus Vulgaris
Study
No. of 
Patients
Patient 
Description
Dose of RTX
Concomitant 
Therapies
Remission
Relapse
Adverse 
Events
Heelan et al. 
2014
92 
(PV: n84)
Severe, 
refractory PV
One cycle
21000 mg IV (D1 and D15)
followed by 2or 1000 mg IV or 
2500 mg b IV as needed, 
6 months or more after first 
cycle
PRE, IS
80% CRoff
(Cycle 1), 
93% CRoff
(Cycle 2), 
95% CRoff
(Cycle 3), 
100% CRoff
(Cycle 4)
61% CRoff
(Cycle 1), 
43% CRoff
(Cycle 2), 
27% CRoff
(Cycle 3), 
43% CRoff
(Cycle 4)
Infusion 
reactions 
(16%), 
bilateral 
paronychia, 
and lichen 
planus. Two 
unrelated 
deaths were 
reported 
during f/u.
Matsukura et al. 
2012
8
Severe (n6), 
refractory (n2) 
PV
One cycle (repeat cycle for 
some patients)
21000 mg IV (D1 and D15)
PRE, AZA, 
MMF, MTX, 
CYC, IV Ig
50% CR (n4) 
(6 months)
50% PR (n4) 
(6 months)
5 months 
(n1)
12 months 
(n2)
13 months 
(n1)
No SAEs on 
treatment.  
One case of 
pneumonia 
(Month 7)
Leshem et al. 
2014
10 a
Severe, 
refractory PV
One cycle (repeat cycle for 
some patients)
21000 mg IV (D1 and D15)
PRE (n10), 
AZA (n1)
90% CR 
(6 months 
post-RTX)
67% (f/u 
22 months)
Infusion 
reaction, 
thoracic 
herpes zoster
Leshem et al. 
2013
47
Severe PV
One cycle (repeat cycles for 
some patients)
21000 mg IV (D1 and D15)
IS
76% CR (first 
cycle), 91% 
CR (repeat 
treatment 
cycle)
22% (median: 
8 months
Cycle 115%, 
Cycle 217%, 
Cycle 325%, 
Cycle 40%
Severe 
infusion 
reaction (n2)


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Uncontrolled Studies and Selected Case Reports of Rituximab in Pemphigus Vulgaris (cont.)
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Study
No. of 
Patients
Patient 
Description
Dose of RTX
Concomitant 
Therapies
Remission
Relapse
Adverse 
Events
Kanwar et al. 
2013
9
Severe (n7), 
refractory (n2) 
PV
One cycle
21000 mg IV (D1 and D15)
PRE, DP, 
AZA, CYC, 
DAP
30% CRoff,
40% CRon,
20% PR
NA
IRRs (n3
[fever, chills, 
angioedema]), 
2 cases of 
sepsis, and 1 
death (from 
sepsis with 
S. aureus)
Cianchini et al. 
2012
37
Severe, 
refractory PV
One cycle
21000 mg IV (D1 and D15)
Additional 500 mg infusion 
administered after 6 months if 
PR or no response
PRE (PO)
86% CR after 
6 months
34 relapses 
(n20)
No SAEs
Kasperkiewicz 
et al. 2012b
23
Severe PV
One cycle
21000 mg IV (week 1 and 3)
IA
IV DP
MMF/AZA
83% CR 
(n19)
13% PR 
(n3)
23% relapse 
(n6)
Two patients 
(9%) with 
severe AEs


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Uncontrolled Studies and Selected Case Reports of Rituximab in Pemphigus Vulgaris (cont.)
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Kasperkiewicz 
et al. 2012a
33
Severe PV
One cycle (repeat cycle for 
some patients)
21000 mg IV (n25)
4375 mg/m2 (n9)
2 cycles of 4375 mg/m2 (n1)
7375 mg/m2 (n1)
PRE, MP, 
MMF, AZA, 
MTX, IV Ig,
IA, UND IS
58% CR 
(n20)
36% PR
6% NR
NA
SAEs (11%), 
including 
severe 
infusion 
reaction, 
bacterial 
sepsis, DVT, 
urticaria with 
dyspnea, and 
transient 
granulocyto-
penia


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Uncontrolled Studies and Selected Case Reports of Rituximab in Pemphigus Vulgaris (cont.)
Rituximab—F. Hoffmann-La Roche Ltd
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Study
No. of 
Patients
Patient 
Description
Dose of RTX
Concomitant 
Therapies
Remission
Relapse
Adverse 
Events
Baum et al. 2013
18
Refractory PV
One cycle
4375 mg/m2
AZA, DAP, 
MMF, MTX, 
PRE
44% CR (8/18)
44% PR (8/18)
11% NR (2/18)
2/8 with CR 
relapsed at 
9 months
No related 
SAEs reported
Balighi et al. 
2013
40
Unresponsive 
PV
One cycle
4375 mg/m2
PRE (PO)
Sustained 
remission 
(n19)
52.5% 
(9 major, 
12 minor)
Lung abscess 
(fatal), sepsis, 
pneumonia, 
cavernous 
sinus 
thrombosis, 
skin abscess, 
DVT, 
generalized 
arthralgia, and 
Stevens-
Johnson 
syndrome


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Uncontrolled Studies and Selected Case Reports of Rituximab in Pemphigus Vulgaris (cont.)
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Colliou et al. 
2013
22
Severe PV
One cycle (repeat cycle for 
some patients)
4375 mg/m2
PRE
95% achieved 
disease 
control 
(mean3.1 
months)
81% relapsed 
(median time 
to relapse16 
months)
One death 
from 
septicemia, 
and another 
had 
pyelonephritis. 
Two patients 
died of CVD 
(29 and 51 
months after 
initial RTX 
infusion).


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Uncontrolled Studies and Selected Case Reports of Rituximab in Pemphigus Vulgaris (cont.)
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Study
No. of 
Patients
Patient 
Description
Dose of RTX
Concomitant 
Therapies
Remission
Relapse
Adverse 
Events
Lunardon et al. 
2012
24
Severe and/or 
refractory PV
One cycle (repeat cycles for 
some patients)
4375 mg/m2 vs. 21000 mg
PRE, MMF,
IV Ig, MTX, 
CYC, 
cyclosporine, 
AZA, DAP
58% response
44% relapse
Six SAEs in 
5 patients 
(osteomyelitis, 
perirectal 
phlegmon and 
intrapelvic 
abscesses, 
syncope due 
to anemia, 
prostate 
cancer,
and 
melanoma)
Cho et al. 2013
23
Severe PV 
(n10), mild to 
moderate PV 
(n13)
Gp 1: 3, 4375 mg/m2
Gp 2: 2375 mg/m2
PRE, AZA, 
MP 
Gp 1: 60% 
CR, 40% PR
Gp 2: 69% 
CR, 31% PR
13% relapse 
(2 pts. flared 
before 
Month 12)
No SAEs 
reported. 
One patient 
experienced 
mild, transient 
fever and 
tachycardia 
during RTX
infusion.


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Uncontrolled Studies and Selected Case Reports of Rituximab in Pemphigus Vulgaris (cont.)
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Study
No. of 
Patients
Patient 
Description
Dose of RTX
Concomitant 
Therapies
Remission
Relapse
Adverse 
Events
Kim et al. 2011
27
Severe, 
refractory PV
Gp 1: 2375 mg/m2 (n12)
Gp 2: 3, 4375 mg/m2 (n15)
NA
59% CR 
(n16)
18% PR
(n16)
No diff. in CR, 
Gp 2 had 
fewer flares
Gp 1: 067% 
relapse (to 
Month 12)
Gp 2: no 
relapses
One death 
(3 months 
after RTX 
therapy) due 
to gastric 
perforation 
(may not have 
been related 
to RTX)
Joly et al. 2007
21
Severe PV (CS 
refractory 
disease)
One cycle
4375 mg/m2
PRE
86% CR at 
3 months 
following RTX 
cycle
45% relapse 
after mean of 
18.97.9 
months
Two severe 
AEs: 1 patient 
had 
pyelonephritis 
12 months 
after RTX 
treatment and 
1 patient died 
from 
septicemia 
18 months 
after RTX 
treatment


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Uncontrolled Studies and Selected Case Reports of Rituximab in Pemphigus Vulgaris (cont.)
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Study
No. of 
Patients
Patient 
Description
Dose of RTX
Concomitant 
Therapies
Remission
Relapse
Adverse 
Events
Morrison 2004
3
Moderate/ 
severe PV
One cycle (repeat cycle for 
2 cases)
4375 mg/m2
CYC, PRE
CR (18 
months), CR 
(4 months), 
oral lesions 
healed 
(9 months)
NA
Fatal PCP, 
mild 
leukopenia
AEadverse event; AZAazathioprine; CRcomplete remission; CRoffcomplete remission off systemic therapy; CRoncomplete remission on 
systemic therapy; CScorticosteroid; CVDcardiovascular disease; CYCcyclophosphamide; D1Day 1; D15Day 15; DAPdapsone;
DPdexamethasone pulse; DVT deep vein thrombosis; f/ufollow-up; Gp 1Group 1; Gp 2Group 2; IRRinfusion-related reaction; 
IV Igintravenous immunoglobulin; IAimmunoadsorption; ISimmunosuppressant; MMFmycophenolate mofetil; MPmethylprednisone;
MTXmethotrexate; PCPPneumocystis carinii pneumonia; NAnot available; NRno response; POoral; PREprednisone; PRpartial 
remission; PVpemphigus vulgaris; RTXrituximab; SAEserious adverse event; UNDundefined.
a Patients were previously part of a larger study (Leshem et al. 2013) on the clinical efficacy of rituximab 2 1000 mg IV dose (Day 1 and Day 15).
b This dose was used when deemed appropriate by the treating physician or by necessity when the full dose was not affordable for the patient.


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Appendix 11
Telemedicine
OVERVIEW
All general study detailsat site(s) using telemedicine (TM) to enroll patients are identical 
to those sites not participating in TM.  The Telemedicine Principal Investigator (TM PI) 
has the same study-related responsibilities as the Principal Investigators who are not 
participating in TM.  The differences are primarily in the logistics of study assessments, 
methods of interactions with patients, and data collection through TM.  These differences 
are outlined here.
RECRUITMENT
Patients will be recruited from selected site(s) within the United States where the TM
investigators are licensed to practice medicine and provide teledermatology clinical care.
INFORMATIONAL WEBSITES
Patients will be referred to an informational website about the pemphigus vulgaris (PV) 
study from various recruitment sources.  Those who express interest will contact the 
TM PI or request to be contacted by the TM PI to discuss the details of the PV study and 
the specifics of the TM.
SCREENING PERIOD PROCEDURES
PRE-SCREENING
The TM research coordinator or TM PI will directly call the patient to confirm the basic 
eligibility criteria.  If the patient meets all pre-screening eligibility criteria and is interested 
in participating, the following steps will occur:

The electronic Informed Consent Form (eICF) will be made available for the patient 
to review, and the TM PI will schedule a follow-up call to review the eICF and any 
associated questions.  

The patient will be required to complete a medical information release form 
(compliant with the Health Insurance Portability and Accountability Act [HIPAA]) 
permitting the TM PI to contact the local dermatologist (LD) to discuss the patient, to 
obtain relevant medical records, and to verify eligibility criteria.
Informed Consent 

The TM PI will conduct the informed consent process with the patient.  The TM 
PI/TM research coordinator will review the eICF with the patient and answer 
questions about the study.  After the patient has had ample time to review the eICF, 
the TM PI or TM research coordinator will address any additional questions, the 
patient will sign the eICF, and the TM PI or TM research coordinator will countersign 
the eICF.  After the informed consent form and eICF have been completed, the 


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Telemedicine (cont.)
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TM PI will continue to verify eligibility and proceed with the standard screening and 
enrollment procedures, as defined in the protocol.
Verification of Eligibility

The TM PI will verify with the patient that he or she meets the inclusion and 
exclusion criteria specified in the protocol.

The TM PI will contact the LD to obtain pathology reports and any other relevant 
medical information and supportive records to verify inclusion and exclusion criteria.
Transition of Care Responsibility

After the eICF is completed, the TM investigators will assume responsibility of care 
for the patient regarding PV and associated medications (both study-related 
investigational medications and concomitant therapies for PV) and for all 
study-related decisions.  The TM investigators will interact with the patient via TM, 
as is typical for this type of care in TM.  The TM investigators will coordinate this 
transition of care with the LD and interact with the LD as needed throughout the 
study.
SCREENING (DAY 28 TO DAY 1)
Logistics and Planning for Study Visit at the Patient’s Home
A mobile research nurse (MRN) will visit patients at their home for the initial (screening)
visit if they reside in states that allow the patient-physician relationship to be established 
through TM.
1. After the eICF is signed and all pre-screening criteria are met, an initial visit from the 
MRN will be scheduled at the patient’s home.
2. An iPhonewill be shipped pre-loaded with the necessary TM applications and 
software to the MRN. 
3. The MRN will be trained on how to use the TM application, how to photograph 
patients reproducibly, and all relevant details of the study.
4. The MRN will bring the iPhone to the patient’s home for the screening visit.  The 
iPhone will remain with the patient for the duration of the study.
Screening Visit in the Patient’s Home
1. A secure video conference will take place between the TM investigators, the patient, 
and the MRN at the patient’s home, using the iPhone.  During this session, the 
following will occur:

Final details of inclusion and exclusion criteria will be re-confirmed.

The patient will be oriented to the functionality and usage of the iPhone and the 
TM application with assistance of the MRN. 


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Telemedicine (cont.)
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
Study logistics will be discussed, and any additional questions will be answered.
2. The MRN will conduct and record the following assessments:

Body weight

Height

Vital signs

Collect all screening laboratory samples

Disease activity will be assessed:
–
The MRN will establish the best circumstances and location in the home for 
medical photography (i.e., lighting, privacy, etc.).  The MRN will use the TM 
application to photograph all areas of the body and mucosa using 
standardized anatomic positions and transmit the images using a 
HIPAA-compliant platform in accordance with American Telemedicine 
Association Teledermatology guidelines.  One entire set of images will be 
transmitted (these will be used to determine the Pemphigus Disease Area 
Index [PDAI]; see Day 1 assessment of disease activity below).  The quality 
of photographs will be confirmed immediately by the efficacy assessor in 
the event that additional photographs need to be taken.
–
The efficacy assessor will evaluate the photographs sent by the MRN (see 
Step 1 above) to determine the screening PDAI.

Review all other requirements of the study with the patient using the TM 
application, including capture of the following information:
–
Any other new medical issues and other relevant medical history
–
Concomitant medications
–
Confirmation of the current prednisone dose and the safety assessor’s 
instructions for the prednisone taper

Confirm that the patient is scheduled for a physical examination, 
electrocardiogram (ECG), and chest X-ray (CXR) with a local healthcare 
provider and radiology facility, respectively, to occur in a timely fashion.  These 
reports will be reviewed by the safety assessor before any study treatments are 
initiated and administered.
Assessments

Complete physical examination:
A complete physical examination will be conducted by the local healthcare 
provider.  The findings will be reported to the safety assessor, who will review 
the findings and document appropriately.  

ECGs:


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Telemedicine (cont.)
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ECGs will be conducted by the local healthcare provider.  The findings will be 
reported to the safety assessor, who will review the findings and document 
appropriately.

CXR:
The patient will go to a local radiology facility for a baseline CXR.  The CXR 
report will be sent to the safety assessor, who will review the report and 
document appropriately.
Logistics and Planning for Study Visit at TM PI site
In states where the patient-physician relationship must be established in person before 
TM-based patient care is conducted, the initial (screening) visit will occur at the TM PI 
site.
After the eICF is signed and all pre-screening criteria are met, the TM research 
coordinator will schedule a day when the patient will travel to the TM site to complete the 
screening visit.
1.
The screening visit assessments will be completed as outlined in the schedule of 
assessments (Appendix 1).
2.
Study personnel will instruct the patient on the basic functions of the TM technology 
and iPhone use during the visit.
3.
The patient will be sent home with an iPhone pre-loaded with TM technology for 
study use.
RANDOMIZATION (DAY 1, WEEK 1)

After all of the screening procedures are confirmed and within 72 hours prior to the 
Day 1 infusion, the patient will be randomized using an interactive web/voice 
response system (IxRS), as detailed in Section 4.2.

Once the patient is randomized, an unblinded TM research pharmacist will prepare 
study treatments as specified (rituximab, mycophenolate mofetil [MMF], matching 
placebos, methylprednisolone, and saline solution).  Blinded study treatments will be 
dispensed to the MRN/infusion center staff.  The pharmacy will also prepare 
non-study medications at the discretion of the TM investigator or per local guidelines 
(e.g., prednisone, gastrointestinal prophylaxis, Pneumocystis jirovecii pneumonia 
prophylaxis, topical agents) to be dispensed to the MRN/infusion center staff.  For 
non-study medications, the patient may use their local pharmacy if desired.


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Telemedicine (cont.)
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INFUSION DAYS 1 (WEEK 1), 15 (WEEK 2), 168 (WEEK 24), AND 
182 (WEEK 26) 
All patients, regardless of state of residence, will receive their infusions and associated 
study visit assessments at the TM PI site. 

Infusions:  Rituximab (and matching placebo) should be administered in a hospital, 
clinic, or healthcare-related environment where full resuscitation facilities are 
immediately available and under the close supervision of an experienced healthcare 
professional.

All infusion reactions and adverse events will be documented and communicated 
immediately, as appropriate, to the TM safety assessor and the Sponsor as per the 
protocol.

