Conditions: Pemphigus
Keywords: Pemphigus Vulgaris (PV) Pemphigus Foliaceus (PF)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 131
Healthy volunteers: no

Brief summary:
This was a Phase 3 randomized, parallel-group, double-blind, placebo-controlled trial (blinded treatment \[BT\] period) followed by an open-label extension \[OLE\] period intended to evaluate the efficacy and safety of oral PRN1008 in moderate to severe pemphigus. After completing the open-label extension period, eligible participants might continue in a long term extension (LTE) Period of 48 weeks.

Detailed description:
A total of 131 male or female participants with newly diagnosed or relapsing moderate to severe pemphigus (pemphigus vulgaris \[PV\] or pemphigus foliaceus \[PF\]) were enrolled in the trial worldwide.

The trial would last 68 weeks (approximately 17 months) for each participant. For participants eligible to enroll in the LTE, the trial might last up to 116 weeks.

Participants were randomized at Day 1, using a 1:1 ratio to receive PRN1008 or placebo twice per day, by relapsing/newly diagnosed disease history (newly diagnosed defined as within 6 months of screening).

Arms:
arm 1: In BT period, participants received placebo orally twice daily (BID) up to 37 weeks along with sponsor-provided corticosteroids (CS). After at least two weeks of control of disease activity (CDA; no new lesions and established lesions begin to heal), based on protocol-specified clinical criteria, investigators could decrease the CS dose to a minimum of 5 milligrams (mg) prednisone/prednisolone per day from Week 29 to Week 37. Post completion of BT period, eligible participants received rilzabrutinib 400 mg BID up to Week 61 in OLE period and those who were eligible after OLE period completion, continued the same treatment until Week 109 in LTE period according to protocol-specified criteria. arm 2: In BT period, participants received rilzabrutinib 400 mg orally BID up to 37 weeks along with sponsor-provided CS. After at least two weeks of CDA (no new lesions and established lesions begin to heal), based on protocol-specified clinical criteria, investigators could decrease the CS dose to a minimum of 5 mg prednisone/prednisolone per day from Week 29 to Week 37. Post completion of BT period, eligible participants received rilzabrutinib 400 mg BID up to Week 61 in OLE period and those who were eligible after OLE period completion, continued the same treatment until Week 109 in LTE period according to protocol-specified criteria.

Interventions: intervention 1: Rilzabrutinib intervention 2: Placebo
Intervention descriptions: intervention 1: Pharmaceutical form: Tablet Route of administration: Oral intervention 2: Pharmaceutical form: Tablet Route of administration: Oral

Protocol document:
Prot_000.pdf: 


Amended Clinical Trial Protocol 07 
PRN1008/SAR444671-PRN1008-012/EFC17092 - rilzabrutinib 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
 