Infusion day laboratory assessments: 
All laboratory assessments scheduled for infusion days should be performed as 
described in the schedule of assessments (see Appendix 1).  Blood draws that 
are timed to occur before and after the first infusions will be performed at the 
infusion center. 
ALL OTHER STUDY VISITS
Weeks 420 and 3252, Withdrawal, and Safety Follow-Up
(Weeks 12, 24, 36, and 48 after Withdrawal or Completion of Treatment)
For all patients, regardless of state of residence, these study visits will be conducted by 
a MRN at the patient’s home.

TM research coordinator coordinates with MRN to schedule visits to the patient’s
home
Assessments specified for evaluation days other than infusion days should be performed 
within 3 days of the scheduled visit.
The MRN will visit the patient’s home on each evaluation day noted in the schedule of 
assessments (see Appendix 1 and Appendix 2).  Assessments and procedures, 
including laboratory assessments and recording of adverse events and concomitant 
medications will be performed by the MRN.  Results will be made available to the safety 
assessor via the TM application.  
For assessments of disease activity:

Disease activity will be assessed by the patient using the Patient Global Impression 
of Change (PGIC).  The patient will complete the patient-reported outcome (PRO)
questionnaires (Dermatology Life Quality Index [DLQI], European Quality of Life 


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Telemedicine (cont.)
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135/Protocol WA29330, Version 5
5-Dimension Questionnaire, three-level version [EQ-5D-3L], and Skindex-29), and 
the MRN will collect and mail the completed forms to the TM site.

The MRN will use the TM application to photograph all areas of the body and 
mucosa; these photographs will be transmitted to the efficacy assessor for PDAI 
scoring and Clinician Global Impression of Change (CGIC) determination.  The 
MRN will use the same location in the home as previously used to limit unnecessary 
variability.
DATA 
All laboratory results will be transmitted securely to the safety assessor.  As described in 
the protocol, the efficacy assessor will review all of the efficacy data and the safety 
assessor will review the laboratory data and all efficacy and safety data independently.
Within 24 hours, the efficacy assessor will evaluate disease activity, lesion count, flare 
assessment, calculate the PDAI score, and complete the CGIC.  The safety assessor 
will make all treatment decisions.  The safety assessor will call the patient to discuss all 
study treatment and management decisions.  Serious adverse events, non-serious 
adverse events of special interest, and pregnancies will be reported to the Sponsor 
within 24 hours.
Safety data from TM will be reviewed by the independent Data Monitoring Committee 
(see Section 3.1.4).
ANALYSES AND DECISION POINTS TO CONTINUE TM
Initially, approximately 10 patients will be recruited for participation in TM.  Adverse 
events, data quality and completeness, and enrollment statistics will be reviewed 
monthly by the Sponsor and compared with the general enrollment arms of the study.  
The TM investigators will ensure that the images and data collected via TM provide 
adequate information for evaluating the primary efficacy endpoint and for ensuring 
patient safety.


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Telemedicine (cont.)
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The measures of success of TM will include, but is not limited to, the screening and 
enrollment rates at the TM site(s), iDMC review of the safety data, health authority 
interactions, as well as the Sponsor’s review of the quality and completeness of the data, in 
determining whether to continue or expand participation in TM.  Analyses will be 
performed comparing the average performance with all other traditional (non-TM) sites, 
including, but not limited to:

Total number of missed study days

Average percentage of missing data per visit

Screening rate

Enrollment rate

Retention rate (or dropout rate)

SAP_003.pdf: 
 
Official Title: 
 
A RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, ACTIVE-
COMPARATOR, MULTICENTER STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF RITUXIMAB VERSUS MMF IN 
PATIENTS WITH PEMPHIGUS VULGARIS 
NCT Number: 
NCT02383589 
Document Date: 
SAP Version 4: 10-December-2018 
SAP Version 1: 18-October-2019 
 
 


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STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Rituximab—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan WA29330
STATISTICAL ANALYSIS PLAN
TITLE:
A RANDOMIZED, DOUBLE-BLIND, DOUBLE 
DUMMY, ACTIVE-COMPARATOR MULTICENTER 
STUDY TO EVALUATE THE EFFICACY AND 
SAFETY OF RITUXIMAB VERSUS 
MYCOPHENOLATE MOFETIL IN PATIENTS WITH 
PEMPHIGUS VULGARIS
PROTOCOL NUMBER:
WA29330
STUDY DRUG:
Rituximab
VERSION NUMBER:
4
IND NUMBER:
121595
EUDRACT NUMBER:
2014-000382-41
SPONSOR:
F. Hoffmann-La Roche Ltd.
PLAN PREPARED BY:
, Ph.D.
DATE(S) AMENDED:
Version 1: 4 November 2015
Version 2: 1 February 2018
Version 3: 12 July 2018
DATE FINAL:
See electronic date stamp below
 
Name                                                             Reason for Signing                              Date and Time
(UTC)
10-Dec-2018 20:35:42
Company Signatory


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TABLE OF CONTENTS
1.
BACKGROUND ............................................................................................ 6
2.
STUDY DESIGN........................................................................................... 6
2.1
Protocol Synopsis.................................................................... 6
2.2
Outcome Measures ................................................................. 6
2.2.1
Primary Efficacy Outcome Measures ...................................... 6
2.2.2
Secondary Efficacy Outcome Measures.................................. 7
2.2.3
Safety Outcome Measures ...................................................... 7
2.2.4
Exploratory Outcome Measures .............................................. 7
2.3
Determination of Sample Size ................................................. 8
2.4
Analysis Timing ....................................................................... 9
3.
STUDY CONDUCT....................................................................................... 9
3.1
Randomization Issues ............................................................. 9
3.2
Data Monitoring ..................................................................... 10
4.
STATISTICAL METHODS .......................................................................... 10
4.1
Analysis Populations ............................................................. 10
4.1.1
Randomized Population......................................................... 10
4.1.2
Pharmacokinetic-Evaluable Population ................................. 10
4.1.3
Safety Population .................................................................. 10
4.1.4
Intent-to-Treat Population...................................................... 11
4.1.5
Modified Intent-to-Treat Population ....................................... 11
4.2
Treatment Failure .................................................................. 11
4.3
Analysis of Study Conduct..................................................... 13
4.4
Analysis of Treatment Group Comparability .......................... 13
4.4.1
Demographics ....................................................................... 14
4.4.2
Disease Characteristics......................................................... 14
4.5
Data-Cut for Analyses............................................................ 15
4.6
Visit Windows ........................................................................ 15
4.7
Efficacy Analysis.................................................................... 16
4.7.1
Primary Efficacy Endpoint...................................................... 17
4.7.1.1
Sustained Complete Remission............................................. 17


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4.7.1.2
Pemphigus Disease Area Index ............................................ 17
4.7.1.3
Prednisone (or Equivalent) Dose........................................... 18
4.7.1.4
Treatment Failure .................................................................. 18
4.7.1.5
Sensitivity Analyses............................................................... 19
4.7.1.6
Exploratory Analyses............................................................. 19
4.7.2
Secondary Efficacy Endpoints............................................... 19
4.7.2.1
Oral Corticosteroids............................................................... 19
4.7.2.2
Total Number of Flares.......................................................... 22
4.7.2.3
Time to Start of Sustained Complete Remission ................... 22
4.7.2.4
Time to Disease Flare............................................................ 23
4.7.2.5
Dermatology Life Quality Index.............................................. 24
4.7.3
Exploratory Efficacy Endpoints.............................................. 25
4.7.3.1
Duration of Remission ........................................................... 25
4.7.3.2
Patient Global Impression of Change.................................... 26
4.7.3.3
Clinician Global Impression of Change.................................. 26
4.7.3.4
Remission Endpoints............................................................. 26
4.7.3.5
Complete Remission ............................................................. 26
4.7.3.6
Partial Remission................................................................... 27
4.7.3.7
Pemphigus Disease Area Index ............................................ 27
4.7.3.8
European Quality of Life 5-Dimension 
Questionnaire, 3-Level Version ............................................. 27
4.7.3.9
Skindex-29............................................................................. 28
4.7.3.10
Disease Control..................................................................... 29
4.7.4
Subgroup Analyses ............................................................... 29
4.8
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 29
4.9
Safety Analyses..................................................................... 30
4.9.1
Exposure to Study Medication............................................... 30
4.9.2
Adverse Events ..................................................................... 31
4.9.3
Deaths ................................................................................... 32
4.9.4
Laboratory Data..................................................................... 32
4.9.4.1
Safety Laboratory Parameters............................................... 32
4.9.4.2
Immunoglobulins ................................................................... 32
4.9.4.3
Lymphocyte Populations........................................................ 33


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4.9.4.4
Desmoglein-1 and Desmoglein-3 Autoantibody 
Titers...................................................................................... 33
4.9.4.5
Anti-Drug Antibodies.............................................................. 34
4.9.5
Vital Signs.............................................................................. 34
4.10
Data Handling Methods ......................................................... 34
4.10.1
Presentation of Data.............................................................. 34
4.10.2
Definitions.............................................................................. 34
4.10.3
Multiple Values ...................................................................... 35
4.10.4
Missing Data.......................................................................... 35
4.11
Interim Analyses .................................................................... 35
5.
REFERENCES ........................................................................................... 36


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LIST OF TABLES
Table 1
Time Windows of Study Days to Assign Study Visit (for DLQI)
.................................................................................................... 16
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 37
Appendix 2
Overview of Study Design........................................................... 44
Appendix 3
Schedule of Assessments........................................................... 45
Appendix 4
Corticosteroid Treatment Guideline ............................................ 51
Appendix 5
Pemphigus Disease Area Index.................................................. 52
Appendix 6
Dermatology Quality of Life Index (DLQI) Questionnaire ............ 56
Appendix 7
Patient Global Impression of Change ......................................... 57
Appendix 8
Clinician Global Impression of Change....................................... 58
Appendix 9
European Quality of Life 5-Dimension Questionnaire, 3-Level 
Version........................................................................................ 59
Appendix 10
Skindex-29 Manual ..................................................................... 63
Appendix 11
Imputation Rules for Partial or Missing Dates ............................. 74


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Study WA29330 (PEMPHIX) aims to evaluate the efficacy and safety of rituximab (RTX) 
versus mycophenolate mofetil (MMF) in patients with Pemphigus vulgaris (PV).  PV is a 
rare, serious autoimmune disease characterized by blisters and erosions of the skin 
and mucosal areas.
Study WA29330 is a multicentre, randomized, double-blind, double-dummy, 
active-comparator, two-arm, parallel-group study, which consists of three periods: 
a screening period of up to 28 days, a 52-week, double-blinded, treatment period 
followed by a 48-week safety follow up (SFU) period, that begins at the time of study 
treatment completion or discontinuation.
This preliminary Statistical Analysis Plan (SAP) describes the statistical methodology 
and data handling rules to be used for the Week 52 primary analysis.  The primary 
reporting event will include all data up to Week 52 or early withdrawal.  The SAP will be 
finalized prior to database lock and data unblinding for the primary analysis.
A final reporting event and study database lock will occur after all patients complete the 
48-week SFU period or withdraw early from SFU, details of which will be documented in 
a separate SAP.
2.
STUDY DESIGN
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is provided in Appendix 1.  Additional details including the study 
flowchart, schedule of assessments, and corticosteroid treatment guideline can be found 
in the Appendices (Appendix 2, Appendix 3, and Appendix 4).
2.2
OUTCOME MEASURES
2.2.1
Primary Efficacy Outcome Measures
The proportion of patients (excluding telemedicine [TM] patients) who achieve a 
sustained complete remission without experiencing an event that constitutes treatment 
failure (as defined in Section 4.2) beforehand, during the 52-week treatment period.
Sustained complete remission is defined as achieving healing of lesions with no new 
active lesions (i.e., pemphigus disease area index [PDAI] activity score of 0) while on 
0 mg/day prednisone or equivalent, and maintaining this response for a total of at least
16 consecutive weeks, during the 52-week treatment period.  Patients with transient new 
lesions for 1 week or less that heal without additional systemic corticosteroid therapy will 
not be considered to have experienced treatment failure.
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1.
BACKGROUND


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2.2.2
Secondary Efficacy Outcome Measures
The secondary efficacy outcome measures are as follows:

Cumulative oral corticosteroid dose (prednisone or equivalent) over the treatment
period

Total number of disease flares during the treatment period

Time to initial sustained complete remission

Time to disease flare
–
Disease flare is defined as appearance of three or more new lesions a month
that do not heal spontaneously within 1 week, or by the extension of 
established lesions, in a patient who has achieved disease control.

Change in health-related quality of life (HRQoL), as measured by the dermatology 
life quality index (DLQI) score, from baseline to Week 52

Duration of sustained complete remission

Patients’ impression of change in PV symptoms, as measured by the patient global 
impression of change (PGIC) score, during the treatment period

Clinician impression of change in patients’ PV symptoms, as measured by the 
clinician global impression of change (CGIC) score, during the treatment period.
The first five secondary efficacy outcome measures will be included in a hierarchical 
testing procedure to control for Type I error (See Section 4.7); the remaining secondary 
endpoints will be considered exploratory and will not be tested for Type 1 error.
2.2.3
Safety Outcome Measures
The safety outcome measures are as follows:

Nature, frequency, and severity of adverse events (AEs), including serious adverse 
events and AEs leading to discontinuation

Vital signs and clinical laboratory test results (including complete blood count and
blood chemistry)

Incidence of anti-drug antibodies(ADA)

Circulating B cells, T cells, natural killer (NK) cells, plasma cells, and other
leukocytes

Plasma immunoglobulin (Ig) levels (total Ig, IgG, IgM, and IgA)

Corticosteroid-related AEs in relation to corticosteroid exposure
2.2.4
Exploratory Outcome Measures
The exploratory outcome measures are as follows:

Proportion of patients achieving a complete remission by Week 24 and by Week 52


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Complete remission is defined as achieving wound healing with no new active
lesions (i.e., PDAI activity score of 0) for at least 8 consecutive weeks during
the 52-week treatment period.

Proportion of patients achieving a partial remission by Week 24 and by Week 52
Partial remission is defined as the presence of transient new lesions that heal
within 1 week (while the patient is receiving minimal therapy, including topical
corticosteroids). Minimal therapy is defined as 10 mg/day prednisone 
(or equivalent) for at least 8 consecutive weeks during the 24-week or 52-week
treatment period.

Pharmacokinetics/pharmacodynamics (PK/PD) of RTX
PK/PD parameters include, but are not limited to, serum levels of RTX,
peripheral CD19B-cell counts, HACA, and autoantibody concentrations.

To explore the PD of MMF in patients with PV

Change in total PDAI activity score during the treatment period

Change from baseline in anti-desmoglein-1 (Dsg1) and anti-desmoglein-3 (Dsg3)
autoantibodies

Change in health utilities as assessed by the European quality of life (EuroQol) 
5-dimension questionnaire, 3-level version (EQ-5D-3L) score from baseline to 
Week 52

Change in HRQoL, as measured by the Skindex-29 from baseline to Week 52

Proportion of patients experiencing treatment failure from Week 12 to Week 52.
2.3
DETERMINATION OF SAMPLE SIZE
The primary efficacy endpoint of this study is the proportion of patients (excluding TM 
patients) achieving a sustained complete remission, as assessed at Week 52, that has 
been maintained for 16 consecutive weeks during the 52-week treatment period.  With 
use of limited data available in the literature from randomized clinical trials of MMF and 
investigator-initiated trials of rituximab (Beissert et al. 2010), it is estimated that 
approximately 40% of patients with PV receiving MMF will achieve a sustained complete 
remission. It is estimated that patients receiving rituximab will induce a sustained 
complete remission rate of 65%.  On the basis of these assumptions, a total of 
122 patients randomized to either the rituximab arm or the MMF arm in a 1:1 ratio 
(61 patients in the rituximab arm and 61 patients in the MMF arm) will yield 
approximately 80% power in a two-sided test at the 5% significance level.  To account 
for the 10 TM patients excluded from the primary efficacy analysis, approximately 
132 patients will be randomized in total. The sample size calculation was performed 
using nQuery Advisor 7 using the two-group chi-squared test of equal proportions. The 
primary analysis method using a Cochran-Mantel-Haenszel test adjusting for 
stratification factors is expected to provide at least 80% power to detect the difference in 
proportions.


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No adjustment will be made for dropouts.  Patients withdrawing early from the study or 
meeting the criteria for treatment failure (including rescue therapy) will be assessed 
based on available data up until the point of withdrawal or treatment failure only for the 
primary endpoint.  Patients with missing or incomplete data where a status cannot be 
determined after applying relevant imputation rules will be set to non-responders.
2.4
ANALYSIS TIMING
The primary analysis will be conducted when all patients have completed the Week 52 
study visit or have withdrawn early from the study.  The reporting event for the primary 
analysis will include data for all patients up to their Week 52 assessment visit within the 
treatment period, or data up to the point of withdrawal.  Safety follow up (SFU) data will 
not be included within the primary analysis data-cut.  All data up to the Week 52 study 
visit will form part of the Primary Week 52 Clinical Study Report (CSR).
A final reporting event and study database lock will occur after all patients complete the 
48-week SFU period or withdraw early from SFU, details of which will be documented in 
a separate SAP and final CSR. The final CSR will include all available data up to study
completion (last patient’s last visit [LPLV] in SFU) or early withdrawal from SFU. 
3.
STUDY CONDUCT
3.1
RANDOMIZATION ISSUES
After completing the informed consent form, eligible patients will be enrolled into the 
study and randomized using a central Interactive Voice/Web Response System (IxRS). 
Patients will be randomly allocated to receive RTX plus MMF placebo or RTX placebo 
plus MMF in a 1:1 ratio.  Randomization will be performed according to a stratified 
permuted block design using the two baseline stratification factors (duration of illness
[diagnosed1 year from screening versus.1 year] and geographical region [North 
America vs Rest of World]).
A mock randomization schedule was generated by the IxRS vendor (
) and user 
acceptance testing was performed on the IxRS system for both voice and web based 
methods.  Testing of the system by the Sponsor’s study statistician confirmed the 
following: correct strata and block allocation, correct treatment assignment, and 
agreement between IxRS output and the IxRS datasets delivered to the Sponsor.
The independent Data Coordinating Center (iDCC) will perform one round of 
randomization checks early during the recruitment period.  The checks will be similar to 
those performed during user acceptance testing and will be carried out no later than 
when 30% patients have been randomized.  The iDCC will notify the Sponsor’s study 
statistician of any potential issues.  Further checks at additional time points may be 
performed if necessary.


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3.2
DATA MONITORING
Safety data and data pertaining to trial conduct will be reviewed by an independent Data 
Monitoring Committee (iDMC).  The iDMC will meet according to the schedule below, 
whichever occurs first:

After the first 10 patients have completed at least 3 months of study treatment or 
have withdrawn early from the study

After the first 5 TM patients have completed at least 3 months of study treatment or 
have withdrawn early
Thereafter, meetings will be held approximately every 4 or 6 months (frequency may be 
adjusted during the recruitment period), after 10 TM patients have completed at least 
3 months of study treatment or withdrawn early from the study, or as requested by the
iDMC.
Efficacy data will be available on request, to enable a benefit-risk assessment should 
there be a safety concern.
The Sponsor’s study team will have no direct contact with the iDMC during the trial 
conduct except for the scheduled open sessions of the iDMC.
Further details can be found in the iDMC charter.
4.
STATISTICAL METHODS
All analyses, summaries, and listings will be performed using SASsoftware 
(Version 9.2 or later).
4.1
ANALYSIS POPULATIONS
All patient populations for the analysis of the 52-week, double-blind treatment period will 
be defined and documented prior to unblinding the data collected up to Week 52.
4.1.1
Randomized Population
The randomized population will include all patients randomized into the study.
4.1.2
Pharmacokinetic-Evaluable Population
The pharmacokinetic-evaluable population (PK population) will include all patients 
randomized to and received any dose of RTX given as study medication, have at least 
one post-dose PK sample that is evaluable, and have no major protocol deviations that 
would impact the PK results.
4.1.3
Safety Population
The safety population will include all patients who were randomized and received any 
part of an infusion of study drug or oral administration of study drug. Patients who 
received the incorrect treatment throughout the study from that assigned at 


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randomization will be reported under the treatment actually received.  Patients who were 
not randomized but who received study drug will be included in the safety population and 
reported under the treatment actually received.
Patients receiving at least one dose of both active study treatments during the study 
(e.g., in error, or in the unlikely event of crossing over) will be reported under the original 
treatment received.  This does not include MMF or RTX received as rescue therapy.
All safety analyses including AEs, in addition to analysis of previous and concomitant 
medications, previous and concomitant diseases, laboratory data, and compliance with 
study treatment, will be performed using the safety population.
4.1.4
Intent-to-Treat Population
The intent-to-treat (ITT) population will include all randomized patients who received any 
part of an infusion of study drug or oral administration of study drug.
Patients who prematurely withdraw from the study for any reason and for whom an 
assessment is not performed for whatever reason will still be included in the ITT 
analysis.  Patients who received an incorrect therapy (i.e., different from that to which 
they were randomized) will be summarized in the treatment arm to which they were 
randomized.
Patients with no post-baseline data will still be included in the ITT population but will 
have their efficacy results imputed according to the imputation methods described in this 
SAP for all key efficacy assessments.
Patients who were not randomized but still received study treatment will be excluded 
from the ITT population and subsequent analyses.
Sensitivity analyses of the efficacy outcomes will be performed using the ITT population.
4.1.5
Modified Intent-to-Treat Population
The modified intent-to-treat population (mITT) population includes patients in the ITT 
population, excluding the 10 TM patients.  This population will be used in the analyses of 
efficacy outcomes.
4.2
TREATMENT FAILURE
Treatment failure is the occurrence of any one of the following events:

After disease control has been achieved, a two-step increase in prednisone (or
equivalent) dose to 20 mg/day for more than 2 weeks to treat increased disease
activity during the corticosteroid taper

Failure to achieve disease control after receiving 240 mg/day oral prednisone (or
equivalent) for 1 week


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Disease control is defined as the time at which new lesions cease to form and
established lesions begin to heal (beginning of the consolidation phase).

Increase in MMF/matching placebo dosage above 2 g/day

Initiation of any rescue therapy (addition of another immunosuppressive medication, 
additional RTX or MMF open-label doses, intravenous (IV) Ig, plasmapheresis, or 
another treatment or procedure) as determined by the investigator’s best medical 
judgment
The clinical definitions of treatment failure above are aligned with “non-responder”
classification for the primary analysis.  Patients experiencing treatment failure prior to 
achieving sustained complete remission will be categorized as non-responders in the 
primary analysis, but will continue to be followed in the study per the schedule of 
assessments. Patients who achieve sustained complete remission without experiencing 
an event constituting treatment failure beforehand will not be categorized as 
non-responders, regardless of whether they subsequently meet the criteria during the 
remaining treatment period.
Patients who experience treatment failure will be analyzed using data up to the point of 
treatment failure for efficacy remission endpoints, including the primary endpoint for 
sustained complete remission.
From Week 12 through Week 52, patients who experience treatment failure are eligible 
to receive rescue therapy during the treatment period with another immunosuppressive 
medication, IV Ig, plasmapheresis, or another treatment or procedure as per the 
investigator’s best medical judgment.  An early withdrawal visit is not required for a 
patient to receive rescue therapy, and patients should continue to be followed in the 
study per the 52-week treatment period (see Appendix 1).
Patients who receive rescue therapy will be evaluated up to the point of rescue only for 
all main efficacy analyses.  Methods for data handling and/or imputing post-rescue data 
are described throughout Section 4.7.  Additional exploratory summaries on key efficacy 
assessments will be produced that will include rescue data.  Safety analyses will include 
data up to the point of rescue only.
Listings will include all data, including data post-rescue treatment.
Depending on the proportion of patients receiving rescue, patients will be analyzed 
separately using descriptive statistics for key analyses on study conduct, efficacy, and 
safety.  For relevant summaries, patients may be re-baselined at the time of rescue and 
data presented as pre- and post-rescue treatment. Rescue analyses will use data as 
observed.  Subject to patient counts, a limited number of analyses may be summarized 
by type of rescue received (MMF given as rescue, RTX given as rescue, or other).


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4.3
ANALYSIS OF STUDY CONDUCT
The following analyses of study conduct will be carried out on the safety population or 
mITT, as appropriate.
The patients excluded from each analysis population will be summarized, including the 
reason for exclusion.
A summary of enrollment by country and investigator site will be produced.
The number of patients who completed or discontinued from the study by Week 52, 
including the reason for discontinuation, will be summarized by treatment group.  
A listing of early withdrawals will be produced.
A summary of the number of patients who entered the study and who failed to meet all 
inclusion/exclusion entry criteria will be produced.  Major protocol deviations will be listed
and summarized.
Patient duration in the 52-week treatment period will be summarized. Duration will be 
calculated as:
date of last visit date of the first dose 1
Previous and concomitant medications will be summarised descriptively by mapped term 
and treatment group.  A summary of rescue medications for PV will also be produced.
A summary of the number of patients who experience treatment failure along with the 
reason(s) for treatment failure will be produced.  The number of patients receiving 
rescue will also be listed and summarised.
A summary of exposure to study treatment will be produced using the dose recorded on 
the electronic case report form (eCRF).  The number of RTX/placebo RTX infusions and 
dose received at each infusion and overall will be summarised by treatment group.  The 
mean daily dose, total cumulative dose, and duration of treatment of MMF/placebo MMF 
over the 52-week treatment period will be summarised.
4.4
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Summary tables will be produced for the safety population for baseline demographic and 
disease characteristics.  If it is found that there is a large difference in the number of 
patients in the safety population compared to the ITT population, additional summaries 
will be produced based on treatment as randomized.
Demographic and baseline disease characteristics will be summarized as described in 
the following sections.


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4.4.1
Demographics
Demographics will be summarized, including:

Gender (male/female)

Age (years)

Height (cm)

Weight (kg)

Body mass index (kg/m2)

Race

Ethnicity

Geographic region

Smoking status

Female reproductive status
4.4.2
Disease Characteristics
Baseline values will be summarized, including:

Duration of PV (months)

Prednisone dose (mg/day)

Overall PDAI total activity score

Site of disease (mucosal only, mucocutaneous, cutaneous only.  Site of disease will 
be determined as follows:
–
Mucosal only:  PDAI total mucosal activity score0 and PDAI total skin activity 
score 0 and PDAI total scalp activity score0
–
Cutaneous only:  PDAI total mucosal activity score0 and at least one of PDAI 
total skin activity score or PDAI total scalp activity score is0
–
Mucocutaneous:  PDAI total mucosal activity score0 and at least one of PDAI 
total skin activity score or PDAI total scalp activity score is0

Anti-Dsg-1

Anti-Dsg-3

CD19

Prior MMF treatment

Prior RTX treatment
In addition, any clinically significant ECG or chest X-ray abnormalities at baseline will be 
listed using the safety population.
Medical history data, including surgery and procedures, and baseline conditions will be 
summarized descriptively by treatment group using the safety population. A glossary 


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showing the mapping of investigator verbatim terms to diseases will be produced for the 
medical history data.
4.5
DATA-CUT FOR ANALYSES
For each patient, the day of first dose of study treatment will be designated study day 1.  
Each subsequent assessment point will be assigned a study day calculated as:
date of assessment date of first dose1.
Data beyond the Week 52 visit will not be included in the primary Week 52 CSR.  For 
each patient, data will be cut-off and reported up to and including the earliest of the 
following:

Week 52 visit (using upper visit window of Day 36410 days)

Date of early withdrawal
Patients who complete the 52-week treatment period but have a missing Week 52 visit, 
or where the Week 52 visit falls outside the reporting cut-off will be evaluated up to study 
Day 365 for all analyses involving a duration or exposure element.  In such analyses, 
any references to Week 52 throughout this SAP will imply study day 365 for these 
patients.
Although SFU data will not be included in data displays for the Week 52 primary 
reporting event, any deaths at the time of the data-cut, occurring in SFU will be 
highlighted in the CSR.
4.6
VISIT WINDOWS
In general, data for assessments that are collected by scheduled visits will be mapped to 
visits that appear in the schedule of assessments per the protocol using the actual study 
day of assessment.  Data mapped to scheduled visits will include all data collected up to 
the reporting cut-off date, and may include withdrawal visits and unscheduled visits. 
Data will never be mapped to visits for which the assessment was not scheduled in the 
protocol (i.e., results for an assessment conducted at an unscheduled visit will be 
mapped to the appropriate visit at which the assessment was scheduled).  Visit windows 
will be continuous from the midpoint between two consecutive study visits, and will be 
dependent on the schedule of assessments for each variable independently.  An 
example of the DLQI visit window is given in Table 1.  Visit windows for each variable 
will be constructed in the same manner.


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Table 1
Time Windows of Study Days to Assign Study Visit (for DLQI)
Study Visit
Scheduled Study Day
(±3 days)
Time Window
(Days)
Baseline
1
≤1
Week 12
84
>1 to ≤126
Week 24
168
>126 to ≤224
Week 40
280
>224 to ≤322
Week 52
364
>322 to ≤375
                     DLQI dermatology life quality index.
Derived variables such as remission endpoints or assessments that are collected on an 
ongoing basis, such as flares and oral corticosteroid dose, will be presented using 
appropriate time intervals.
Data displays that are presented by visit will only include visits at which the assessment 
was scheduled to be collected.  The methods for handling multiple values within a visit 
window are described in Section 4.10.3.
4.7
EFFICACY ANALYSIS
The primary and the first five ranked secondary endpoints (listed below) will be tested 
at an overall 5% significance level using two-sided hypothesis tests. The remaining
secondary endpoints will be considered exploratory (Section 2.2.4) and not 
tested for significance.
To control for overall Type I error, the hypothesis testing on study endpoints will be 
conducted sequentially starting with the primary endpoint at 5% level of significance. If 
the null hypothesis relating to the primary endpoint is rejected, the first 5 secondary 
endpoints will then be tested in a fixed-sequence fashion in the following order:
1.
Cumulative oral corticosteroid dose (prednisone or equivalent) over the treatment 
period
2.
Total number of disease flares during the treatment period
3.
Time to initial sustained complete remission
4.
Time to disease flare
5.
Change in health-related quality of life (HRQoL), as measured by the dermatology 
life quality index (DLQI) score, from baseline to Week 52
If at any step in the testing procedure, the p-value associated with a test is not <0.05, the 
remaining endpoints below the sequence will not be considered significant.
The mITT population will be the primary population used for the analysis of efficacy 
outcomes except for duration of sustained complete remission which will be on a subset 


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of mITT population (see Section 4.7.3.1).  Additional analyses will be conducted for 
sensitivity or exploratory purposes, as described in the relevant sections below.
4.7.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the proportion of patients achieving sustained complete 
remission during the 52-week treatment period.
The following two-sided hypothesis will be tested at the 5% significance level:
H0: pRTX = pMMF
H1: pRTX ≠ pMMF
where p denotes the proportion of patients achieving sustained complete remission 
status.
The primary method for comparing the proportion of patients achieving sustained 
complete remission will be the Cochran-Mantel-Haenszel test.  The analysis will be 
stratified by the stratification factors applied at randomization.  The proportion of patients 
achieving sustained complete remission in each treatment group will be presented along 
with the adjusted difference, 95% confidence interval for the difference, and p-value.  
4.7.1.1
Sustained Complete Remission
A patient will be considered a responder for sustained complete remission if the 
following conditions are met for a minimum of 16 consecutive weeks during the 52-week
treatment period:

PDAI total activity score0

Prednisone (or equivalent) dose0 mg/day
Patients who withdraw early from the study or meet the criteria for treatment failure will 
be evaluated using data up to the point of withdrawal or treatment failure only, whichever 
occurs first.  Patients who are in sustained complete remission at the Week 52 visit will 
have their duration cut-off at the Week 52 visit for the purpose of calculating the 
minimum 16 week criteria for the primary analysis, however they will be censored in 
secondary analyses of duration.
Sustained complete remission is a composite endpoint derived using several sources of 
information.  A description of each variable contributing to the composite endpoint is 
given below, including methods for data handling and dealing with missing data.
4.7.1.2
Pemphigus Disease Area Index 
The PDAI is a scoring system ranging from 0 to 263 and assesses the number and sizes 
of lesions across cutaneous and mucosal areas of the body, where higher PDAI scores 
indicate greater disease activity (Appendix 5).  The total PDAI score is made up of two 
components: total activity score (0250) and total damage score (013).  The total 


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damage score measures the extent of post inflammatory hyperpigmentation or erythema 
from resolving lesions.  The trial objective seeks to achieve the absence of new or 
established lesions (i.e., total activity score0), with lesser importance being placed on 
post-inflammatory hyperpigmentation left by lesions that have resolved.  For this reason, 
only the PDAI total activity score will be used for the assessment of sustained complete 
remission, and will be denoted by PDAIa throughout this SAP.
For calculating the duration, a patient with a PDAIa0 at a visit who fails the criteria at 
the next visit will be assumed to fail at the date of the visit where PDAIa0 was not met.  
That is, the patient is assumed to maintain the response during the whole interval 
between the two visits, as any clinically relevant increases in disease activity is expected 
to be captured by an increase in oral corticosteroids.
Missing Data
Missing PDAIa scores at a visit will be imputed using the score from the previous or next 
visit, whichever is higher.  If the PDAIa score is missing at two or more consecutive 
visits then no imputation will be made, and it will be assumed that PDAIa0 for those 
visits.  This imputation will apply for missing overall total scores, and missing anatomical 
location scores.
4.7.1.3
Prednisone (or Equivalent) Dose
Patients entering the study should receive oral corticosteroids at a prednisone or 
equivalent dose of 60 or 80mg/day at Day 1.  After Day 1, the dose will be tapered to a 
target dose of 0 mg/day as outlined in the protocol and will be documented in the eCRF.  
Dose adjustments are tolerated in this trial, however patients inadequately controlled 
after performing clinically relevant dose adjustments will be considered a treatment 
failure.  Further details for treatment failure are provided in Section 4.2.
Oral corticosteroids will be monitored on an ongoing basis to ensure information is 
correctly recorded on the concomitant medication page of the eCRF.  Any missing or 
ambiguous data will be queried and all efforts will be made to resolve data issues prior to 
database lock.
Full details of data handling methods is described in Section 4.7.2.1, this includes 
reporting conventions for prednisone equivalence and imputation methods for dealing 
with missing or partial data.
4.7.1.4
Treatment Failure
The primary method for dealing with treatment failures will be to exclude data from the 
first point a patient meets one of the criteria for treatment failure.  The responder status 
(i.e., responder versus non-responder) for sustained complete remission will be 
determined using available data up to the point of treatment failure only.