Document 
Country/Countries 
impacted by amendment 
Date, version 
Amended Clinical Trial Protocol 07 
All 
[30 Aug 2021], version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 06 
All 
[06 May 2021], version 2 (electronic 3.0) 
Amended Clinical Trial Protocol 06 
All 
[01 April 2021], version 1 (electronic 2.0) 
Clinical Study Protocol Version 5.2 
UK only 
[21 December 2020] 
Clinical Study Protocol Version 5.2 
Germany only 
[30 November 2020] 
Clinical Study Protocol Version 5.1 
UK only 
[22 June 2020] 
Clinical Study Protocol Version 5.1 
Germany only 
[19 May 2020] 
Clinical Study Protocol Version 5 
All 
[22 January 2020] 
Clinical Study Protocol Version 4.1 
US only 
[04 December 2019] 
Clinical Study Protocol Version 4.1 
Germany only 
[30 September 2019] 
Clinical Study Protocol Version 4 
All 
[29 August 2019] 
Clinical Study Protocol Version 3.2 
Germany only 
[22 May 2019] 
Clinical Study Protocol Version 3.1 
Germany only 
[01 May 2019] 
Clinical Study Protocol Version 3.1 
Canada only 
[24 April 2019] 
Clinical Study Protocol Version 3 
All 
[9 October 2018)] 
Clinical Study Protocol Version 2 
US only 
[12 September 2018] 
Clinical Study Protocol Version 1 (original) 
All 
[04 June 2018] 
Note: The name and numbering of the protocol is based on a new numbering system followed by the Sponsor.  
Amended Clinical Trial Protocol 07 (30 Aug 2021) 
This is a global amendment to Amended Clinical Trial Protocol 06 and is considered to be 
substantial. No changes to protocol procedures are included in this global amendment. 
OVERALL RATIONALE FOR THE AMENDMENT 
The primary reasons for this amendment to Protocol PRN1008-012 are: 
• 
Change corticosteroid dose criterion to ≤10 mg/day and modify key secondary endpoints 
to align with FDA comments 
• 
Address statistical analysis of clinical assessments impacted by the COVID-19 pandemic 
including those performed remotely 
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Protocol amendment summary of changes table 
Section # and name 
Description of change 
Brief rationale 
Section 1.1 Synopsis: 
Outcome Measures, 
Section 1.2 Schema Figure 
1: Study Design Flow Chart, 
Section 3 Objectives and 
Endpoints, Section 9.1 
Sample Size 
Determinatinon, Section 
9.3.5 Efficacy analysis 
(mITT Population)  
CS dose criterion for primary efficacy endpoint changed 
from ≤5 mg/day to ≤10 mg/day 
Align with recommendations from 
FDA 
Section 1.1 Synopsis: 
Outcome Measures, 
Section 3 Objectives and 
Endpoints, Section 9.1 
Sample Size 
Determinatinon, Section 
9.3.6 Key Secondary 
Efficacy Sequential Testing 
Changed the following endpoints from Key Secondary 
Endpoints to Other Secondary Endpoints: 
• 
Proportion of patients with at least one disease 
relapse/flare from initial control of disease activity 
(CDA) to Week 37 
• 
Cumulative duration of CR with a CS dose ≤10 
mg/day, from Week 37 to Week 61 
• 
Cumulative duration of CR with a CS dose = 0 
mg/day, from Week 37 to Week 61 
Align with comments from FDA 
Section 1.1 Synopsis: 
Outcome Measures, 
Section 3 Objectives and 
Endpoints 
Changed CS dose criterion for proportion of patients who 
are in CR from Week 29 to Week 37 from ≤10 mg/day to 
≤5 mg/day. 
Align with change to CS dose 
criterion for the primary efficacy 
endpoint 
Section 9.2 Populations for 
Analyses 
Removes statement that the ITT Population will be used for 
sensitivity analyses 
Correction 
Section 9.3.5 Efficacy 
Analysis (mITT population) 
Clarified handling of clinical efficacy data collected in-
person or remotely in analysis 
Align with recommendations from 
FDA 
Section 9.3.5 Efficacy 
Analysis (mITT population) 
Deleted the last sentence in the following paragraph: 
Patients who drop out of the trial, withdraw, or who receive 
a rituximab dose prior to Week 37 will count as non-
responders in the analysis. Additional sensitivity analyses, 
including adjusting for severity, will be described in the 
SAP.  
Correction 
Section 9.3.5 Efficacy 
Analysis (mITT population) 
and Section 9.3.6 Key 
Secondary Efficacy 
Sequential Testing 
Moved statement regarding proportion of patients with at 
least one disease relapse/flare from initial CDA to Week 37 
from Key Secondary to Other Secondary 
Align with changes to Key 
Secondary and Other Secondary 
endpoints 
Section 9.3.5 Efficacy 
Analysis (mITT population) 
Deleted timepoints from the cumulative duration of CR 
analysis: Cumulative duration of CR with CS dose ≤ 
10mg/day from Baseline to Week 37, from Week 37 to 
Week 61, and cumulative duration of CR with CS dose = 0 
mg/day from Week 37 to Week 61 will be analyzed using a 
zero-inflated negative binomial model with terms for 
treatment group and disease history.   
To align with the SAP 
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Section # and name 
Description of change 
Brief rationale 
Section 9.3.6 Key 
Secondary Efficacy 
Sequential Testing 
Replaced the leading sentence to: After testing the primary 
endpoint in the PV mITT population and the mITT 
population (i.e. PV+PF population), key secondary efficacy 
endpoints will be tested sequentially, first on the PV mITT 
population in the order specified below, and then on the 
mITT population in the same order: 
The following sentence was revised to: The proportion of 
patients who are in CR from Week 29 to Week 37 with a 
CS dose of ≤10 mg/day of CS at any time will be 
compared using the same method as the primary 
endpoint. 
Revised for clarity/accuracy 
Section 9.3.9 Long Term 
Extension Analysis 
Deleted the following sentence: The number of received 
doses and treatment duration will be described. 
To align with the SAP 
Section 9.3.10 
First sentence was revised to: Missing data will not be 
imputed except for the situations described in the SAP. As 
a general strategy, missing data will not be imputed in this 
trial. Details on the handling of missing data, including 
missing data due to the COVID-19 pandemic, will be 
described in the SAP. 
To align with the SAP 
 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 07 ........................................................................................... 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 5 
LIST OF TABLES ......................................................................................................................................... 10 
LIST OF FIGURES ........................................................................................................................................ 10 
1 
PROTOCOL SUMMARY ............................................................................................................... 11 
1.1 
SYNOPSIS ..................................................................................................................................... 11 
1.2 
SCHEMA ........................................................................................................................................ 26 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 27 
2 
INTRODUCTION ............................................................................................................................ 34 
2.1 
STUDY RATIONALE...................................................................................................................... 34 
2.2 
BACKGROUND ............................................................................................................................. 34 
2.2.1 
Overview of pemphigus ................................................................................................................. 34 
2.2.2 
BTK inhibitor (rilzabrutinib) ............................................................................................................. 35 
2.2.3 
Nonclinical experience ................................................................................................................... 35 
2.2.4 
Clinical experience ......................................................................................................................... 35 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 36 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 37 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 39 
4 
STUDY DESIGN ............................................................................................................................ 40 
4.1 
OVERALL DESIGN ........................................................................................................................ 40 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 43 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 44 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 45 
5 
STUDY POPULATION .................................................................................................................. 46 
5.1 
INCLUSION CRITERIA .................................................................................................................. 46 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 47 
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6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 50 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 50 
6.1.1 
Rilzabrutinib/Placebo ..................................................................................................................... 50 
6.1.1.1 
Packaging ...................................................................................................................................... 50 
6.1.2 
Corticosteroids ............................................................................................................................... 50 
6.1.2.1 
Corticosteroid starting doses and management during screening and at Day 1 ........................... 50 
6.1.2.2 
Corticosteroid management during blinded treatment period, open-label extension period, 
and long term extension period ...................................................................................................... 51 
6.1.2.3 
Corticosteroids and rituximab ........................................................................................................ 51 
6.1.3 
Rituximab ....................................................................................................................................... 52 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 52 
6.2.1 
Preparation, administration and storage ........................................................................................ 52 
6.2.1.1 
Rilzabrutinib/Placebo ..................................................................................................................... 52 
6.2.1.2 
Corticosteroids ............................................................................................................................... 52 
6.2.1.3 
Rituximab ....................................................................................................................................... 52 
6.2.2 
Drug management ......................................................................................................................... 53 
6.2.3 
Drug accountability......................................................................................................................... 53 
6.2.4 
Destruction of investigational product ............................................................................................ 54 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 54 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 55 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 55 
6.5.1 
Prohibited medications ................................................................................................................... 55 
6.5.2 
Particular permissible medications ................................................................................................ 56 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 57 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 57 
7.1.1 
Permanent discontinuation ............................................................................................................ 57 
7.1.2 
Sponsor trial termination ................................................................................................................ 57 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 57 
7.2.1 
Patient Discontinuation and Stopping Rules .................................................................................. 57 
7.2.2 
Patient withdrawal .......................................................................................................................... 58 
7.3 
LOST TO FOLLOW-UP ................................................................................................................. 59 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 60 
8.1 
TRIAL RECRUITMENT PROCEDURES ....................................................................................... 60 
8.2 
TRIAL ENROLLMENT PROCEDURES ......................................................................................... 60 
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8.3 
VISIT OVERVIEW .......................................................................................................................... 60 
8.3.1 
Screening (Day -29 to Day -1) ....................................................................................................... 61 
8.3.2 
Baseline (Day 1) ............................................................................................................................. 61 
8.3.3 
Blinded treatment period (Weeks 1 to 37) ..................................................................................... 62 