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4.7.1.5
Sensitivity Analyses
The primary analysis described in Section 4.7.1.1 will be repeated with the treatment 
failure criteria relaxed to include patients in whom rescue therapy is initiated.  Patients 
who receive rescue therapy will continue to be analyzed using data up to the point of 
rescue only; however, patients who meet treatment failure criteria and do not receive 
rescue therapy will be analyzed using all available data during the 52-week treatment 
period.  
A robustness analysis of patients who withdraw will be conducted using a tipping point 
analysis. The tipping point is defined as the difference in the number of missing events 
between the treatment groups that result in a change in the primary outcome 
conclusions (Yan et al. 2009). A two-dimensional plot will be produced to evaluate 
where the tipping point lies.  The tipping point analysis will be used to assess what the 
outcome might have been had patients carried on in the trial.  All other analysis methods 
will remain as described for the primary analysis, including the handling of patients who 
qualify for treatment failure.  Patients who experience treatment failure and later 
withdraw will continue to be analyzed using data up to the point of failure, as this would 
have been their outcome had they continued in the study.
The primary analysis will also be repeated to include the patients who participated in the 
trial via TM (10 patients at one investigational site) in order to determine whether the trial 
conclusions are upheld and independent of the logistics of conducting study 
assessments, methods of interactions with patients, and method of data collection 
through TM.
4.7.1.6
Exploratory Analyses
Additional analyses may be carried out, for example:

Logistic regression analysis to control for additional baseline factors (e.g., PDAI total 
activity score, prednisone (or equivalent) dose at baseline, location of PV lesions)

Investigate any effects caused by changes to trial conduct made during the trial, 
such as changes to the treatment failure criteria between protocol versions 2 and 3

Further analyses investigating rescue patients who receive an alternative treatment

Descriptive statistics for the TM subset
4.7.2
Secondary Efficacy Endpoints
Hypotheses related to secondary endpoints will be tested in a fixed-sequence manner 
for the first five ranked secondary endpoints at the two-sided 5% significance level 
using the procedure discussed in Section 4.7.
4.7.2.1
Oral Corticosteroids
Oral corticosteroid exposure over the 52-week treatment period will be compared 
between RTX and MMF using a Wilcoxon Mann-Whitney test, assuming that the data 
will be non-normally distributed.  If it is found that the data follows a normal distribution 


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using Shapiro-Wilk W Test, a t-test will be used to compare the difference in the two 
treatment groups. 
Oral corticosteroid use over time will be further investigated; this includes data during the 
screening period.  Summaries and plots will be generated, which will include:

Mean and median daily dose per visit interval with error bars

Total cumulative dose per visit interval

Total number of days on oral corticosteroids over the 52-week period

Categories of mean daily dose per visit interval (e.g., 0 mg/day, 010 mg/day,
≥10 mg/day)
The mean daily dose for a given visit interval will be calculated as follows:
sum of total daily dose across all days in the visit interval(end date of visit 
intervalstart date of visit interval1).
Data presented by specified visit intervals will use all available; if a patient withdraws 
during a time interval, no imputation will be made for the remaining days in the interval, 
and only available data up to the time of withdrawal will be used in the calculation.  
Rescue data will be included in descriptive summaries.
Additional summaries may be produced to investigate corticosteroid use for rescue 
patients.
A listing showing oral corticosteroid dosing for patients over the 52-week treatment 
period will be produced using all available data up to the exposure date, with rescue 
data being flagged.
Data Handling for Oral Corticosteroids
Oral corticosteroids will be recorded in the eCRF under the concomitant medications 
page.  Dose modifications will be tracked by entering the start and stop dates for each 
dose received.  Medications will be flagged as oral corticosteroids using the Sponsor’s 
corticosteroid drug basket and the route administered information as recorded on the 
eCRF.  The Sponsor will review the concomitant medications data on an ongoing basis 
to ensure medications are being correctly recorded, and are being flagged as 
appropriate.
For reporting purposes, all relevant oral corticosteroid entries will be standardized by 
converting to a prednisone equivalent dose, and will be reported under the term 
‘Prednisone’.  A listing of all compounds reported as prednisone will be produced along 
with the conversion factor applied.
The study management team will monitor oral corticosteroids on an ongoing basis for 
data quality and to ensure all dose adjustments are being correctly captured. All efforts 


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will be made to resolve missing or ambiguous data prior to database lock.  In the case 
that data queries cannot be resolved, data will be handled in a conservative manner as 
described in the sections below.
The intervals for each dose of oral corticosteroid captured during the taper are expected 
to be continuous and non-overlapping.  Patients who are adequately controlled by their 
blinded treatment may discontinue oral corticosteroids altogether, but may re-start 
treatment as required to treat any increases in disease activity.  With this in mind, the 
use of available data will be maximized and incorporated into the imputation of missing 
or partial dates as follows:
Missing Term
Imputation Method
Start Date
Missing Day
Latest of the following:
Previous End Date1
First day of the month
Missing Month
Previous End Date1
Missing Year
No imputation
End Date
Missing Day
Earliest of the following:
Next Start Date1
Last day of the month
Missing Month
Next Start Date1
Missing Year
No imputation
Within two consecutive dosing intervals, if the end date of the first dose interval is 
missing and the start date of the second dose interval is missing, a midpoint approach 
using the start date of the first interval and the end date of the second interval will be 
used to assign a cut-off end date, providing these dates are available.
A missing or ‘ongoing’ final end date will be imputed with the exposure date.  A missing 
initial start date will be imputed with Day 1 providing the end date is after Day 1, 
otherwise no imputation will be made.
If the total daily dose is missing then the dose will be imputed using the dose from the 
previous dose or the next dose, whichever is higher.
In the event of overlapping dose intervals, the patient will be assumed to be taking the 
higher dose for the maximum amount of time possible and the lower dose for the 
minimum amount of time possible within the dates provided, such that the total daily 
dose will never be double counted.


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4.7.2.2
Total Number of Flares
The total number of flares occurring during the treatment period will be evaluated by 
taking into account the number of flares experienced and the exposure period.  Patient 
level flare and exposure data will then be aggregated, and the rate of flares compared 
between the RTX and MMF treatment groups.  Rate of flare will be analyzed using a 
Poisson regression model with a log link and the log of each patient’s duration in study 
as an offset variable.  The model will include factors for treatment, region, duration of 
illness, baseline PDAI activity score, and baseline prednisone dose.  The total number of 
flares, total exposure (weeks), and rate of flare will be presented by treatment group 
along with maximum likelihood estimates for the rate ratio, 95% confidence interval for 
the rate ratio, and p-value.  A Pearson Chi-Square test will be used to assess over-
dispersion of Poisson model. If an over-dispersion is detected based on this test, then a 
negative binomial model will be used. If the number of flares has an excess 
of zero counts according to the score test (van den Broek, 1995), a zero-inflated 
negative binomial model will be applied.
The exposure period for a patient will be the duration from Day 1 to the earliest of the 
following: early withdrawal, receipt of rescue, Week 52 visit.
Additional exploratory work may be undertaken to investigate the potential changes of 
flare rates over time, for example by assessing the number of flares over specified time 
intervals. 
4.7.2.3
Time to Start of Sustained Complete Remission
Time to sustained complete remission is defined as:
date of first sustained complete remission response-date of first dose1
The date of first sustained complete remission is the first date at which a patient meets 
both criteria below, providing it was maintained for a minimum of 16 consecutive weeks:

PDAI total activity score0

Prednisone (or equivalent) dose0 mg/day
Data will be censored as follows:

Patients withdrawing early from the study without achieving sustained complete 
remission will be censored at the time of study withdrawal.

Patients meeting the criteria for treatment failure who have not achieved sustained 
complete remission prior to treatment failure will be censored at the Week 52 visit.

Patients completing the 52-week treatment period who have not achieved sustained 
complete remission will be censored at the Week 52 visit.
Time to first sustained complete remission will be summarized using Kaplan-Meier 
curves along with the median, 95% confidence interval for the median, 25th and 75th


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percentiles for each treatment group if available.  The log-log transformation will be used 
to compute the 95% confidence intervals.
A stratified log-rank test will be used to test the time to first sustained complete 
remission between the RTX and MMF treatment arms over the 52-week treatment 
period, adjusting for the stratification factors used at randomization.  A sensitivity 
analysis may be carried out using the Wilcoxon test.  The Wilcoxon test is expected to 
be more sensitive when the log-rank assumptions do not hold (e.g., convergence of the 
Kaplan-Meier curves).
The time to first sustained complete remission will be converted to weeks for the 
presentation of Kaplan-Meier curves and all associated statistics.  The Proc Lifetest 
procedure in SAS will be used to generate the Kaplan-Meier curves and hypothesis 
testing.
4.7.2.4
Time to Disease Flare
Time to (first) flare is defined as:
date of first flaredate of first dose1
For the purpose of the analysis, only flares occurring on or after Day 1 in patients who 
have previously achieved disease control will be analyzed.  Flares occurring during the 
screening corticosteroid taper period will not be considered.  Note that patients may not 
necessarily be in a state of disease control at Day 1; however, date of first dose (Day 1) 
will be used as the primary time origin as it is more reliable and less subjective than the 
date of disease control, which is determined by the investigator.
Time to disease flare during steroid taper and time to disease flare during CS withdrawal 
will be analyzed separately for the mITT population.
Data will be censored as follows:

Patients withdrawing early from the study who do not experience a flare prior to 
withdrawal will be censored at the time of study withdrawal.

Patients completing the 52-week treatment period who do not experience a flare will 
be censored at the date of study completion.
Time to first flare will be summarized using Kaplan-Meier curves along with the median, 
95% confidence interval for the median, 25th and 75th percentiles for each treatment 
group if available.  The log-log transformation will be used to compute the 
95% confidence intervals.
A stratified log-rank test will be used to test the time to first flare between the RTX and 
MMF treatment arms over the 52-week treatment period, adjusting for the stratification 
factors used at randomization.


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The time to first flare will be converted to weeks for the presentation of Kaplan-Meier 
curves and all associated statistics.  The Proc Lifetest procedure in SAS will be used to 
generate the Kaplan-Meier curves and hypothesis testing.
Sensitivity Analyses
The analysis of time to disease flare will be repeated using disease control as the origin, 
defined as follows:
time to disease flaredate of first flaredate of disease control1
This sensitivity analysis aims to evaluate the onset of flares after the disease is 
adequately controlled.  Patients withdrawing from the study who fail to achieve disease 
control prior to withdrawal will be excluded from the analysis.
All other methods including censoring methods will remain the same.
4.7.2.5
Dermatology Life Quality Index
The DLQI is a validated patient-reported outcome consisting of 10 questions assessing 
the impact of dermatologic diseases on patients’ lives over the past seven days (Finlay 
and Khan, 1994). The DLQI questions are categorized into the following domains:

Symptoms and feelings

Daily activities

Leisure

Work and school

Personal relationships

Treatment
Responses to questions are ordinal in nature ranging from “Not at all” to “Very much”.  
The DLQI will be completed and calculated as per the DLQI instructions for use and 
scoring manual (Appendix 6).  The DLQI has a minimum score of 0 and a maximum 
score of 30, with higher scores indicating greater impairment on quality of life. A change 
in DLQI score of at least 4 points is considered clinically important (Basra et al, 
2015).
Change from baseline to Week 52 in DLQI will be analyzed using a maximum 
likelihood-based repeated measures model. The analysis will adjust for treatment arm, 
region, duration of illness, baseline DLQI score, visit, and an interaction term for 
visitbaseline DLQI score.  An appropriate variance structure will be used to model the 
within-patient errors. The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom.  Rescue data will be set to missing, otherwise data will 
be used in the analysis as observed. Missing DLQI scores will be handled within the 
framework of the repeated measures model, this includes data missing due to 
withdrawal or rescue.


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The absolute value and change from baseline in DLQI at each visit will be summarized 
descriptively using observed data.  Patients who withdraw or rescue will be summarized 
for visits up to withdrawal or rescue.
4.7.3
Exploratory Efficacy Endpoints
The following endpoints will provide additional information to assess treatment efficacy 
during the 52-week double blind treatment period.  Exploratory endpoints will be 
summarized using frequency counts and percentages for categorical data and summary 
statistics for continuous data.  Graphical displays will be used where relevant to show 
trends over time.
Treatment Failure:
The number and percentage of patients having treatment failure (defined in Section 4.2) 
from Week 12 to Week 52 will be summarized descriptively.
All data handling methods will follow those used for the derivation and classification of 
sustained complete remission.
4.7.3.1
Duration of Remission
Throughout this section, remission is referred to as a patient demonstrating the following 
criteria:

PDAIa score 0

Prednisone (or equivalent) dose 0 mg/day
Duration of remission will be calculated as the number of consecutive days a patient is in 
remission during the 52-week treatment period.  Duration of remission will be analyzed 
using an analysis of covariance (ANCOVA) with logarithmic transformation (or any other 
suitable transformation depending on the distribution of the data) of duration of remission, 
adjusting for the stratification factors (duration of illness and geographical region) and 
presented as days. Patients who demonstrate fluctuating remission flare disease 
behaviour will be evaluated using their best response (i.e., longest duration) observed 
during the 52-week treatment period.  For patients who withdraw or receive rescue 
therapy, the duration of remission will be calculated as the number of days in remission 
up until the point of withdrawal or receipt of rescue, respectively.  Patients who never 
achieved remission will be assigned a duration of 0; this includes withdrawals.
A separate analysis will evaluate the duration of sustained complete remission.  This will 
be conducted on the subset of patients who met the primary endpoint of sustained 
complete remission, and will follow a similar method to the mITT analysis.  The duration 
of sustained complete remission will begin on the first day that a patient entered 
remission, providing the response was maintained for at least 16 consecutive weeks.  
Thus, the minimum duration, in the duration of sustained complete remission analysis, 
will be 16 weeks.


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4.7.3.2
Patient Global Impression of Change
The PGIC is a measure of perceived change in PV symptoms as assessed by the 
patient.  The patient uses a 7-item categorical scale ranging from “very much 
improved” to “very much worse” to answer “How would you rate the change of your 
pemphigus vulgaris symptoms since you started taking the study drug?” (Appendix 7).
The PGIC categories will be summarized by visit up to Week 52.  Rescue data will be 
set to missing from the point of rescue onwards; no imputation will be made for rescue 
data. 
4.7.3.3
Clinician Global Impression of Change
The CGIC is a measure of perceived change in PV symptoms as assessed by the 
clinician.  The clinician uses a 7-item categorical scale ranging from “very much 
improved” to “very much worse” to answer “How would you rate the change in the 
patient’s pemphigus vulgaris symptoms since the patient started taking the study drug?” 
(Appendix 8).
Data for CGIC will be described in the same manner as PGIC, as described in 
Section 4.7.3.2. 
4.7.3.4
Remission Endpoints
Several remission endpoints will be evaluated in this study to assess the degree of 
remission attained within each treatment arm.  The following five remission endpoints
will be evaluated:

Sustained Complete Remission

Complete Remission – off therapy

Complete Remission – on minimal therapy

Partial Remission – off therapy

Partial Remission – on minimal therapy
Complete remission (CR) off-therapy may be regarded as a subset of sustained CR; a 
patient who achieves CR off-therapy may also achieve sustained complete remission.  
The four categories of CR on/off therapy and partial remission (PR) on/off therapy will be 
regarded as mutually exclusive events.  A patient will fall into the category that is the 
highest degree of remission obtained.
All remission endpoints will be derived using PDAIa, prednisone (or equivalent), 
treatment failure, or withdrawal date in the same manner as that used for sustained 
complete remission in Section 4.7.1.
4.7.3.5
Complete Remission
CR is defined as absence of new or established lesions on 0 mg/day prednisone or 
equivalent for at least 8 consecutive weeks.  Two categories of complete remission will 


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be evaluated: off-therapy and on minimal therapy.  A patient will be considered a 
complete responder if the following criteria are achieved and maintained for a minimum 
of 8 consecutive weeks:

CR off-therapy:  PDAIa0 and prednisone0 mg/day

CR on minimal therapy:  PDAIa0 and 0prednisone 10 mg/day
The number and percentage of patients achieving CR by Week 24 and Week 52 will be 
summarized descriptively.  A patient is considered a responder at a visit if they have 
demonstrated and maintained a response by that visit.
All data handling methods will follow those used for the derivation and classification of 
sustained complete remission.
4.7.3.6
Partial Remission
PR is defined as having transient lesions that heal within a week (as determined by no 
increase in PDAI total activity score between visits) for a minimum of 8 consecutive 
weeks.  Two categories of PR will be evaluated: off-therapy and on minimal therapy.  A 
patient will be considered a partial responder if the following criteria are achieved and 
maintained for a minimum of 8 consecutive weeks:

PR off-therapy: No increase in PDAI total activity score and prednisone0 mg/day

PR on minimal therapy: No increase in PDAI total activity score and 
0 prednisone 10 mg/day
The number of patients achieving PR by Week 24 and Week 52 will be summarized 
descriptively.
All data handling methods will follow those used for the derivation and classification of 
sustained complete remission.
4.7.3.7
Pemphigus Disease Area Index
The absolute value and change from baseline in PDAI score will be summarized by visit 
for each treatment arm.  Plots of mean total PDAI score over time will be produced.
The main method for dealing with missing PDAI data will be via imputation.  Details of 
PDAI imputation methods are described in Section 4.7.1.  Patients who receive rescue 
therapy will be analyzed up to the point of rescue; no imputation will be carried out for 
post-rescue data.
4.7.3.8
European Quality of Life 5-Dimension Questionnaire, 3-Level 
Version
The EuroQol 5-dimension questionnaire (EQ-5D) is a generic HRQoL measure used to 
generate a utility score for use in health economic modeling.  This self-reported 
questionnaire consists of two pages comprising the EQ-5D descriptive system and the
EuroQol visual analogue scale (EQ VAS).  The EQ-5D-3L descriptive system includes 


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three response options for each domain ranging from “no problems” to “extreme 
problems.”  The EQ-5D-3L comprises 5 dimensions of health on the following domains:

Mobility

Self-care

Usual activities

Pain/discomfort

Anxiety/depression
The EQ VAS records the respondent’s self-rated health status on a vertical graduated 
(0100) visual analogue scale.  The EQ-5D-3L will be converted to a single index utility 
score as per the EQ-5D-3L user guide (Version 4.0, Appendix 9).
Absolute values and change from baseline up to Week 52 in EQ-5D-3L single index 
utility score and the EQ VAS will be analyzed using summary statistics.  Plots may also 
be produced.
Additional post hoc analysis may be done, depending on requirements for economic 
modelling.
Missing data will be handled as per the EQ-5D-3L user guide.  Rescue data will be set to 
missing from the point of rescue onwards, no imputation will be made for rescue data.
4.7.3.9
Skindex-29 
The Skindex-29 is a HRQoL measure evaluating the impact of patients’ dermatologic 
condition over the previous 4 weeks.  The Skindex-29 consists of 30 questions on a 
5-point Likert-type scale ranging from “Never” to “All the time” and comprises the 
following four domains:

Emotions

Symptoms

Functioning

Treatment
The single item asking about treatment is not scored.  All other responses will be 
transformed to a linear scale (0100), with higher scores indicating higher impact of skin 
disease. Scores will be calculated per the Skindex Manual (Version 2.0 or later;
Appendix 10).
The mean and change from baseline global score will be summarized by visit and 
treatment group.  Plots may also be produced.