8.3.4 
Open-label extension period (Weeks 37 to 61) ............................................................................. 62 
8.3.5 
Long term extension period (Beginning Week 61) ......................................................................... 62 
8.3.6 
OLE EOT/Week 65 and LTE EOT/Week 113 visits (follow-up period, 4 weeks after last trial 
dose) .............................................................................................................................................. 62 
8.3.7 
Early termination visit ..................................................................................................................... 62 
8.4 
TRIAL ASSESSMENTS ................................................................................................................. 62 
8.4.1 
Body height and weight .................................................................................................................. 62 
8.4.2 
Physical examination ..................................................................................................................... 63 
8.4.3 
Biopsies .......................................................................................................................................... 63 
8.4.4 
Medical history ............................................................................................................................... 63 
8.4.5 
Vital signs ....................................................................................................................................... 63 
8.4.6 
Electrocardiogram monitoring ........................................................................................................ 64 
8.4.7 
Clinical laboratory tests .................................................................................................................. 64 
8.4.8 
Pharmacokinetic/Pharmacodynamic assessments ....................................................................... 64 
8.4.8.1 
Vaccine IgG .................................................................................................................................... 64 
8.4.9 
Pemphigus disease area index (PDAI) .......................................................................................... 65 
8.4.10 
Autoimmune bullous disease quality of life (ABQOL) .................................................................... 65 
8.4.11 
Treatment autoimmune bullous disease quality of life (TABQOL) ................................................. 65 
8.4.12 
EuroQOL (EQ-5D-5L) .................................................................................................................... 65 
8.4.13 
Glucocorticoid toxicity index (GTI) ................................................................................................. 65 
8.4.14 
Photography ................................................................................................................................... 66 
8.4.15 
SARS-CoV-2 testing requirement (for German participants only) ................................................. 66 
8.5 
ASSESSMENT OF EFFICACY ...................................................................................................... 66 
8.5.1 
Specification of the efficacy parameters ........................................................................................ 66 
8.5.2 
Methods and timing for assessing, recording and analyzing of efficacy parameters .................... 66 
8.6 
ASSESSMENT OF SAFETY ......................................................................................................... 66 
8.6.1 
Overview ........................................................................................................................................ 66 
8.6.2 
Data safety monitoring board (DSMB) and interim analysis .......................................................... 67 
8.6.3 
Adverse Events .............................................................................................................................. 67 
8.6.3.1 
Adverse event collection period ..................................................................................................... 67 
8.6.3.2 
Clinical adverse events .................................................................................................................. 67 
8.6.3.3 
Adverse event intensity grading ..................................................................................................... 69 
8.6.3.4 
Adverse event relationship to trial medication ............................................................................... 69 
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8.6.3.5 
Treatment and follow-up of adverse events ................................................................................... 70 
8.6.3.6 
Laboratory and ECG abnormalities ................................................................................................ 70 
8.6.3.7 
Serious adverse event reporting .................................................................................................... 71 
8.6.4 
Pregnancy ...................................................................................................................................... 73 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 74 
9.1 
SAMPLE SIZE DETERMINATION ................................................................................................. 74 
9.2 
POPULATIONS FOR ANALYSES ................................................................................................. 75 
9.3 
STATISTICAL ANALYSES ............................................................................................................ 75 
9.3.1 
Disposition of the trial patients ....................................................................................................... 75 
9.3.2 
Demographic and baseline characteristics .................................................................................... 75 
9.3.3 
Exposure to study treatment .......................................................................................................... 76 
9.3.4 
Safety and tolerability analysis (safety population) ........................................................................ 76 
9.3.5 
Efficacy analysis (mITT Population) ............................................................................................... 77 
9.3.6 
Key secondary efficacy sequential testing ..................................................................................... 77 
9.3.7 
Pharmacokinetic and pharmacodynamic analysis ......................................................................... 78 
9.3.8 
Exploratory analysis ....................................................................................................................... 78 
9.3.9 
Long term extension analysis ........................................................................................................ 79 
9.3.10 
Missing data ................................................................................................................................... 79 
10 
INVESTIGATOR RESPONSIBILITIES .......................................................................................... 80 
10.1 
DATA QUALITY ASSURANCE ...................................................................................................... 80 
10.2 
PROTOCOL AMENDMENTS AND TRIAL COMPLETION ........................................................... 81 
10.3 
INFORMED CONSENT ................................................................................................................. 81 
10.4 
PATIENT CONFIDENTIALITY AND DISCLOSURE OF DATA ..................................................... 82 
10.5 
ELECTRONIC CASE REPORT FORMS ....................................................................................... 83 
10.6 
RETENTION AND AVAILABILITY OF RECORDS ........................................................................ 83 
10.7 
AUDITS AND INSPECTIONS ........................................................................................................ 83 
11 
ETHICAL ASPECTS...................................................................................................................... 85 
11.1 
LOCAL REGULATIONS/DECLARATION OF HELSINKI .............................................................. 85 
11.2 
INSTITUTIONAL REVIEW BOARD REVIEW ................................................................................ 85 
12 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 86 
12.1 
APPENDIX 1 CORTICOSTEROID AND RITUXIMAB MANAGEMENT ........................................ 86 
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12.2 
APPENDIX 2 PEMPHIGUS DISEASE ACTIVITY: PDAI ............................................................... 89 
12.3 
APPENDIX 3 PEMPHIGUS QUALITY OF LIFE EVALUATION: ABQOL ...................................... 90 
12.4 
APPENDIX 4 PEMPHIGUS QUALITY OF LIFE EVALUATION: TABQOL ................................... 93 
12.5 
APPENDIX 5 GENERAL QUALITY OF LIFE EVALUATION: EQ-5D-5L ...................................... 97 
12.6 
APPENDIX 6 GLUCOCORTICOID TOXICITY INDEX (GTI) ........................................................ 99 
12.7 
APPENDIX 7 STRONG TO MODERATE CYP3A INHIBITORS AND INDUCERS AND 
SENSITIVE CYP3A SUBSTRATES .............................................................................................. 99 
12.8 
APPENDIX 8 EFFICACY OUTCOME ASSESSMENT FLOWCHART ........................................ 100 
12.9 
APPENDIX 9 UPDATED GUIDELINES TO SITES FOR DELAYED PATIENT VISITS OR 
MISSED VISITS DUE TO TRAVEL RESTRICTIONS AND ANY FORESEEABLE 
IMPACTS OF COVID-19 ............................................................................................................. 101 
12.9.1 
Appendix 9A - Remote Study Visits for Active Patients ............................................................... 104 
12.9.2 
Appendix 9B - IP Shipment/Delivery Process .............................................................................. 107 
12.9.3 
Appendix 9C - PRN1008-012 Packing Slip ................................................................................. 108 
12.9.4 
Appendix 9D - World Courier Ordering Process - Site to Patient Courier Services .................... 109 
12.10 
APPENDIX 10 COUNTRY-SPECIFIC REQUIREMENTS ........................................................... 112 
12.11 
APPENDIX 11 VACCINE RESPONSE ........................................................................................ 115 
12.12 
APPENDIX 12 ABBREVIATIONS ................................................................................................ 116 
12.13 
APPENDIX 13 PROTOCOL AMENDMENT HISTORY ............................................................... 119 
12.13.1 Clinical Study Protocol Version 2 (12 September 2018).............................................................. 119 
12.13.2 Clinical Study Protocol Version 3 (9 October 2018) .................................................................... 138 
12.13.3 Clinical Study Protocol Version 3.1 for Canada (24 April 2019) .................................................. 142 
12.13.4 Clinical Study Protocol Version 3.1 for Germany (01 May 2019) ................................................ 144 
12.13.5 Clinical Study Protocol Version 3.2 for Germany (22 May 2019) ................................................ 147 
12.13.6 Clinical Study Protocol Version 4 (29 August 2019) .................................................................... 172 
12.13.7 Clinical Study Protocol Version 4.1 for Germany (30 September 2019) ..................................... 186 
12.13.8 Clinical Study Protocol Version 4.1 for US (04 December 2019) ................................................ 199 
12.13.9 Clinical Study Protocol Version 5 (22 January 2020) .................................................................. 202 
12.13.10 Clinical Study Protocol Version 5.1 for Germany (19 May 2020) ................................................ 219 
12.13.11. Clinical Study Protocol Version 5.2 for Germany (30 November 2020) ...................................... 239 
12.13.12. Clinical Study Protocol Version 5.1 for UK (22 June 2020) ......................................................... 245 
12.13.13. Clinical Study Protocol Version 5.2 for UK (21 December 2020) ................................................ 247 
12.13.14. Amended Clinical Trial Prototocol 06 (06 May 2021) .................................................................. 255 
13 
REFERENCES ............................................................................................................................. 266 
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LIST OF TABLES  
Table 1: 
Definitions of Moderate to Severe Population and Starting CS doses......................................... 14 
Table 2: 
Schedule of Assessments - Blinded Treatment Period ................................................................ 27 
Table 3: 
Schedule of Assessments - Open-Label Extension Period ......................................................... 30 
Table 4: 
Schedule of Assessments - Long Term Extension Period ........................................................... 32 
Table 5: 
Objectives and endpoints ............................................................................................................. 37 
Table 6: 
Example Taper for a 60 mg Dose of CS ...................................................................................... 87 
 
 
LIST OF FIGURES  
Figure 1: 
Study Design Flow Chart ............................................................................................................ 26 
 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol Title 
A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial to Evaluate the Efficacy 
and Safety of Oral BTK Inhibitor Rilzabrutinib (PRN1008) in Moderate to Severe Pemphigus 
Protocol Number  
PRN1008-012 
Sponsor  
Principia Biopharma Inc. 
Trial Medication 
The investigational drug product is PRN1008 (Rilzabrutinib) in combination with tapering 
doses of oral corticosteroid (CS, [prednisone or prednisolone]).  
Phase 
This is a Phase 3 pivotal study. 
Study Population 
Approximately 120 male or female patients with newly diagnosed or relapsing moderate to 
severe pemphigus (pemphigus vulgaris [PV] or pemphigus foliaceus [PF]) will be enrolled with 
a targeted minimum of 90 patients with PV, and a target maximum of 22 patients with PF.  
Duration of Trial Participation 
For each patient, the trial will last approximately 68 weeks including Screening Period (up to 
4 weeks), the Blinded Treatment Period (Week 1 through Week 37), the Open-Label Extension 
Period (Week 37 to Week 61), and a 4-week end of treatment follow-up (up to Week 65).  
Long Term Extension Period 
Study duration for the patients who enter the Long Term Extension Period will be determined 
by the criteria described in the Study Design of the Study Synopsis. 
Number of Study Sites 
Approximately 100 sites worldwide. 
 