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The overall (global) score will be set to missing if more than 25% of the responses are 
missing.  Data for patients who rescue will be set to missing from the point of rescue 
onwards, no imputation will be made for rescue data.
4.7.3.10
Disease Control
The number and percentage of patients in a state of disease control will be summarized 
by visit up to Week 52.  Patients who receive rescue therapy will be considered as not in 
control from the point of rescue onwards, regardless of the recorded value on the eCRF.
4.7.4
Subgroup Analyses
The proportion of patients achieving complete and partial remission by Week 24 and 
Week 52, and sustained complete remission by Week 52 will be summarized 
descriptively for the following subgroups (summaries will only be carried out for 
subgroups where there is a minimum of 20% of patients from the overall population):

Gender (male, female)

Age (50 years, 50 years)

Region (North America, Rest of World)

Duration of illness (0 to 1 years, 1 to 2 years)

Baseline prednisone dose (60 or 80 mg/day by Day 1)

Site of disease (mucosal only, mucocutaneous, cutaneous only)

Baseline PDAIa score (quartiles)
Additional descriptive analyses for subgroups may be carried out, as required.
4.8
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
Serum rituximab concentrations will be listed by patient and nominal time of collection.  
Summary statistics of serum rituximab concentrations will be presented by nominal time 
of collection including n, mean, SD, coefficient of variation, geometric mean, median, 
and range.
Individual and mean serum rituximab concentration versus time profiles will be plotted on 
both linear and logarithmic scales.
A population PK analysis will be conducted to estimate the typical PK parameter values
and to characterize the between-patient variability of those parameters. The effect of 
several physiological covariates on between-patient variability will also be studied in this 
patient population.
Exploratory graphical and statistical techniques, including linear, nonlinear, and logistic 
regression, faceted group comparison plots, etc., will be used to explore potential 
relationships between treatment groups, and markers of rituximab exposure, safety, 


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and/or efficacy (e.g., peripheral CD19+ B-cell counts, ADA, and autoantibody 
concentrations).
Depending on the number of PK samples available from this study where the 
investigation of rituximab PK is an exploratory objective, the data may be pooled with 
data from previous studies.  Once the data is available and reviewed, a separate PK 
analysis plan may be drafted, if appropriate.
Full methodology will be documented with the final results of the analyses in a separate
report.
4.9
SAFETY ANALYSES
The safety analysis will be performed on the safety population as defined in
Section 4.1.3.  Analyses of safety data up to Week 52 will include rescue patients up to 
the point of rescue only.  Post-rescue data for patients who receive rescue therapy will 
be summarized separately for selected key safety outputs.
4.9.1
Exposure to Study Medication
The number and percentage of patients who received RTX will be summarized by 
treatment course, along with summary statistics for the dose of RTX received at each 
infusion and overall.  
Duration of rituximab exposure will be calculated as:
exposure date date of first rituximab infusion 1 where exposure date is the 
earliest of the following:
- Week 52 visit (using upper visit window of Day 364+10 days)
- Date of early withdrawal
RTX exposure data will be determined using the dosing information as recorded on the 
RTX administration log on the eCRF and the actual treatment received as per IxRS. 
Exposure to RTX will not include RTX given as rescue, which will be analyzed 
separately.
MMF exposure data will be determined using the dosing information as recorded on the 
MMF administration log on the eCRF and the actual treatment received as per IxRS.  
Exposure to MMF will be calculated as:
date of the last MMF administrationdate of the first MMF administration1
Exposure to MMF will not include MMF given as rescue, which will be analyzed 
separately.
The total cumulative dose will be calculated by summing the total daily dose over the
treatment duration.  Average daily dose will be calculated as:
total cumulative dosetreatment duration


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4.9.2
Adverse Events
Adverse events will be mapped and reported using the Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus using the most current version at the time of analysis 
(version 17.1 or later). Glossaries showing the mapping of investigator verbatim terms 
to coded events will be produced.
A listing of AEs occurring during screening (prior to Day 1) will be produced to capture 
AEs occurring during the oral corticosteroid taper.
Treatment-emergent AEs (TEAEs) will be summarized.  All AEs referenced in the 
section below will be TEAEs.  TEAEs are defined as those AEs with observed or 
imputed onset date on or after the start date of trial treatment. Only where the most 
extreme intensity is greater than the initial intensity (or if most extreme intensity is not 
missing and initial intensity is missing) will events with an onset date prior to the start of 
trial treatment be considered treatment-emergent.  An AE with a completely missing start 
date will be assumed to be treatment-emergent unless the AE has a complete 
non-imputed end date that is prior to study Day 1.
Listings will show all AEs reported, including AEs occurring after rescue therapy, and 
any AEs that may have occurred during the oral corticosteroid dose adjustments in the 
screening period.
AEs will be summarized by system organ class (SOC) and preferred term (PT), and will 
be presented in order of descending frequency summed across the treatment arms 
within each SOC and PT.
The following will be summarized, and/or listings produced where required:

AEs

Serious Adverse Events (SAEs)

AEs by relationship to study medication

AEs leading to study drug dose modification or interruption

AEs by common terminology criteria grade

Infections

Serious Infections

Corticosteroid-related AEs

Infusion related reactions (IRRs) (Roche Standard AE Grouped Term [AEGT]
MedDRA Basket)

Serious IRRs

AEs leading to withdrawal


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
AEs leading to death

Opportunistic infections (OI) , including serious OI (Roche Standard AE Grouped 
Term [AEGT] MedDRA Basket for Opportunistic Infections)
If an imbalance in exposure is found between treatment groups, AE rates per 
100 patient-years exposure may be calculated.  AE rate per 100 patient-years is defined 
as:
(number of eventstotal exposure)100
The 95% CIs will be calculated based on exact Χ2 distribution.
4.9.3
Deaths
Details of any deaths will be presented in the form of an individual patient listing.
4.9.4
Laboratory Data
4.9.4.1
Safety Laboratory Parameters
All laboratory data will be converted to SI units.  The Safety Laboratory Data 
Standardization will be used to implement reference ranges and marked abnormalities 
for laboratory data where possible.
Summary statistics for the absolute and change from baseline values will be produced 
by visit for laboratory parameters.
Marked abnormalities will be summarized for laboratory parameters.  Summaries by 
National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) grade will also be produced for lab assessments, including shift tables 
from baseline to highest grade post-baseline.
Shift tables from baseline to highest NCI-CTCAE grade post-baseline will be produced 
for liver function laboratory tests.
Positive pregnancy results will be listed, as identified using the serum test results, 
where the data will be taken from CRF “pregnancy report” page.
4.9.4.2
Immunoglobulins
The absolute values and change from baseline will be summarized by treatment group 
and visit for total Ig, IgA, IgG, and IgM.
The proportion of patients with a value of total Ig, IgA, IgG, and IgM which is less than 
the lower of limit of normal per visit will be produced.
A plot of the mean value over time will be produced for total Ig, IgA, IgG, and IgM.  The 
plots will display error bars (meanstandard deviation) around the mean.


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4.9.4.3
Lymphocyte Populations
The following NK, T and B lymphocytes will be analyzed via flow cytometry:

CD19

CD3

CD4

CD8

Naïve B cells (CD19CD27-)

Transitional B cells (CD24highCD38high

Memory B cells (CD19 CD27 

NK cells (CD56
The absolute, change and percent change from baseline values will be summarized by 
visit and treatment group for the above lymphocyte populations.
The proportion of patients with a lymphocyte value less than the lower limit of normal by
visit and treatment group will be produced for the following lymphocytes:

CD3

CD4

CD8

CD19
A plot of the mean and median values over the 52-week treatment period will be 
produced for the following:

CD19

CD3

CD4

CD8
Plots will display error bars (meanstandard deviation) around the mean.
Patients who received rituximab rescue therapy will be analyzed separately.
4.9.4.4
Desmoglein-1 and Desmoglein-3 Autoantibody Titers
Plots of mean anti-Dsg1 and anti-Dsg3 titers over the 52-week treatment period will be 
produced by treatment group, along with summary statistics.  Listings will include 
positive/negative status.
Patients who received rituximab rescue therapy will be analyzed separately.


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4.9.4.5
Anti-Drug Antibodies
The proportion of patients that are ADA (anti-rituximab antibodies [referred to as 
HACA in the protocol]) positive/negative at each visit will be summarized by 
treatment group.  A listing of ADA results will be produced.
Depending on patient counts, subgroup analyses on ADA positive patients may be 
carried out on key safety and efficacy variables.  Such analyses may include AEs, SAEs, 
IRRs, CD19, and remission endpoints before/after ADA positivity.
4.9.5
Vital Signs
Vital signs are measured at baseline, Week 52, and at infusion visits immediately prior to 
an infusion and then every 30 minutes until the end of the infusion. 
Summary tables for the absolute value and change from baseline in vital sign 
assessments will be presented by visit up to Week 52.  Abnormal results will also be 
summarized. Vital sign assessments include respiratory rate, pulse rate, temperature, 
systolic and diastolic blood pressure.  Body weight will be measured at baseline, 
Week 24, and Week 52.  Body mass index will be calculated for these time points.
4.10
DATA HANDLING METHODS
4.10.1
Presentation of Data
Data displays include listings, tables, and plots.  All data displays will be presented by 
treatment group.
Data presented in summary tables will be displayed using summary statistics.  
Continuous data will include number of patients, mean, standard deviation, median, 
minimum, and maximum.  Categorical data will include the number and percentage of 
patients.
4.10.2
Definitions
Baseline
Baseline is defined as the last non-missing value prior to receipt of study treatment.  
Typically, baseline will be the pre-dose Day 1 assessment, but may include screening 
results if the pre-dose Day 1 result is not available or missing.  If the Day 1 or screening 
result is missing then no imputation will be made and the baseline result will be set to 
missing. 
Study Day
For each patient, the first day of study treatment will be designated study day 1.  Each 
subsequent assessment will be assigned a study day calculated as:
date of assessmentdate of first dose1


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4.10.3
Multiple Values
For summaries displayed by visit, multiple values for a given assessment within a time 
window will be handled as follows:
Safety and Efficacy
The nearest non-missing value to the nominal timepoint will be assigned to the visit.  If 
two values are equidistant from the nominal timepoint then the latest value will be 
selected.
4.10.4
Missing Data
Methods for handling missing data for efficacy analyses are described in detail 
throughout Section 4.7.  Missing or partial dates for AEs, concomitant medications 
(except oral corticosteroids), laboratory assessments, and medical history will be 
imputed as detailed in Appendix 11.
4.11
INTERIM ANALYSES
No efficacy interim analyses are planned.


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5.
REFERENCES
Basra MK, Salek MS, Camilleri L, Sturkey R, et al. Determining the minimal clinically 
important difference and responsiveness of the Dermatology Life Quality Index 
(DLQI): further data. Dermatology. 2015;230(1):27-33.
Beissert S, Mimouni D, Kanwar AJ, et al. Treating Pemphigus Vulgaris with Prednisone 
and Mycophenolate Mofetil: A Multicenter, Randomized, Placebo-Controlled Trial, 
Journal of Investigative Dermatology, 2010;130(8):2041-8.
Yan X, Lee S, Li N. Missing Data Handling Methods in Medical Device Clinical Trials, 
Journal of Biopharmaceutical Statistics, 2009;19(6):1085-98.
Finlay AY, Khan G. Dermatology Life Quality Index (DLQI)—a simple practical measure 
for routine clinical use. Clinical and experimental dermatology. 1994 May
1;19(3):210-6.
Van den Broek J. A score test for zero inflation in a Poisson distribution. Biometrics. 
1995 Jun 1:738-43.


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Appendix 1 Protocol Synopsis
PROTOCOL SYNOPSIS
TITLE:
A RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, 
ACTIVE-COMPARATOR, MULTICENTER STUDY TO EVALUATE 
THE EFFICACY AND SAFETY OF RITUXIMAB VERSUS MMF IN 
PATIENTS WITH PEMPHIGUS VULGARIS
PROTOCOL NUMBER:
WA29330
VERSION NUMBER:
5
EUDRACT NUMBER:
2014-000382-41
IND NUMBER:
121595
TEST PRODUCT:
Rituximab (RO 0452294)
PHASE:
III
INDICATION:
Moderate-to-severely active pemphigus vulgaris
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
Efficacy Objectives
The primary efficacy objective for this study is as follows:

To evaluate the efficacy of rituximab compared with mycophenolate mofetil (MMF) in 
achieving sustained complete remission, evaluated by the Pemphigus Disease Area Index
(PDAI; see Section 3.4.1.1), and assessed at Week 52 in patients with 
moderate-to-severely active pemphigus vulgaris (PV)
The secondary efficacy objectives for this study are as follows:

To evaluate the efficacy of rituximab compared with MMF, as measured by the time to 
disease flare, the duration of sustained complete remission, the total number of disease 
flares during the treatment period, and the time to initial sustained complete remission

To assess corticosteroid exposure over 52 weeks 

To assess the effect of rituximab compared with MMF on health-related quality of life 
(HRQoL), as measured by the Dermatology Life Quality Index (DLQI) 

To assess the effect of rituximab compared with MMF on patients’ impression of PV 
symptoms, as measured by the Patient Global Impression of Change (PGIC) questionnaire

To assess the effect of rituximab compared with MMF on clinician impression of patients’
PV symptoms, as measured by the Clinician Global Impression of Change (CGIC) 
questionnaire
Safety Objectives
The safety objectives for this study are as follows:

To evaluate the safety of rituximab compared with MMF, with a focus on AEs and safety 
laboratory values

To evaluate corticosteroid-related AEs in relation to corticosteroid exposure


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Appendix 1 Protocol Synopsis (cont.)
Exploratory Objectives
The exploratory objectives for this study will include, but are not limited to, the following:

To evaluate the efficacy of rituximab compared with MMF, as measured by the proportion of 
patients achieving complete or partial remission by 24 weeks and 52 weeks

To explore the pharmacokinetics and pharmacodynamics of rituximab, and the 
pharmacodynamics of MMF, in patients with PV

To evaluate the effect of rituximab as compared with MMF on the change in PDAI activity 
score

To evaluate the effect of rituximab as compared with MMF on anti-desmoglein (anti-Dsg) 
autoantibody titers (anti-Dsg1 and anti-Dsg3) and other mechanistic studies of interest in 
patients with PV

To assess the effect of rituximab compared with MMF on health utilities as measured by the 
European Quality of Life (EuroQol) 5-Dimension Questionnaire, 3-level version (EQ-5D-3L)

To assess the effect of rituximab compared with MMF on HRQoL, as measured by the 
Skindex-29 

To evaluate the efficacy of rituximab compared with MMF, as measured by the proportion of 
patients experiencing treatment failure from Week 12 to Week 52
Study Design
Description of Study
This is a Phase III, randomized, double-blind, double-dummy, active-comparator, parallel-arm, 
multicenter study to evaluate the efficacy and safety of rituximab compared with MMF in 
patients with moderate-to-severely active PV requiring 60120 mg/day oral (PO) prednisone or 
equivalent (1.0-1.5 mg/kg/day).  Patients must have a confirmed diagnosis of PV within the 
previous 24 months (by skin or mucosal biopsy and immunohistochemistry) and evidence of 
moderate-to-severely active disease at screening (defined as at total PDAI activity score of 15).
This international study will be conducted at investigational sites throughout North America, 
Europe, the Middle East, and Latin America.  It is expected that approximately 60 centers will 
participate.  Approximately 132 patients will be randomized in a 1:1 ratio to receive either 
rituximab plus MMF placebo or rituximab placebo plus MMF.  Randomization will be stratified by 
duration of illness (newly diagnosed [i.e., diagnosed within the 1 year prior to screening] vs. 
diagnosed greater than 1 year) and geographical region (North America [U.S./Canada] vs. rest 
of world). 
The study will consist of three periods:  a screening period of up to 28 days, a 52-week 
double-blind treatment period, and a 48-week safety follow-up (SFU) period that begins at the 
time of study treatment completion or discontinuation. 
Rituximab (1000 mg or matching placebo) will be administered by intravenous (IV) infusion on 
Day 1 and Day 15, with repeat rituximab (or matching placebo) administration on Day 168 and 
Day 182 provided specific safety criteria have been met (see Section 4.6.4).  MMF (500 mg or 
matching placebo) will be administered PO twice daily (every 12 hours [Q12H]), starting with a 
total dose of 1 g/day on Day 1.  The MMF dose will be titrated to achieve a goal of 2 g/day in 
divided doses (1 g Q12H) by Week 2.  Treatment with MMF (or matching placebo) will continue 
through Week 52.  
All patients who withdraw from the treatment period or who complete the total 52-week 
treatment period must return for post Week 52 SFU assessments at 12, 24, 36, and 48 weeks 
after either the early withdrawal visit or study treatment completion, respectively. Thus, patients 
will be followed for approximately 1 year in the SFU period. 