 
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Outcome Assessment Definitions (Consensus Guidelines) (1)  
Control of Disease Activity (CDA): 
Control of disease activity (disease control) is defined as the visit at which new lesions cease to 
form and established lesions begin to heal. This is also considered the beginning of the 
consolidation phase. The expected interval of time to reach the control of disease activity is on 
the order of weeks, although it may be shorter.  
End of Consolidation Phase (ECP): 
The end of the consolidation phase is defined as the visit at which no new lesions have 
developed for a minimum of 2 weeks and the majority (approximately 80%) of established 
lesions have healed. Therefore, in order to achieve ECP, CDA must be confirmed at a visit 
≥2 weeks later and 80% of the lesions seen previously must have healed.   
Complete Remission (CR): 
Complete remission is defined as the absence of new and established lesions and is intended to 
mean “no disease activity”. Various qualifying statements are added to this definition for 
endpoints in this protocol.  
Relapse/Flare: 
A relapse of disease and a flare of disease are synonymous. They are defined by the appearance 
of 3 or more new lesions after CDA and within a month that do not heal spontaneously within 
1 week, or by the extension of established lesions, in a patient who has achieved CDA. 
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Objectives 
Efficacy Objectives 
• To evaluate the efficacy of rilzabrutinib in achieving durable CR on low to zero doses 
of oral corticosteroid (CS) and on the timecourse of quantitative disease activity scores 
• To assess the ability of rilzabrutinib to reduce CS exposure and the adverse effects of 
CS 
• To evaluate the time to specified clinical endpoints  
• To assess the longer term durability of CR 
Safety Objectives 
• To evaluate the safety of rilzabrutinib 
• To evaluate differences in potentially CS-related adverse events 
PK/PD Objectives 
• To evaluate the pharmacokinetics (PK) of rilzabrutinib 
• To evaluate pharmacodynamic (PD) effects of rilzabrutinib on anti-desmoglein (anti-
dsg) autoantibody titers (anti-dsg1 and anti-dsg3) 
Exploratory Objectives 
• To evaluate the PK of rilzabrutinib metabolites 
• To examine the effects of rilzabrutinib if any, of the baseline covariates on PK 
and/or PD, and the relationship between PK, PD, and efficacy  
• To explore association of vaccine response with rilzabrutinib 
• To examine the effect of rilzabrutinib on the costs of hospitalizations, outpatient 
medical visits, adverse events, concomitant medication use, and other relevant health 
economic outcomes 
• To examine the temporal relationship of change from baseline in Pemphigus Disease 
Area Index (PDAI) total activity score and quality of life and health economic 
measures 
Long Term Extension Objective 
• To evaluate the long-term safety and efficacy of rilzabrutinib. 
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Investigational Plan 
Study Design 
This is a randomized, parallel-group, double-blind, placebo-controlled trial with 36 weeks of 
treatment during a Blinded Treatment Period followed by an Open-Label Extension Period of 
24 weeks. After completing the Open-Label Extension Period, eligible patients may continue 
in the Long Term Extension Period of 48 weeks. Patients will continue to have a 4 week 
follow-up visit after the patient’s last dose of rilzabrutinib as detailed in the End of Trial 
(Follow-up Period, 4 Weeks after last Trial Dose) Section below. 
Blinded Treatment Period (Weeks 1 to 37): 
Table 1: 
Definitions of Moderate to Severe Population and Starting CS doses  
 
PDAI entry criteria 
Required CS dose starting at 
Screeninga 
Newly diagnosed (diagnosed ≤ 6 months prior to 
Screening) 
PDAI ≥ 15 
≥ 0.5 mg/kg/day 
Relapsing, chronic (diagnosed > 6 months prior 
to Screening) 
PDAI ≥ 9 
≥ 0.2 mg/kg/day 
a Doses shown above are minimum requirements. Actual doses will be determined by Investigator judgment. 
After informed consent is obtained, patients with moderate to severe pemphigus (PV and PF) 
will be screened and if eligible will be randomized in a 1:1 allocation ratio to receive either 
rilzabrutinib 400 mg twice daily (bid) (n ~ 60) or placebo bid (n ~ 60) during the Blinded 
Treatment Period (Week 1 to Week 37). 
At Screening, patients will begin to take Sponsor-provided CS according to the minimum dose 
requirements, shown in Table 1 above, and as required to adequately treat the disease. CS 
doses may be adjusted per Investigator discretion during the Screening period (Appendix 1 
Section 12.1) but the dose should not be reduced below the required minimum initial dose 
levels (Table 1) (2, 3). CS taper below the required minimum dose level should not begin until 
ECP has been achieved. 
Rilzabrutinib (400 mg tablet) or placebo will be taken twice daily by mouth starting on Day 1. 
Tablets may be taken with or without food.  
If a patient achieves CDA (no new lesions and established lesions begin to heal), a follow-up 
visit ≥2 weeks later must confirm the finding of no new lesions prior to declaring ECP 
and tapering CS. ECP is achieved with the confirmation of CDA (no new lesions for 
≥2 weeks) with approximately 80% of the established lesions epithelialized (healed). If 
needed, confirmation of CDA and achievement of ECP may be documented at an Unscheduled 
Visit, prior to the next scheduled study visit. See Table 2 for all required assessments for 
an Unscheduled Visit, which also includes Efficacy Outcome Assessment and PDAI. 
While continuing on rilzabrutinib or placebo, following the achievement of ECP, patients will 
undergo a moderately rapid CS taper regimen as recommended by recently published 
consensus guidelines (1) with the goal to reduce the CS dose to 5 mg/day by no later than 
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Study Week 29, with CS dose-adjustment as clinically indicated to control disease (CS and 
Rituximab Management protocol, Appendix 1 Section 12.1).  
CS taper should not begin until ECP has been achieved.  
If the first documentation of CDA coincides with no disease activity (PDAI = 0), a follow-up 
visit ≥2 weeks later must still confirm that no new lesions are seen and PDAI = 0. At this time 
the patient is deemed to have confirmed CDA, ECP, and CR and therefore CS tapering can 
begin. If new lesion(s) are seen, the patient is no longer in CDA and therefore CS tapering 
should not begin. If a patient has not achieved CDA or new lesions emerge or existing lesions 
worsen but do not meet definition of relapse/flare, refer to Appendix 1 Section 12.1 regarding 
increasing steroid dosage. 
Throughout the Blinded Treatment Period, patients who fail to respond to treatment 
or experience a worsening of disease should have their CS dose increased per CS Management 
Guidelines (Appendix 1 Section 12.1) until CDA is obtained. If ECP is not achieved in 
a timely manner, it is encouraged that CS dose be further increased unless clinically 
contraindicated. The Principal Investigator (PI) should consult with the Medical Monitor in 
such cases.  
Efficacy Outcome Assessment should be performed per the Efficacy Outcome Assessment 
Flowchart, Appendix 8 Section 12.8. 
Once patients achieve CR on a dose of 5 mg/day of CS, that dose should be maintained 
(not tapered further) until Study Week 37 (time of primary endpoint). 
Rituximab treatment may be administered during the Blinded Treatment Period at or after the 
Week 5 Visit, only after a second “qualifying relapse/flare” occurs, unless contraindicated 
(Appendix 1 Section 12.1). 
If rituximab is administered, patients should continue to take rilzabrutinib/placebo, remain on 
trial and blinded to treatment assignment. After completing the Blinded Treatment Period, 
patients will enter the Open-Label Extension Period to receive active treatment with 
rilzabrutinib described below. A patient in the Blinded Treatment Period requiring an 
additional “top up” dose of rituximab after their initial rituximab course of treatment must be 
discontinued from the trial.  
Open-Label Extension Period (Weeks 37 to 61): 
From Week 37, all patients will receive active drug in the Open-Label Extension Period for 
24 weeks per Table 3. Patients who received placebo will thus receive active treatment with 
rilzabrutinib 400 mg bid. Patients requiring treatment by rituximab or other 
immunosuppressants (other than CS) for relapse/flare during this period, must be discontinued 
from the study. If a patient has a qualifying relapse/flare during the Blinded Treatment Period 
and the second infusion from the rituximab course of treatment occurs during the Open-Label 
Extension period, the patient may continue in the trial. 
Patients that received rituximab during the Blinded Treatment Period and are continuing in the 
study, will complete TBNK testing (T and B and Natural Killer Lymphocyte Panel) at their 
Week 37 Visit. 
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From Week 37 (time of primary endpoint), further tapering to 0 mg CS should be attempted in 
patients with CR unless medically contraindicated. Patients who fail to respond to treatment 
or experience worsening of disease should have their CS dose increased per CS management 
guidelines (Appendix 1 Section 12.1) until CDA is obtained. If ECP is not achieved in a timely 
manner, it is encouraged that CS dose be further increased unless clinically contraindicated. 
The PI should consult with the Medical Monitor in such cases. 
Long Term Extension (LTE) Period (Week 61 to Week 109): 
After completing the Open-Label Extension Period, patients who are responding to 
rilzabrutinib treatment will be eligible to enter the Long Term Extension Period and will 
continue to receive open-label rilzabrutinib 400 mg bid for 48 weeks per Table 4. 
Patients are eligible to participate in the LTE if: 
a) 
they have achieved and/or maintained an ECP with ≤10 mg/day CS at any time 
between 37 and 61 weeks in the study. 
Patients are not eligible to participate in the LTE if: 
a) 
they have more than one relapse/flare following ECP requiring treatment with 
>10 mg/day CS (excluding CS taken short-term for dental work or surgery), or  
b) 
have failed to adequately recover after a relapse/flare despite maximal tolerated CS 
dose. 
Failure to adequately recover is defined as: <25% decrease from peak PDAI despite treatment 
with maximal steroid doses (minimum of 1.5 mg/kg/day unless there is a specific documented 
medical contraindication) for at least 2 weeks.  
CS doses above refer to doses of prednisone or its equivalent. 
Patients may continue in the LTE until: 
a) 
they have had more than one relapse/flare following ECP that requires >10 mg/day 
CS (excluding CS taken short-term for dental work or surgery) or have failed to 
adequately recover after a relapse/flare despite maximal tolerated CS dose 
(per definition of failure to adequately recover above);  
b) 
the drug is no longer being developed by the Sponsor for this indication;  
c) 
the program is stopped for safety reasons. 
Patients who have previously completed the Open-Label Extension Period prior to this 
amendment and were responders per the LTE requirement may enroll into the LTE.   
Patients entering the LTE will receive Sponsor-provided CS, following CS Management 
Guidelines (Appendix 1 Section 12.1). 
Patients requiring rituximab during the Long Term Extension Period will be discontinued from 
the trial. 
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End of Trial (Follow-up Period, 4 Weeks after last Trial Dose):  
End of Trial (EOT) for the overall clinical trial is defined as the point at which the last patient 
has completed the last visit of the study. 
For patients eligible for the Long Term Extension, the EOT is defined as the point at which the 
patient has completed their Week 113 Visit (4 weeks after the patient’s last dose of 
rilzabrutinib).  
For patients that are not eligible for the Long Term Extension, the EOT is defined as the point 
at which the patient has completed their Week 65 Visit (4 weeks after the patient’s last dose of 
rilzabrutinib).  
Patients who are not able to complete the Blinded Treatment Period, Open-Label Extension 
Period or Long Term Extension Period as planned and discontinue the study early should be 
encouraged to come back for an Early Termination (ET) Visit as soon as possible. Patients that 
discontinue early will have the ET assessments completed as outlined in the Schedule of 
Assessments based upon from which phase treatment they are terminating, Table 2 (Blinded 
Treatment Period), Table 3 (Open-Label Extension Period), or Table 4 (Long-Term Extension 
Period). 
In addition to the ET Visit, patients should return for the EOT Visit 4 weeks following their 
last dose of rilzabrutinib/placebo or rilzabrutinib.   
In the event the ET Visit occurs ≥4 weeks after their last dose of rilzabrutinib/placebo or 
rilzabrutinib, this will be recorded as the ET Visit and there is no need for the 4-week safety 
follow-up (EOT) Visit. 
Urgent Safety Measures Initiated Due to Coronavirus disease 2019 (COVID-19) 
Pandemic:  
Each participating site, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), and drug regulatory authority was informed of urgent safety measures implemented 