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Appendix 1 Protocol Synopsis (cont.)
Telemedicine
For a small proportion of patients (approximately 10 patients) at one investigational site, the 
Sponsor is proposing the use of telemedicine (TM) consultation visits between the patient and 
the Principal Investigator to make the trial more accessible to this population of patients with a 
rare disease.  The local dermatologist, a research nurse, and other medical personnel in the 
patient’s immediate vicinity will participate throughout the trial as needed.  Data collected via TM 
will be in accordance with the American Telemedicine Association 2012 Guidelines for 
Teledermatology (ATA 2012).  The software platform to be used in the trial will allow efficient, 
high-quality data collection of all relevant clinical data (including the images of the skin and 
mucosa, prior medical records, notes, and laboratory tests) for easy and reliable review by the 
Principal Investigator.  This type of assessment has become the standard for TM clinical care 
for the diagnosis and treatment of both mild and severe types of skin diseases.  Images will be 
time-stamped and stored in a Health Insurance Portability and Accountability Act 
(HIPAA)-compliant advanced TM platform adapted for this specific trial use.  Other safety and 
efficacy data sets will be transmitted through the TM platform to the Principal Investigator as 
well.  The local dermatologist or other local primary care doctors may still provide 
standard-of-care services that do not require training on the protocol or investigational drug.  All 
clinical trial-related medical decisions will be made by the Principal Investigator and or safety 
assessor.
Number of Patients
Approximately 132 patients with active moderate-to-severely active PV will be recruited into 
this study. 
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Age 1875 years

Signed Informed Consent Form

First confirmed diagnosis of PV within the previous 24 months, based on the presence of
histological features of acantholysis via skin or mucosal biopsy and one of the following:  
tissue-bound immunoglobulin G (IgG) antibodies by direct immunofluorescence on the 
surface of affected epithelium or serological detection of serum Dsg3 autoantibodies 
against epithelial cell surface either by indirect immunofluorescence microscopy or by 
enzyme-linked immunosorbent assay

Presence of moderate-to-severely active disease, defined as overall PDAI activity score of
15

Receiving standard-of-care corticosteroids consisting of 60120 mg/day PO prednisone or 
equivalent (1.01.5 mg/kg/day) and, in the judgment of the investigator, expected to benefit 
from the addition of immunosuppressive therapy

For women who are not postmenopausal (12 months of nontherapy-induced amenorrhea) 
or surgically sterile (absence of ovaries and/or uterus):  agreement to remain abstinent or 
use two effective methods of contraception, including at least one method with a failure rate 
of 1% per year, during the treatment period and for at least 12 months after the last dose 
of study treatment  
Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.
Barrier methods must always be supplemented with the use of a spermicide.
Examples of contraceptive methods with a failure rate of 1% per year (highly effective 
contraceptive methods) include tubal ligation, male sterilization, hormonal implants, 
established, proper use of combined oral or injected hormonal contraceptives, and 
certain intrauterine devices.


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Appendix 1 Protocol Synopsis (cont.)

For men (including those who have undergone a vasectomy): agreement to remain 
abstinent or use a condom during the treatment period and for at least 12 months after the 
last dose of study treatment and agreement to refrain from donating sperm during this same 
period
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.
In addition to male contraception, agreement to advise female partners of childbearing 
potential to use highly effective contraception during the study and for at least 12 months 
after the last dose of study treatment

Agreement to avoid excessive exposure to sunlight during study participation

Able to comply with the study protocol, in the investigator’s judgment
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Diagnosis of pemphigus foliaceus or evidence of paraneoplastic pemphigus or other 
non-PV autoimmune blistering disease

History of a severe allergic or anaphylactic reaction to humanized or murine monoclonal 
antibodies, or known hypersensitivity to any component of rituximab

Known hypersensitivity or contraindication to MMF, mycophenolic acid, polysorbate, or oral 
corticosteroids

Lack of peripheral venous access

Pregnant or lactating, or intending to become pregnant during the study
Women who are not postmenopausal (12 months of nontherapy-induced amenorrhea) 
or surgically sterile must have two negative results with a sensitivity of 25 mIU/mL:  one
from a serum pregnancy test at Day 8 to Day 10 of screening and another from a 
urine pregnancy test at Day 1 prior to randomization.

Participated in another interventional clinical trial within 28 days prior to randomization

Use of any investigational agent within 28 days or 5 elimination half-lives prior to 
randomization (whichever is the longer)

Significant cardiovascular or pulmonary disease (including obstructive pulmonary disease)

Evidence of any new or uncontrolled concomitant disease that, in the investigator’s 
judgment, would preclude patient participation, including but not limited to nervous system, 
renal, hepatic, endocrine, malignant, or gastrointestinal disorders 

Any concomitant condition that required treatment with oral or systemic corticosteroids 
within 12 weeks prior to randomization

Treatment with IV immunoglobulin (Ig), plasmapheresis, or other similar procedure within 
8 weeks prior to randomization

Treatment with immunosuppressive medications (e.g., azathioprine, MMF) within 1 week 
prior to randomization

Treatment with cyclophosphamide within 12 weeks prior to randomization

History of or currently active primary or secondary immunodeficiency, including known 
history of HIV infection and other severe Immunodeficiency blood disorders 

Known active infection of any kind (excluding fungal infections of nail beds) or any major 
episode of infection requiring hospitalization or treatment with IV anti-infectives within 
4 weeks prior to screening, or completion of oral anti-infectives within 2 weeks prior to 
randomization
Entry into this study may be reconsidered once the infection has fully resolved.


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Appendix 1 Protocol Synopsis (cont.)

History of or current cancer, including solid tumors, hematologic malignancies, and 
carcinoma in situ (except basal cell carcinoma and squamous cell carcinoma of the skin 
that have been excised and cured)

Currently active alcohol or drug abuse, or history of alcohol or drug abuse within 24 weeks 
prior to screening

Major surgery within 4 weeks prior to randomization, excluding diagnostic surgery

Treatment with rituximab or a B celltargeted therapy (e.g., anti-CD20, anti-CD22, or 
anti-BLyS) within 12 months prior to randomization

Treatment with a live or attenuated vaccine within 28 days prior to randomization
It is recommended that a patient’s vaccination record and the need for immunization 
prior to study entry be carefully investigated.

Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or amylase 2.5 the 
upper limit of normal (ULN)

Absolute neutrophil count (ANC) 1.5103/L 

Hemoglobin 8.0 g/dL

Positive test results for hepatitis B surface antigen (HBsAg), hepatitis B core antibody 
(HBcAb), or hepatitis C virus (HCV) serology at screening
Length of Study
Based on study enrollment projections, this study is estimated to take approximately 4 years to 
complete, from first patient in to last patient’s last visit (LPLV), when the final patient completes 
the 48-week SFU period.
End of Study
The end of the study is defined as the date when the LPLV occurs.  LPLV is expected to occur 
approximately 2 years after the last patient is enrolled, assuming a 52-week treatment period 
and a 48-week SFU period for the last patient.
Outcome Measures
Primary Efficacy Outcome Measure
The primary efficacy outcome measure for this study is as follows:

Proportion of patients (excluding TM patients) who achieve a sustained complete remission 
without experiencing an event that constitutes treatment failure (as defined in Section 3.1.3), 
as measured at Week 52
Sustained complete remission is defined as achieving healing of lesions with no new 
active lesions (i.e., PDAI activity score of 0) while on 0 mg/day prednisone or equivalent, 
and maintaining this response for a total of at least 16 consecutive weeks, during the 
52-week treatment period. 
Patients with transient new lesions for 1 week or less that heal without additional 
systemic corticosteroid therapy will not be considered to have experienced treatment 
failure.
Secondary Efficacy Outcome Measures
The secondary efficacy outcome measures are as follows:

Cumulative oral corticosteroid dose (prednisone or equivalent) over the treatment period

Total number of disease flares during the treatment period 

Time to sustained complete remission

Time to disease flare 

Disease flare is defined as the appearance of three or more new lesions a month that 
do not heal spontaneously within 1 week or by the extension of established lesions in a 
patient who has achieved disease control.

Change in HRQoL, as measured by the DLQI score from baseline to Week 52


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Appendix 1 Protocol Synopsis (cont.)

Duration of sustained complete remission

Patients’ impression of change in PV symptoms, as measured by the PGIC score during the 
treatment period

Clinician impression of change in patients’ PV symptoms, as measured by the CGIC score 
during the treatment period
Safety Outcome Measures
The safety outcome measures include, but are not limited to, the following:

Nature, frequency, and severity of adverse events, including serious adverse events and 
adverse events leading to discontinuation

Vital signs and clinical laboratory test results (including complete blood count and blood 
chemistry) 

Incidence of human antichimeric antibody (HACA)

Circulating B cells, T cells, natural killer (NK) cells, plasma cells, and other leukocytes  

Plasma Ig levels (total Ig, IgG, IgM, and IgA)  

Corticosteroid-related adverse events in relation to corticosteroid exposure
Exploratory Outcome Measures
The exploratory outcome measures for this study will include, but are not limited to, the 
following:

Proportion of patients achieving a complete remission by Week 24 and by Week 52
Complete remission is defined as achieving wound healing with no new active lesions 
(i.e., PDAI activity score of 0) for at least 8 consecutive weeks during the 52-week 
treatment period.  

Proportion of patients achieving a partial remission by Week 24 and by Week 52
Partial remission is defined as the presence of transient new lesions that heal within 
1 week (while the patient is receiving minimal therapy, including topical corticosteroids).  
Minimal therapy is defined as 10 mg/day prednisone (or equivalent) for at least 
8 consecutive weeks during the 52-week treatment period.

Pharmacokinetics (PK)/pharmacodynamics (PD) of rituximab
PK/PD parameters include, but are not limited to, serum levels of rituximab, peripheral 
CD19B-cell counts, HACA, and autoantibody concentrations. 

To explore the pharmacodynamics of MMF in patients with PV

Change in total PDAI activity score during the treatment period

Change from baseline in anti-Dsg1 and anti-Dsg3 autoantibodies

Change in health utilities as assessed by the EQ-5D-3L score from baseline to Week 52 

Change in HRQoL as measured by the Skindex-29 from baseline to Week 52
Investigational Medicinal Products
Test Product-Rituximab
Patients randomized to the rituximab arm will receive treatment with 1000 mg IV rituximab (or 
matching placebo) on Day 1 and Day 15, with repeat rituximab (or matching placebo) 
administration on Day 168 and Day 182 provided specific safety criteria have been met (see 
Section 4.6.4).
Comparator-MMF
Patients randomized to the MMF arm will receive treatment with 500 mg MMF (or matching 
placebo) administered orally twice daily (Q12H) starting on Day 1.  MMF dose will then be 
titrated to achieve a maximum dose goal of 2 g/day given as a divided oral dose (1 g Q12H) by 
Week 2.  Slower titration will be allowed on the basis of tolerability.  Treatment with MMF
(or matching placebo) will continue through Week 52.


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Appendix 1 Protocol Synopsis (cont.)
Non-Investigational Medicinal Products
In order to reduce the frequency and severity of infusion-related reactions, all patients will 
receive methylprednisolone 100 mg or saline solution prior to infusion of rituximab or rituximab 
placebo, respectively.  This premedication will be administered by slow IV infusion, and 
administration should be completed at least 30 minutes prior to infusion of rituximab or rituximab 
placebo.  
All patients should be premedicated with paracetamol/acetaminophen (1 g PO) and an 
antihistamine (diphenhydramine HCl 50 mg PO [or IV equivalent] or equivalent dose of a similar 
agent, or in accordance with local approved labeling) 30 to60 minutes prior to the start of the 
infusion of rituximab or rituximab placebo.
Statistical Methods
Primary Analysis
The proportion of patients (excluding TM patients) achieving a sustained complete remission 
(as defined in Section 3.4.1.1) in the rituximab and MMF arms will be compared using a 
stratified Cochran-Mantel-Haenszel test, adjusting for randomization stratification variables.  
Results will be summarized descriptively by treatment arm and expressed as proportions, 
corresponding adjusted 95% confidence intervals of the difference between response rates, and 
p-values.
Patients who meet the pre-specified definitions of treatment failure before entering sustained 
complete remission (as defined in Section 3.1.3) will be deemed non-responders in the primary 
analysis.  
Determination of Sample Size  
The primary efficacy endpoint of this study is the proportion of patients (excluding TM patients)
achieving a sustained complete remission, as assessed at Week 52, that has been maintained 
for 16 consecutive weeks during the 52-week treatment period.  With use of limited data 
available in the literature from randomized clinical trials of MMF and investigator-initiated trials 
of rituximab, it is estimated that approximately 40% of patients with PV receiving MMF will 
achieve a sustained complete remission.  It is estimated that patients receiving rituximab will 
induce a sustained complete remission rate of 65%. On the basis of these assumptions, a total 
of 122 patients randomized to the rituximab arm or the MMF arm in a 1:1 ratio (61 patients in 
the rituximab arm and 61 patients in the MMF arm) will yield approximately 80% power in a 
two-sided test at the 5% significance level.  To account for the 10 TM patients excluded from 
the primary efficacy analysis, approximately 132 patients will be randomized in total.
No adjustment will be made to account for dropouts.




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Appendix 3 Schedule of Assessments
Week
Screen
(28 to 
1)
1
2
4
8
12
16
20
24
26
32
40
48
52
WD a
SFU b
Day
1 (BL 
and Rz)
15
1
28
3
56
3
84
3
112
3
140
3
168
3
182
1
224
3
280
3
336
3
364
3
Informed consent
x
Medical history, c
previous 
medications, and 
baseline conditions
x
Pregnancy test 
(serum) d
x
Pregnancy test 
(urine) d
x
x
x
x
x
x
x
x
x
x
x
x
Complete physical 
examination e
x
Body weight
x
x
x
x
Height
x
Vital signs f
x
x g
x g
x g
x g
x
x
ECG
x
CXR h
x
Efficacy and PRO/ClinRO
Disease activity 
(PDAI) 
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Flare assessment
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


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Appendix 3 Schedule of Assessments (cont.)
Week
Screen
(28 to 
1)
1
2
4
8
12
16
20
24
26
32
40
48
52
WD a
SFU b
Day
1 (BL 
and Rz)
15
1
28
3
56
3
84
3
112
3
140
3
168
3
182
1
224
3
280
3
336
3
364
3
DLQI i
x
x
x
x
x
x
x
PGIC i
x
x
x
x
x
x
CGIC i
x
x
x
x
x
x
EQ-5D-3L i
x
x
x
x
x
x
Skindex-29 i
x
x
x
x
x
x
x
Prednisone (or 
equivalent) dose 
assessment/ 
adjustment j
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Safety and Routine Laboratory Assessments
Adverse events k
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x l
Concomitant 
medications
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x l
Hematology m
x
x n
x n
x
x
x
x n
x n
x
x
x
x
x
Blood chemistry o
x
x n
x n
x
x
x
x n
x n
x
x
x
x
x
HBsAg, HBcAb, and 
HCV antibody
x
Urinalysis p
x
x
x
x
x
x
x
x


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Appendix 3 Schedule of Assessments (cont.)
Week
Screen
(28 to 
1)
1
2
4
8
12
16
20
24
26
32
40
48
52
WD a
SFU b
Day
1 (BL 
and Rz)
15
1
28
3
56
3
84
3
112
3
140
3
168
3
182
1
224
3
280
3
336
3
364
3
Immunology and Other Labs
Lymphocyte 
subtypes and FACS 
panel q
x n
x n
x
x
x
x n
x n
x
x
x
x
Quantitative Ig r
x
x
x
x
x
x
Autoantibodies s
x
x
x
x
x
x
x
HACA
x
x
x
x
x
PK samples 
x t
x t
x
x
x
x t
x t
x
x
x
x
x
Optional serum
biomarker sample 
for RCR
x u
x
x
x
x u
x u
x
x
Optional whole 
blood sample (RNA) 
for RCR
x u
x
x
x
x u
x u
x
x
Optional whole 
blood sample (DNA) 
for RCR v
x