to ensure continued supply of study medication and safety monitoring for patients. These 
measures are described in the “Updated Guidelines to Sites for Delayed Patient Visits 
or Missed Visits Due to Travel Restrictions and Any Foreseeable Impacts of COVID-19” 
(Appendix 9 Section 12.9). When the COVID-19 pandemic resolves, the measures will be 
repealed back to the previous state as government rules and benefit/risk assessment allow. 
Study Assessments Overview: 
See Schema in Section 1.2. 
Figure 1 for a diagram of the study design and the Schedules of Assessments (Table 2, 
Table 3, and Table 4) and for description of the assessments. 
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Corticosteroid Management (Appendix 1 Section 12.1) 
Corticosteroid Starting Doses and Management During Screening and at Day 1 
Required initial doses of CS for the duration of Screening are ≥0.2 mg/kg/day of CS for 
patients with relapsing disease (diagnosed >6 months prior to Screening) and ≥0.5 mg/kg/day 
for patients with newly diagnosed disease (diagnosed ≤6 months prior to Screening). 
At Screening, patients will begin to take Sponsor-provided CS according to the minimum dose 
requirements, and as required to adequately treat the disease during the Screening period. CS 
doses may be adjusted per Investigator discretion during the Screening period (Appendix 1 
Section 12.1) but the dose should not be reduced below the required minimum initial dose 
levels (Table 1). CS taper below the required minimum dose level should not begin until ECP 
has been achieved. 
If disease significantly (Investigator judgment) worsens during the Screening period, 
up-titration of CS dose by 50-100% should occur, as often as every 5-7 days if needed (4).  
Corticosteroid Management during Blinded Treatment Period, Open-Label Extension 
Period, and Long Term Extension Period 
Corticosteroid-Tapering (Consensus Guidelines) (1) 
CS will be tapered from ECP towards a goal of 5 mg/day by ≤Week 29. Once the 5 mg level is 
achieved it will be kept at 5 mg/day until the time of the primary endpoint at Week 37 is 
reached. From Week 37, further tapering to 0 mg CS should be attempted in patients with CR 
unless medically contraindicated. At Investigator discretion, the CS may be switched to 
equivalent doses of oral hydrocortisone instead of prednisone or prednisolone when tapering 
from 5 mg to 0 mg CS. 
CS tapering should follow the modified dosing guidelines below (1):  
Adjustment of the dosing guideline protocol by investigators is permitted for safety reasons, 
based on assessment and documentation of clinical need.  
• Start tapering CS as soon as ECP is confirmed. 
• Decrease CS by 25% every two weeks, until 20 mg per day 
• Once at 20 mg per day, decrease CS by 2.5 mg per week 
• Once at 10 mg/day, decrease CS by 1 mg per week 
Note, because 1 mg will be the smallest CS dosage provided and tablet splitting is not allowed, 
the Investigator must round up or down to the nearest whole milligram for CS dose after 
calculation of the new dose level. 
Corticosteroid-Up-Titration (4) 
Patients who fail to respond to treatment or experience a worsening of disease should have 
their CS dose increased per CS Management Guidelines (Appendix 1 Section 12.1 ) until CDA 
is obtained. If ECP is not achieved in a timely manner, it is encouraged that CS dose be further 
increased unless clinically contraindicated. The PI should consult with the Medical Monitor in 
such cases. 
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For full details of up-titration see Appendix 1 Section 12.1. 
Concomitant Medications 
Strong to Moderate Inducers or Inhibitors of cytochrome P450 (CYP)3A, and “Sensitive” 
CYP3A Substrate Drugs with a narrow therapeutic index are not permitted (Appendix 7 
Section 12.7). 
Other “Sensitive” CYP3A drugs should be used cautiously by administering them only if the 
benefit/risk is favorable, using staggered administration at least 2 hours after rilzabrutinib 
or placebo. 
Patients on proton pump inhibitor drugs should have their medication changed to histamine 2 
(H2) blockers during Screening and at least 3 days before Day 1. H2 blockers should be 
administered at least 2 hours after rilzabrutinib or placebo. 
Inclusion Criteria 
Patients may be included in the study if ALL of the following criteria are met: 
Type of participant and disease characteristics 
I01. 
Male or female patients, aged 18 to 80 years old with moderate to severe, newly 
diagnosed or relapsing PV or PF, with a clinical presentation and 
histopathology consistent with PV or PF (see Section 8.4.3).  
I02. 
Positive circulating anti-dsg1 or 3 autoantibody titer. 
I03. 
At Screening, PDAI score of at least 9 points for relapsing patients (diagnosed 
>6 months prior to Screening) or at least 15 points for newly diagnosed patients 
(diagnosed ≤6 months prior to Screening). 
I04. 
Adequate hematologic, hepatic, and renal function (including but not limited to 
absolute neutrophil count ≥1.5 × 109/L, hemoglobin [Hgb] >9 g/dL, platelet 
count ≥100 × 109/L, aspartate aminotransferase [AST] and/or alanine 
aminotransferase [ALT] ≤1.5 × upper limit of normal [ULN], albumin ≥3 g/dL, 
creatinine ≤1.5 × ULN). 
Sex, contraceptive/barrier method and pregnancy testing requirements 
I05. 
Female patients who are of reproductive potential must agree for the duration of 
the study to use an effective means of contraception (eg, hormonal 
contraception methods that inhibit ovulation, intrauterine device, intrauterine 
hormone-releasing system, bilateral tubal ligation, vasectomized partner or 
condoms).  
For females considered not to have reproductive potential:  
Any woman of age ≥55 years with amenorrhea for >1 year, will be considered 
as having confirmed menopause and follicle-stimulating hormone (FSH) or 
pregnancy testing will not be needed. Postmenopausal females <55 years of age 
(defined as amenorrhea >1 year) must have menopause confirmed by elevated 
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FSH levels at screening. Surgically sterile females do not require any further 
confirmation of menopause and will not be considered to have reproductive 
potential. 
For participants in Germany, please see specific instructions in Appendix 10 
Section 12.10. 
Informed Consent 
I06. 
Able to provide written informed consent and agreeable to the schedule of 
assessments. 
Exclusion Criteria 
Patients will be excluded from the trial if any of the following criteria are met: 
Medical conditions 
E01. 
Suspected paraneoplastic pemphigus and other forms of pemphigus that are not 
pemphigus vulgaris or pemphigus foliaceus. 
E02. 
Previous use of a Bruton tyrosine kinase (BTK) inhibitor. 
E03. 
Pregnant or lactating women. 
E04. 
Electrocardiogram (ECG) findings of QT corrected for heart rate (QTc) >450 
msec (males) or >470 msec (females), poorly controlled atrial fibrillation (ie, 
symptomatic patients or a ventricular rate above 100 beats/min on ECG), or 
other clinically significant abnormalities. 
E05. 
A history of malignancy of any type within 5 years before Day 1, other than 
surgically excised non-melanoma skin cancers or in situ cervical cancer.  
Prior/concomitant therapy 
E06. 
Use of immunologic response modifiers as concomitant medication and with 
the following washout periods: A) stop at least 2 weeks prior to Screening: 
mycophenolate mofetil, azathioprine, methotrexate, cyclosporine, dapsone, 
intravenous immunoglobulin (IVIG), Kinaret (anakinra), Enbrel (etanercept), or 
any other immunosuppressant not mentioned in this exclusion criterion; B) 
12 weeks prior to Screening: Remicade (infliximab), Humira (adalimumab), 
Simponi (golimumab), Orencia (abatercept), Actemra (tocilizumab), Cimzia 
(certolizumab), Cosentyx (secukinumab), plasmapheresis; C) 6 months prior to 
Screening (or shorter if there is documented B cell reconstitution for anti-
CD20 drugs): anti-CD20 drugs such as rituximab, ofatumumab, other long-
acting biologics. 
E07. 
Use of proton pump inhibitor drugs such as omeprazole and esomeprazole 
within 3 days of Day 1 (it is acceptable to change patient to H2 receptor 
blocking drugs prior to Day 1). 
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E08. 
Concomitant use of known strong-to-moderate inducers or inhibitors of CYP3A 
within 3 days or 5 half-lives (whichever is longer) of Day 1 (Appendix 7 
Section 12.7). 
E09. 
Use of CYP3A-sensitive substrate drugs with a narrow therapeutic index within 
3 days or 5 half-lives (whichever is longer) of Day 1 and for the remainder of 
the trial including, but not limited to alfentanil, astemizole, cisapride, 
cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus (topical and oral), or terfenadine.  
E010. 
Has received any investigational drug (or is currently using an investigational 
device) within the 30 days before Day 1, or at least 5 times the respective 
elimination half-life time (whichever is longer). 
E011. 
History of drug abuse within the previous 12 months. 
E012. 
Alcoholism or excessive alcohol use, defined as regular consumption of more 
than approximately 3 standard drinks per day. 
Other exclusions 
E013. 
Refractory nausea and vomiting, malabsorption, external biliary shunt, or 
significant bowel resection that would preclude adequate rilzabrutinib/placebo 
absorption. 
E014. 
Donation of a unit or more of blood or blood products within 4 weeks prior to 
Day 1. 
E015. 
History of solid organ transplant. 
E016. 
Positive at Screening for human immunodeficiency virus (HIV), hepatitis B 