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Appendix 3 Schedule of Assessments (cont.)
Week
Screen
(28 to 
1)
1
2
4
8
12
16
20
24
26
32
40
48
52
WD a
SFU b
Day
1 (BL 
and Rz)
15
1
28
3
56
3
84
3
112
3
140
3
168
3
182
1
224
3
280
3
336
3
364
3
Study Treatment Dispensed
Methylprednisolone/ 
saline solution 
premedication w
x
x
x
x
Rituximab/matching 
placebo x
x y
x
x
x
MMF/matching 
placebo z
x
x
x
x
x
x
x
x
x
x
x
ALT alanine aminotransferase; AST aspartate aminotransferase; BLbaseline; BUNblood urea nitrogen; CGICClinician Global Impression 
of Change; ClinRO clinician-reported outcomes; CXRchest X-ray; DLQIDermatology Life Quality Index; Dsg1desmoglein 1; 
Dsg3desmoglein 3; ECG electrocardiogram; eCRF electronic Case Report Form; EQ-5D-3LEuroQol 5-Dimension Questionnaire, 
three-level version; FACSfluorescence-activated cell sorting; HACAhuman anti-chimeric antibodies; HBcAghepatitis B core antibody; 
HBsAghepatitis B surface antigen; HCVhepatitis C virus; Igimmunoglobulin; IVintravenous; LDHlactate dehydrogenase; 
MMFmycophenolate mofetil; PDAIPemphigus Disease Area Index; PGICPatient Global Impression of Change; PKpharmacokinetic;
PROpatient-reported outcome; Q12Hevery 12 hours; RBCred blood cell; RCRRoche Clinical Repository; Rzrandomization; SFU safety 
follow-up; WBCwhite blood cell; WDwithdrawal visit.
Notes:  All assessments and laboratory sampling should be performed within 3 days of the scheduled visit, unless otherwise specified.  On 
treatment days, all assessments should be performed prior to dosing, unless otherwise specified.
a Patients who discontinue both study treatments early, and patients who experience treatment failure (as defined in Section 3.1.3) before 
Week 12, will be asked to return to the clinic for a treatment WD visit.  If a patient withdraws at or during a scheduled or unscheduled visit, the 
visit should proceed as the withdrawal visit, that is, only the withdrawal visit assessments should be conducted.  After the withdrawal visit, the 
patient will be asked to enter the SFU period of the study.  An early withdrawal visit is not required for a patient to receive rescue therapy
between Week 12 through Week 52, and patients should continue to be followed in the 52-week treatment period.
b Safety follow-up required at 12, 24, 36, and 48 weeks ( 1 week) after withdrawal from or completion of treatment (see Appendix 2- Schedule 
of Assessments for the Safety Follow-Up Period of protocol for Study WA29330).  Required follow-up information will be collected every 
3 months or until death, loss to follow-up, or study termination by the Sponsor.


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Appendix 3 Schedule of Assessments (cont.)
c Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, smoking history, use of alcohol and drugs of abuse, and all previous medications (e.g., prescription drugs, over-the-counter drugs, 
herbal or homeopathic remedies, nutritional supplements) used by the patient within 6 months prior to the screening visit.
d All women who are not postmenopausal (12 months of nontherapy-induced amenorrhea) or surgically sterile will have a serum pregnancy 
test at screening.  Urine pregnancy tests will be performed at specified subsequent visits.  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test.  Prior to starting study drug, female patients of childbearing potential must have two negative pregnancy 
tests.  The second test on Day 1 prior to randomization should be performed 8 to 10 days after the first test during the screening period.
e Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurologic systems.  Record abnormalities observed at baseline on the eCRF.  Record new or worsened 
clinically significant abnormalities on the Adverse Event eCRF.
f
Includes respiratory rate, pulse rate, temperature, and systolic and diastolic blood pressure while the patient is in a seated position.
g Vital signs should be taken immediately prior to infusion and then every 30 minutes until completion of the rituximab or rituximab placebo 
infusion.
h If screening chest radiographs taken within the past 3 months show no clinically significant abnormality, further radiographic assessment is not 
required.
i
The DLQI, PGIC, EQ-5D-3L, and Skindex-29  will be completed by the patient before any other non-PRO assessments and before the patient 
receives any disease-status information or study drug during that visit.  The CGIC, where possible, will be completed prior to the completion of 
other non-PRO assessments.
j
To be captured on the eCRF.
k After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  In addition, any adverse events occurring during any corticosteroid dose adjustment during the screening 
period should be reported. 
l
See Appendix 2 (Schedule of Assessments for the Safety Follow-Up Period) of protocol for Study WA29330.
m Includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, and other cells).
n Samples to be collected prior to administration of IV methylprednisolone or saline solution and 30 minutes following completion of rituximab or 
rituximab placebo infusion, respectively.
o Includes sodium, potassium, chloride, bicarbonate, glucose (except at 30 minutes following completion of study drug infusion at Weeks 1, 2, 24, 
and 26), BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total and direct bilirubin, alkaline phosphatase, ALT, AST, uric 
acid, and LDH.
p Dipstick for blood, protein, and glucose (microscopic examination at central laboratory if abnormal and applicable).


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Appendix 3 Schedule of Assessments (cont.)
q See Section 4.5.6 for T- and B-cell assessments.
r Total Ig, IgG, IgA, and IgM.
s Anti-Dsg1 and anti-Dsg3 antibodies.
t
On infusion days, PK samples will be collected prior to administration of IV methylprednisolone or saline solution and 30 minutes following 
completion of rituximab or rituximab placebo infusion, respectively.
u Samples to be collected prior to administration of IV methylprednisolone or saline solution for patients in the rituximab or rituximab placebo 
arms, respectively. 
v The optional DNA sample can be collected prior to or after study drug administration.
w Methylprednisolone or saline solution should be administered by slow IV infusion to be completed at least 30 minutes prior to each infusion of 
rituximab or rituximab placebo, respectively.
x Rituximab at a dose of 1000 mg (or matching placebo) will be administered by IV infusion on Day 1 and Day 15, with repeat rituximab (or 
matching placebo) administration on Day 168 and Day 182 provided specific safety criteria have been met (see Section 4.6.4).  See Appendix 3
(Procedures for the Intravenous Administration of Rituximab) of protocol for Study WA29330 for administration instructions.
y Administration of the first dose of study treatment (Day 1) should occur within 24 hours following the baseline assessments; however, 
administration up to 72 hours will be allowed when necessary.  The second infusion should occur on Day 15 1 day.
z MMF (500 mg or matching placebo) will be administered orally twice daily (Q12H) starting on Day 1.  Patients will be initiated on MMF at 
1 g/day or matching placebo in divided oral doses (Q12H).  The MMF dose will be titrated to achieve a goal of 2 g/day in divided oral doses (1 g 
Q12H) by Week 2.


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Appendix 4 Corticosteroid Treatment Guideline
Step
No. of Weeks
Daily Dose of 
Prednisone or 
Equivalent
Presence of Disease Activity a
No
Yes
1 (start) b
1 week
80 mg
Go to Step 2
Go to Step A
A
1 week
120 mg
Go to Step 2
Go to Step B
B
1 week
240 mg
Go to Step A
Discontinue taper c
2 (start) b
1 week
60 mg
Go 1 step forward
Go to Step 1
3
1 week
40 mg
Go 1 step back
4
2 weeks
30 mg
5
2 weeks
20 mg
Go 2 steps back
6
2 weeks
15 mg
7
2 weeks
12.5 mg
8
2 weeks
10 mg
9
2 weeks
7.5 mg
10
2 weeks
5 mg
11
2 weeks
2.5 mg
Stop corticosteroid
12
During complete 
remission
0 mg
Restart at Step 5
Notes:  On Day 1, start the oral corticosteroid regimen with an initial dosage of 60 or 
80 mg/day prednisone (or equivalent), as outlined in the schedule.  Increase the dose if 
disease activity is present after 1 week.  If necessary, increase the dose again (to 240 mg/day) 
if disease activity is still present after the second week.
a Disease activity is defined as the appearance of new lesions or the extension of established 
lesions.
b Patients on 80 mg/d on Day 1 will start at Step 1.  Patients on 60 mg/d on Day 1 will start at 
Step 2.
c Patients whose disease is not controlled after increasing the corticosteroid dose to 
240 mg/day will be considered to have experienced treatment failure and may receive 
standard-of-care treatment per the investigator’s best medical judgment.
Source:  Modified from Mentink LF, Mackenzie MW, Tóth GG, et al. Randomized controlled 
trial of adjuvant oral dexamethasone pulse therapy in pemphigus vulgaris (PEMPULS Trial). 
Arch Dermatol 2006;142:5706.






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Appendix 5 Pemphigus Disease Area Index (cont.)
The Pemphigus Disease Area Index (PDAI) lesion counts (number of lesions3) for the 
Skin and Mucous membrane are assigned a score used in calculating the Total Skin and 
Total Mucosa Activity scores, respectively, when the anatomical location activity score 
is 1 or 2.
Skin
When an anatomical location is scored a 1 (13 lesions, up to one2 cm in any 
diameter, none6 cm), record the number of lesions at that site, ranging from 
13 lesions.  Incorporate the lesion count into the scoring by giving each location a 
score of 1 if 1 lesion is present, a score of 1.3 if 2 lesions are present, and a score of 1.6 
if 3 lesions are present.
When an anatomical location is scored a 2 (23 lesions, at least two2 cm diameter, 
none6 cm), record the number of lesions at that site, ranging from 23 lesions.  
Incorporate the lesion count into the scoring by giving each location a score of 2 if 
2 lesions are present and a score of 2.3 if 3 lesions are present.
Skin 
anatomical location activity score
Number of lesions if 3
Final score
1
(13 lesions, up to one 2 cm in any 
diameter, none 6 cm)
1
1
2
1.3
3
1.6
2
(23 lesions, at least two 2 cm diameter, 
none 6 cm)
2
2
3
2.3
Mucous Membrane
When an anatomical location is scored a 1 (1 lesion), record the number one for number 
of lesions at that site.  Incorporate the lesion count into the scoring by giving each 
location a score of 1 when 1 lesion is present.
When an anatomical location is scored a 2 (23 lesions), record the number of lesions 
at that site, ranging from 23 lesions.  Incorporate the lesion count into the scoring by 
giving each location a score of 2 if 2 lesions are present and a score of 2.3 if 3 lesions 
are present.


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Appendix 5 Pemphigus Disease Area Index (cont.)
Mucous membrane 
anatomical location activity score
Number of lesions if 3
Final score
1
(1 lesion)
1
1
2
(23 lesions)
2
2
3
2.3
Source:  Rosenbach M, Murrell DF, Bystryn JC, et al. Reliability and convergent validity of two 
outcome instruments for pemphigus. J Invest Dermatol 2009;129:240410; Victoria Werth, 
personal communication.




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Appendix 7 Patient Global Impression of Change
How would you rate the change of your pemphigus vulgaris symptoms since you 
started taking the study drug?
1  Very much improved
2  Much improved
3  Minimally improved
4  No change
5  Minimally worse
6  Much worse
7  Very much worse


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Appendix 8 Clinician Global Impression of Change
How would you rate the change in the patient’s pemphigus vulgaris symptoms 
since the patient started taking the study drug? 
1  Very much improved
2  Much improved
3  Minimally improved
4  No change
5  Minimally worse
6  Much worse
7  Very much worse
































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Appendix 11 Imputation Rules for Partial or Missing Dates
Start Date/Time
End Date/Time
Concomitant 
Medications
Partially Missing
Day: First day of the month (i.e., 01)
Month: January
Year: No imputation
Seconds: 00
Minutes: 00
Hours: 00
Completely Missing
Date:  No imputation
Time: 00:00:00
Note:  if end time is available and start/end dates are equal 
and the imputed start time is after end time then impute start 
time with end time
Partially Missing
Day: Last day of the month
Month: December
Year: No imputation
Seconds: 59
Minutes: 59
Hours: 23
Completely Missing
Date:  No imputation
Time: 23:59:59
Medical History
Partially Missing
Day: First day of the month (i.e., 01)
Month: January
Year: No imputation
Seconds: 00
Minutes: 00
Hours: 00
Completely Missing
Date:  No imputation
Time: 00:00:00
Note:  if end ime is available and start/end dates are equal 
and the imputed start time is after end time then impute start 
time with end time
Partially Missing
Day: Last day of the month
Month: December
Year: No imputation
Seconds: 00
Minutes: 00
Hours: 00
Completely Missing
Date:  No imputation
Time: 00:00:00


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Appendix 11 Imputation Rules for Partial or Missing Dates (cont.)
Start Date/Time
End Date/Time
Laboratory
Partially Missing
Day: No imputation
Month: No imputation
Year: No imputation
Seconds: 23
Minutes: 59
Hours: 59
Completely Missing
Date:  No imputation
Time: 23:59:59
Partially Missing
Day: No imputation
Month: No imputation
Year: No imputation
Seconds: 23
Minutes: 59
Hours: 59
Completely Missing
Date:  No imputation
Time: 23:59:59
Adverse Events
Partially Missing
Day: If the MM-YYYY of start date is not equal to the MM-
YYYY of first treatment date then set to 01-MM-YYYY.  If the 
MM-YYYY of start date is equal to the MM-YYYY of first 
treatment date then if the end date is ≥date of first treatment 
set to max(01-MM-YYYY, date of first treatment) , otherwise  
if end date < date of first treatment set to 01-MM-YYYY. 
Month: Set to max(01-01-YYYY, date of first treatment). 
Year: Set to start date of first treatment. 
Seconds: 59
Minutes: 59
Hours: 23
Completely Missing
Set to start date of first treatment.  
Note:  For all imputations above, if the resulting imputed start 
date is after the end date then set start date to end date.
Partially Missing
Day: Set to last day of the month, unless the 
outcome is death in which case impute with min(last 
day of month, date of death)
Month: December, unless he outcome is death in 
which case impute with min(DD-12-YYYY, date of 
death)
Year: If the outcome is death then impute with the 
date of death, otherwise no imputation.
Seconds: 59
Minutes: 59
Hours: 23
Completely Missing
If the outcome is death then impute with the date of 
death, otherwise no imputation.


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STATISTICAL ANALYSIS PLAN APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Rituximab—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan WA29330
STATISTICAL ANALYSIS PLAN
48-WEEK SAFETY FOLLOW-UP
TITLE:
A RANDOMIZED, DOUBLE-BLIND, DOUBLE 
DUMMY, ACTIVE-COMPARATOR 
MULTICENTER STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF RITUXIMAB 
VERSUS MYCOPHENOLATE MOFETIL IN 
PATIENTS WITH PEMPHIGUS VULGARIS
PROTOCOL NUMBER:
WA29330
STUDY DRUG:
Rituximab
VERSION NUMBER:
1
IND NUMBER:
121595
EUDRACT NUMBER:
2014-000382-41
SPONSOR:
F. Hoffmann-La Roche Ltd.
PLAN PREPARED BY:
, Ph.D.
DATE FINAL:
See electronic date stamp below.
 
Date and Time(UTC)        Reason for Signing                              Name
18-Oct-2019 13:14:46
Company Signatory


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TABLE OF CONTENTS
1.
BACKGROUND ............................................................................................ 4
2.
ANALYSIS TIMING....................................................................................... 4
3.
STATISTICAL METHODS ............................................................................ 4
3.1
Analysis Populations ............................................................... 4
3.2
Data-Cut for Analyses.............................................................. 5
3.2.1
Rescue Patients ...................................................................... 5
3.3
Visit Windows .......................................................................... 5
3.4
Analysis of Study Conduct....................................................... 6
3.5
Pharmacokinetic and Pharmacodynamic 
Analyses.................................................................................. 6
3.6
Safety Analyses....................................................................... 6
3.6.1
Adverse Events ....................................................................... 7
3.6.2
Deaths ..................................................................................... 7
3.6.3
Laboratory Data....................................................................... 7
3.6.3.1
Immunoglobulins ..................................................................... 7
3.6.3.2
Lymphocyte Populations.......................................................... 7
3.6.3.3
Desmoglein-1 and Desmoglein-3 Autoantibody 
Titers........................................................................................ 8
3.6.3.4
Anti-Drug Antibodies................................................................ 8
3.7
Exploratory Analyses............................................................... 8
3.7.1.1
Oral Corticosteroids................................................................. 8
3.7.1.2
Pemphigus Disease Area Index .............................................. 9
3.7.1.3
Total Number of Flares............................................................ 9
3.7.1.4
Dermatology Life Quality Index................................................ 9
3.7.1.5
Skindex-29............................................................................... 9
3.7.1.6
Patient Global Impression of Change.................................... 10
3.7.1.7
Clinician Global Impression of Change.................................. 10
3.8
Data Handling Methods ......................................................... 10


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LIST OF TABLES
Table 1
Time Windows in Study Days Assigned to the SFU Study 
Visit ............................................................................................... 6
LIST OF APPENDICES
Appendix 1
Schedule of Assessments for the Safety Follow-Up Period ........ 11


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1.
BACKGROUND
Study WA29330 (PEMPHIX) aims to evaluate the efficacy and safety of rituximab (RTX) 
versus mycophenolate mofetil (MMF) in patients with pemphigus vulgaris (PV).  PV is a 
rare, serious autoimmune disease characterized by blisters and erosions of the skin and 
mucosal areas.
Study WA29330 is an international, multicentre, randomized, double-blind, 
double-dummy, active-comparator, two-arm, parallel-group study, which consists of 
three periods: a screening period of up to 28 days; a 52-week, double-blinded,
treatment period; and a 48-week safety follow up (SFU) period that begins at the time of 
study treatment completion or discontinuation. All patients who withdraw early from the 
52-week treatment period or who complete the 52-week treatment period, must return 
for post-study treatment SFU assessments at 12, 24, 36, and 48 weeks after either the 
early withdrawal visit or study treatment completion, respectively.
A separate primary Statistical Analysis Plan (SAP) which describes the statistical 
methodology and data handling rules used for the 52-week treatment period was
finalized before primary database freeze, the analyses completed, and Clinical Study 
Report (CSR) finalized. This SAP describes the timing and data handling rules to be 
used for the 48-week SFU period prior to final database lock.
2.
ANALYSIS TIMING
The SFU analysis will be conducted when all patients have completed the 48-week SFU 
period or withdraw early from SFU (Appendix 1).  The final CSR will include all available 
data up to study completion (last patient’s last visit [LPLV] in SFU) or early withdrawal 
from SFU.
3.
STATISTICAL METHODS
All analyses, summaries, and listings will be performed using SASsoftware 
(Version 9.2 or later).
3.1
ANALYSIS POPULATIONS
The primary analysis populations are defined in the primary SAP, Section 4.1.
The rescue population (RP) includes patients who received at least one rescue therapy 
during the study (i.e., between Week 12 to Week 52 of the study treatment period).
The analysis populations in SFU will be the subset of patients in the primary analysis 
populations who entered the SFU period.


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3.2
DATA-CUT FOR ANALYSES
SFU period begins at the time of study treatment completion (for patients who complete 
the 52-week treatment period) or discontinuation. 
For each patient, start of SFU period will be earliest of the following:

Cut-off for Week 521 day (i.e., Day 3751 day)

Date of early treatment discontinuation1 day
Each subsequent assessment point will be assigned a study day calculated as:
date of assessment date of first dose1.
For patients who had their Week 52 visit after the Week 52 cut-off date 
(Day 36510 days), the Week 52 data will be included in the analysis of the SFU period.
3.2.1
Rescue Patients
Rescue patients are patients who received rescue therapy during the study (i.e., 
Week 12 to Week 52). There is no rescue therapy in the SFU.
The analysis of safety will be performed separately for rescue patients after the point of 
rescue therapy initiation.
The analysis of exploratory efficacy will be performed on the patients who haven’t 
received rescue therapy during the 52-week treatment period, and the data for rescue 
patients will be excluded.
3.3
VISIT WINDOWS
In general, data for assessments that are collected by scheduled visits will be mapped to 
visits that appear in the schedule of assessments per the protocol using the actual study 
day of assessment.  Data will not be mapped to visits for which the assessment was not 
scheduled in the protocol (i.e., results for an assessment conducted at an unscheduled 
visit will be mapped to the appropriate visit at which the assessment was scheduled).  
Visit windows will be continuous from the midpoint between two consecutive study visits, 
and will be dependent on the Schedule of Assessments for each variable independently. 
Since patients start the SFU period at different times, the start day of SFU will be 
considered in defining the SFU visit windows (See Table 1).


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Table 1
Time Windows in Study Days Assigned to the SFU Study Visit
Study Visit
Time Window (Days)
Start of SFU (BLSFU)
BLSFU
Week 12
BLSFU toBLSFU126
Week 24
BLSFU126 toBLSFU210
Week 36
BLSFU210 toBLSFU294
Week 48
BLSFU294 toLPLV
LPLVlast patient last visit; SFUsafety follow-up.
Data displays that are presented by visit will be visits at which the assessment was 
scheduled to be collected. The methods for handling multiple values within a visit 
window are described in the Primary SAP.
3.4
ANALYSIS OF STUDY CONDUCT
The following analyses of study conduct will be carried out on the safety, intent-to-treat, 
modified intent-to-treat population (mITT) and rescue populations, as appropriate 
(See primary SAP, Section 4.1).
The number of patients who completed or discontinued from the study during the SFU 
period, including the reason for discontinuation, will be summarized by treatment group.  
A listing of early withdrawals will be produced.
Concomitant medications given for PV will be summarised descriptively by mapped term 
and treatment group.
Demographic and baseline disease characteristics will be summarized for patients who 
entered SFU, as described in the primary SAP, Section 4.1.
Summary statistics for duration of SFU period per treatment group will be produced. 
The duration of SFU period for a patient will be the duration from BLSFU to the last 
available SFU assessment for that patient.
3.5
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
Serum rituximab concentrations will be listed by patient and nominal time of collection.  
Summary statistics of serum rituximab concentrations will be presented by nominal time 
of collection including n, mean, SD, coefficient of variation, geometric mean, median, 
and range.
3.6
SAFETY ANALYSES
The safety analysis will be performed on the safety population as defined in the primary 
SAP, Section 4.1.3, for patients who entered SFU.
Rescue patients entered SFU will be analyzed separately.


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Serious adverse events (SAEs) and all infectious adverse events, irrespective of 
causality, will be analyzed in the SFU period. Pregnancy information will be reported for 
the duration of the SFU period.
3.6.1
Adverse Events
Adverse events (AEs) will be mapped and reported using the MedDRA thesaurus using 
the most current version at the time of analysis (version 17.1 or later). Glossaries 
showing the mapping of investigator verbatim terms to coded events will be produced.
AEs with observed or imputed onset date, on or after the start date of the SFU period, 
will be summarized and listed.
AEs will be summarized by system organ class (SOC) and preferred term (PT), and will 
be presented in order of descending frequency summed across the treatment arms 
within each SOC and PT.
Listings will show AEs reported, and highlight the telemedicine patients, the patients who 
received rescue therapy in the 52-week treatment period and the patients who received 
rituximab in the SFU period.
The following will be summarized, and/or listings produced where required:

SAEs

Infections

Serious Infections

Symptoms of Serious Infusion Related Reactions (IRRs)

SAEs leading to withdrawal
3.6.2
Deaths
Details of any deaths will be presented in an individual patient listing.
3.6.3
Laboratory Data
3.6.3.1
Immunoglobulins
The absolute values will be summarized by treatment group and visit for total 
immunoglobulin (Ig), IgA, IgG, and IgM.
The proportion of patients with a value of IgA, IgG, and IgM which is less than the lower 
limit of normal at each visit will be produced. Plot of mean and median IgA, IgG and IgM 
will be produced.
3.6.3.2
Lymphocyte Populations
The following natural killer (NK) cells, T, and B lymphocytes will be analyzed via flow
cytometry:

CD19


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
CD3

CD4

CD8

Naïve B cells (CD19CD27)

Transitional B cells (CD24highCD38high

Memory B cells (CD19CD27

NK cells (CD56
The absolute values will be summarized by visit and treatment group for the above 
lymphocyte populations.
The proportion of patients with a lymphocyte value less than the lower limit of normal by
visit and treatment group will be produced for the following lymphocytes:

CD3

CD4

CD8

CD19
3.6.3.3
Desmoglein-1 and Desmoglein-3 Autoantibody Titers
Summary statistics for anti-desmoglein1 (Dsg-1) and anti-Dsg-3 titers during the SFU
period will be produced by treatment group.  A listing of anti-Dsg-1 and anti-Dsg-3 titers
will be produced.
3.6.3.4
Anti-Drug Antibodies
The proportion of patients that are ADA (anti-drug antibodies [referred to as HACA in the 
protocol]) positive/negative at each visit will be summarized by treatment group.  A listing 
of ADA results will be produced.
3.7
EXPLORATORY ANALYSES
The exploratory efficacy analysis will be performed on the mITT population as defined in
primary SAP, Section 4.1.5.
3.7.1.1
Oral Corticosteroids
Oral corticosteroid exposure over the SFU period will be summarized by treatment group.
Oral corticosteroid use over time will be further investigated.  Summaries will be 
generated which will include:

Total cumulative dose per visit interval

Total number of days on oral corticosteroids over the SFU period


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The mean daily dose for a given visit interval will be calculated as follows:
sum of total daily dose across all days in the visit interval(end date of visit 
intervalstart date of visit interval1).
All available data presented by specified visit intervals will be used; if a patient withdraws 
during a time interval, no imputation will be made for the remaining days in the interval, 
and available data up to the time of withdrawal will be used in the calculation.
A listing showing oral corticosteroid dosing for patients over the SFU period will be 
produced.
See primary SAP, Section 4.7.2.1 for Data Handling for Oral Corticosteroids 
3.7.1.2
Pemphigus Disease Area Index
The absolute value of Pemphigus Disease Area Index (PDAI) activity score will be 
summarized by visit for each treatment arm.
The main method for handling missing PDAI data will be via imputation.  Details of PDAI 
imputation methods are described in the primary SAP, Section 4.7.1.2.
3.7.1.3
Total Number of Flares
The total number of flares occurring during the SFU period will be summarized and 
analyzed as described in the primary SAP, Section 4.7.2.2.
3.7.1.4
Dermatology Life Quality Index
The Dermatology Life Quality Index (DLQI) is a validated patient-reported outcome. 
(See primary SAP, Section 4.7.2.5 for more details)
The absolute value (DLQI score) at each visit will be summarized descriptively using 
observed data.  
3.7.1.5
Skindex-29
The Skindex-29 is a health-related quality of life (HRQoL) measure evaluating the impact 
of patient’s dermatologic condition over the previous 4 weeks (See primary SAP, 
Section 4.7.3.9 for more details).
The Skindex-29 score will be summarized by visit and treatment group.
Each scale score is the mean of the items in that scale (domain). The overall score is 
the mean for the 29 items, i.e., excluding item 18.
The overall (global) score will be set to missing if more than 25% of the responses are 
missing.  


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3.7.1.6
Patient Global Impression of Change
The Patient Global Impression of Change (PGIC) is a measure of perceived change in 
PV symptoms as assessed by the patient (See primary SAP, Section 4.7.3.2 for more 
details).
The PGIC categories will be summarized by visit.
3.7.1.7
Clinician Global Impression of Change
The CGIC is a measure of perceived change in PV symptoms as assessed by the 
clinician (See primary SAP, Section 4.7.2.6 for more details).
The CGIC categories will be summarized by visit.
3.8
DATA HANDLING METHODS
Data handling methods are similar to the primary analysis (See primary SAP,
Section 4.10).


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Appendix 1 Schedule of Assessments for the Safety Follow-Up 
Period
All patients who withdraw from both study treatments or complete the study will enter the 
safety follow-up period.  Please note that for patients whose peripheral CD19B cells 
remain depleted (below the lower limit of normal or pre-rituximab baseline level, 
whichever is lower), safety follow-up will not be extended beyond the standard 
protocol-defined 48 weeks after treatment withdrawal or completion.  CD19B-cell 
counts and other blinded laboratory values will be provided to the investigator at the end 
of the safety follow-up period.
Assessment
Week
12
(1 
week)
24
(1 
week)
36
(1 
week)
48
(1 
week)
Safety Assessments to Be Performed for All Patients
Adverse events a
x
x
x
x
Concomitant medications b
x
x
x
x
HACA
x
Autoantibody testing c
x
x
Immunology and Other Labs
Lymphocyte subtypes and FACS panel d
x
x
x
x
Quantitative Ig e
x
x
x
x
PK sample f
x
x
x
x
Disease Status and Activity Limitation Questions
Disease activity (PDAI) and flare assessment
x
x
x
x
DLQI g
x
x
PGIC g
x
x
CGIC g
x
x
Skindex-29 g
x
x
Prednisone (or equivalent) dose assessment/adjustment h
x
x
x
x
CGIC Clinician Global Impression of Change; DLQI Dermatology Life Quality Index; Dsg1 desmoglein 
1; Dsg3 desmoglein 3; eCRF electronic Case Report Form; FACS fluorescence-activated cell sorting; 
HACA human antichimeric antibodies; Ig immunoglobulin; PDAI Pemphigus Disease Area Index; 
PGIC Patient Global Impression of Change; PK pharmacokinetic; PV pemphigus vulgaris; 
SFU safety follow-up.
a
Only serious adverse events and all infectious adverse events, irrespective of causality, will be reported 
in the SFU period.  For all serious infectious adverse events reported, quantitative Ig, and CD19+ cells 
counts should be determined within 1 week of the adverse event becoming serious.  Pregnancy 
information will be reported for the duration of the SFU period.
b
During the SFU period, reporting of concomitant medications should be limited to subsequent PV 
treatments, use of biologics, immunosuppressive medications, and cell-depleting agents.
c
Anti-Dsg1 and anti-Dsg3 antibodies.
d
See protocol Section 4.5.6 for T- and B-cell assessments.
e
Total Ig, IgG, IgA, and IgM. 
f
PK samples will be collected only in patients who withdraw early from study treatment.
g
The DLQI, PGIC, and Skindex-29 should be completed before all other assessments during the study 
visit and prior to providing patient with any disease status information. The CGIC, where possible, should 
be completed prior to the completion of other non-PRO study assessments.
h
To be captured on the eCRF.


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Handling and Reporting of Laboratory Safety Data
This document describes methods used to standardize laboratory safety data for 
analysis and reporting purposes and presents for laboratory parameters that are 
frequently assessed in Roche/Genentech studies the range of values and changes from 
baseline for each laboratory test beyond which a value might be clinically relevant. 
Standardization Methods
In clinical trials, samples for a particular laboratory parameter may be analyzed by 
several laboratories often using different methods. This can result in values being 
reported in different units with different reference ranges. Thus, to make the values 
comparable for analysis and reporting purposes, the following standardization process is 
applied to the data.
Conversion of values to Système International (SI) units
Where applicable, laboratory test values were converted from the investigator reported 
units to Système International (SI) units.
Transformation of data
For those tests that use common methodologies, a ‘Roche Standard Reference Range’ 
(adopted from the New England Journal of Medicine [Kratz and Lewandrowski 1998, 
Kratz et al. 2004]) was applied since their normal ranges show only slight variation 
between different laboratories. For other tests where different methodologies are used 
between laboratories, and thus the reference ranges differ widely, values were linearly 
transformed to a ‘Roche Standard Reference Range’ before analysis and reporting using 
the following formula (Smith and Givens 1993):
(1)
RT = SL + [(RU - IL)/( IH - IL)]) * (SH - SL)
RT
transformed value
RU
untransformed value
IL, IH
investigator limits, low and high 
SL, SH
reference limits, low and high
Note: Values for females (where there are sexdependent reference ranges) were 
transformed to the male reference range by replacing IL, IH by the reference limits for females, 
and SL, SH by the reference limits for males.
This linear transformation did not affect the relative position of a value to its reference 
range. For example, if an untransformed value was above the investigator’s range, the 
transformed value was also above the Roche Standard Reference Range.
In cases where the transformed values could be negative, as could happen for low 
values where the lower limit of the reference range is zero or nearly zero, but the lower 
limit of the investigator range was markedly greater than zero, the investigator lower limit 
was replaced by zero for the transformation. This was considered to be clinically 
justifiable for tests where no abnormal pathology is evident at low values.


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NOTE: For simplicity in technical implementation, standard reference ranges were 
expressed in the format “lower limitupper limit” regardless of whether the actual limits 
were included in the published range (in some cases the reference ranges were one-
sided).  
Examples:

Creatinine – Published reference range was 133 (μmol/L); implemented reference 
range was 0133.  A value equal to 133 was not flagged as high (outside the 
reference range).

HDL Cholesterol -- Published reference range was 1.03 and 1.55 (mmol/L); 
implemented reference range was 1.031.55.  A value equal to 1.55 was not 
flagged as high.
Marked Laboratory Test Value Abnormalities
For each laboratory parameter, a Marked Reference Range which was wider than the 
Roche Standard Reference Range was defined, above and/or below which a value was
considered to be potentially clinically relevant. In addition, for each laboratory test, a 
percentage change, as an increase or decrease from the baseline value, was defined 
which represented a clinically relevant change from baseline. The ranges used to define 
a Marked Abnormality and the required change from baseline are shown in Table 1.    
A Marked Abnormality was therefore defined as a test result:

which is outside of the Marked Reference Range,
AND

which also represents a clinically relevant change from baseline of at least the 
designated amount during, or within a specified window after the end of, trial 
treatment (e.g., 30 days)
If the baseline value was zero and the percentage increase from baseline could not be 
calculated, the second condition was ignored (conservative approach).
Baseline was defined as the last valid value within a window specified by the project 
team (e.g., 30 days) before starting trial treatment. If no baseline was available, then the 
midpoint of the Standard Reference Range was used.
For crossover studies or parallel studies where treatment interruption longer than 
a specified period is of clinical significance: In general, if the wash-out interval was 
sufficient between 2 consecutive treatment periods, the user could derive a new baseline 
for the later of the 2 consecutive periods, as agreed within the project team.
NOTE: For calculating means and mean changes over time, missing values were not 
included.  If no baseline was available, no change from baseline was calculated.














Clinical Study Report: rituximab - F. Hoffmann-La Roche Ltd
Protocol WA29330     Report Number 1100195
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General Hospital. Weekly clinicopathological exercises. Laboratory reference 
values. N Engl J Med. 2004;351:1548-63. Erratum in: N Engl J Med. 
2004;351:2461.
Kratz A, Lewandrowski KB. Case records of the Massachusetts General Hospital. 
Weekly clinicopathological exercises. Normal reference laboratory values. N Engl J 
Med. 1998;339:1063-72. Erratum in: N Engl J Med 1999;340:1300.
New England Journal of Medicine. 1992 SI conversion guide
Smith A and Givens SV. Dealing with and Defining Abnormalities in Laboratory Data, 
Drug Info J 1993;27:771−8