(surface antigen and/or core antibodies), or hepatitis C (anti-HCV antibody 
confirmed with Hep C RNA). 
E017. 
Positive interferon-gamma release assay (IGRA) (eg, T-spot TB Test, 
QuantiFERON®-TB Gold, or QuantiFERON®-TB Gold Plus (QFT Plus), at 
Screening. Unless, the patient has latent tuberculosis (TB) and all of the 
following 3 conditions are true: 
a) Chest X-ray does not show evidence suggestive of active TB disease 
b) There are no clinical signs and symptoms of pulmonary and/or extra-pulmonary 
TB disease 
c) Documented receipt of one of the following prophylactic treatment regimens: 
i. Oral daily Isoniazid for 6 months 
or 
ii. Oral daily Rifampin (RIF) for 4 months 
or 
iii. Isoniazid and Rifapentine weekly for 3 months (3HP)  
On a case by case basis, after discussion and approval by the Sponsor, a local TB test 
that is negative and is considered equivalent to 1 of the above tests may be used for 
eligibility. For example, if a QuantiFERON®-TB Gold, or QuantiFERON-TB Gold 
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Plus (QFT Plus) is indeterminate for any reason and a local blood test or T-Spot TB 
test is negative, the patient may be enrolled using the local result upon approval of the 
Sponsor. 
E18. 
History of serious infections requiring intravenous therapy with the potential for 
recurrence or currently active moderate to severe infection at Screening (Grade 2 
or higher). 
E19. 
Live vaccine within 28 days prior to Day 1 or plan to receive one during the trial. 
E20. 
Any other clinically significant disease, condition [including contraindication to 
CS and/or inability to follow CS dosing as outlined in the protocol (see Table 1 
for more details)], or medical history that, in the opinion of the Investigator, 
would interfere with patient safety, trial evaluations, and/or trial procedures. In 
areas endemic for Chagas disease, screening is recommended prior to enrollment. 
For participants in Germany, please see specific instructions in Appendix 10 
Section 12.10. 
Outcome Measures 
Primary Efficacy Endpoint 
• The proportion of patients who are in CR from Week 29 to Week 37 with a CS dose of 
≤10 mg/day. 
Key Secondary Efficacy Endpoints 
• Cumulative CS dose from Baseline to Week 37 
• Cumulative duration of CR with a CS dose ≤10 mg/day, from Baseline to Week 37 
• Time to first CR with a CS dose ≤10 mg/day, from Baseline to Week 37 
Other Secondary Endpoints 
• The proportion of patients who are in CR from Week 29 to Week 37 with a CS dose of 
≤5 mg/day 
• The proportion of patients who have a PDAI score <3 from Week 29 to Week 37 with 
a CS dose ≤10 mg/day 
• Cumulative duration of CR with a CS dose ≤10 mg/day from Baseline to Weeks 61 
and 109 
• Cumulative duration of CR with a CS dose = 0 mg/day from Baseline to Weeks 61 and 
109 
• GTI score at Week 37 
• Change in PDAI score from Baseline to Weeks 5, 13, 25, 37, 61, and 109 
• Change in Autoimmune Bullous Disease Quality of Life (ABQOL) score from 
Baseline to Weeks 5, 13, 25, 37, 61, and 109 
• Proportion of patients with ABQOL Score of zero at Weeks 5, 13, 25, 37, 61, and 109  
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• Change in EuroQOL-5 Dimension 5 Level (EQ-5D-5L) results (visual analog scale 
[VAS] results and individual dimension) scores from Baseline to Weeks 5, 13, 25, 37, 
61, and 109  
• Time to first CR with a CS dose ≤10 mg/day, from Baseline to Weeks 61 and 109 
• Total number of disease relapses/flares from initial CDA to Week 37 
• Time to initial relapse/flare from initial CDA to Week 37 
• Proportion of patients with 3 or more new lesions within 1 month that do not heal 
spontaneously within 1 week, or with extension of established lesions, from Baseline to 
Week 37 
• Proportion of patients with at least one disease relapse/flare from initial control of 
disease activity (CDA) to Week 37 
• Cumulative duration of CR with a CS dose ≤10 mg/day, from Week 37 to Week 61 
• Cumulative duration of CR with a CS dose = 0 mg/day, from Week 37 to Week 61 
Safety Endpoints 
• Nature, frequency, and severity of adverse events, including serious adverse events, 
adverse events leading to discontinuation and possible corticosteroid-related adverse 
effects. 
• Change from Baseline in vital signs and clinical laboratory test results (including 
complete blood count and blood chemistry). 
Pharmacokinetic Endpoints 
• Plasma concentrations of rilzabrutinib at approximately the time of maximum 
concentration at Day 1 and at varied subsequent timepoints (refer to Table 2 
and Table 3). 
Pharmacodynamic Endpoints 
• Change from Baseline in anti-dsg1 and anti-dsg3 autoantibody levels by enzyme-
linked immunosorbent assay (ELISA) at Weeks 13, 25, 37, 49, 61, and 109. 
Exploratory Endpoints 
• Plasma concentrations of rilzabrutinib metabolites 
• Exploratory PK/PD analysis will examine the effects, if any, of covariates on PK 
and/or PD, and the relationship between PK, PD, and efficacy in this population 
• Cost utilities based on the number and type of hospitalizations, outpatient medical 
visits, concomitant medication use, adverse events and other relevant outcomes 
• Change from Baseline in PDAI by visit and the temporal relationship to changes in 
quality of life and health economic variables 
• Proportion of patients with relapse/flare after achievement of CR between Baseline 
and Weeks 61 and 109 
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• Proportion of patients initially randomized to rilzabrutinib that are in CR with a zero 
CS dose, from Week 53 to Week 61 (no randomized treatment comparison) 
• Proportion of patients initially randomized to placebo that are in CR with a zero CS 
dose, from Week 53 to Week 61 (no randomized treatment comparison) 
• Change in Treatment of Autoimmune Bullous Disease Quality of Life (TABQOL) 
score from Baseline to Weeks 5, 13, 25, 37, 61, and 109 
• Total number of disease relapses/flares from Week 37 to Weeks 61 and 109 
• (Optional) Blood samples for exploratory analysis of vaccine IgG response during 
treatment. 
Long Term Extension Endpoints 
• Nature, frequency, and severity of adverse events, including serious adverse events, 
adverse events leading to discontinuation and possible corticosteroid-related adverse 
effects during the LTE from Week 61 to Week 113 
• Average daily dose of CS from Week 61 to Week 113 
• Time to initial relapse/flare from initial CDA to Week 109. 
Safety Assessments 
The safety of the drug will be evaluated by multiple assessments of patient vital signs, physical 
exams, and laboratory tests. Concomitant medications and adverse events (AEs) will be 
monitored and tracked. 
An independent Data Safety Monitoring Board (DSMB) will regularly review unblinded 
safety data. 
Please refer to Schedule of Assessments (Table 2, Table 3 and Table 4) and Section 8.6. 
Pharmacokinetic and Pharmacodynamic 
Individual and group PK (rilzabrutinib and metabolites as applicable) and PD (anti-
desmoglein-1 and -3) data will be summarized, displayed graphically, and by descriptive 
statistics for each visit, where measured. Please refer to the Statistical Section 9.3.7.  
Sample Size  
See Section 9.1. 
Randomization 
Patients will be randomized at Day 1, in a 1:1 allocation, using a stratification by PV/PF 
disease type, and by newly diagnosed disease (diagnosed ≤6 months prior to Screening) or by 
relapsing disease (diagnosed >6 months prior to Screening.) 
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Other Statistical Considerations 
The primary efficacy analysis will be conducted when all patients have completed the Study 
Week 37 Visit (ie, completed the Blinded Treatment Period). 
A formal Statistical Analysis Plan (SAP) will be developed prior to database lock 
and unblinding. The SAP will contain a more detailed and/or comprehensive presentation of 
statistical methods or procedures, attention to any changes of substance to planned analysis 
procedures relative to those indicated in the protocol, and will be the final authority for all 
statistical analyses. 
Descriptive summaries of variables by treatment will be provided where appropriate. 
For continuous variables, the number of non-missing values (n) and the median, mean, 
standard deviation (SD), minimum, and maximum will be tabulated by treatment and where 
appropriate by study day and study timepoint. 
Summaries will also be presented for the change from baseline, when appropriate. 
For categorical variables, the counts and proportions of each value will be tabulated by 
treatment and where appropriate by study day and study timepoint. For time to event variables, 
point estimates (25th, 50th, and 75th percentiles) along with 95% confidence intervals will be 
tabulated by treatment. Survival estimates will also be shown graphically for each treatment. 
All statistical tests will be two-sided unless otherwise noted. 
An independent DSMB will regularly review unblinded safety data. Full details of DSMB 
functioning will be included in a Charter. 
Please refer to Statistical Section 9. 
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1.2 
SCHEMA  
Figure 1: 
Study Design Flow Chart   
 
 
 
Abbreviations: bid = twice daily; CR = complete remission; CS = corticosteroids; EP = endpoint; PF = pemphigus foliaceus; PV = pemphigus vulgaris; R = randomization; 
SCR = Screening Period; W = week. 
 
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
Table 2: 
Schedule of Assessments - Blinded Treatment Period  
 
Screening 
Blinded Treatment Period 
Early 
Termination 
(ET) 
Unscheduled 
Visit 
Day -29)n,o 
WK (-4) 
Day 1 
Week 1 
Pre-dose 
Day 1 
Week 1 
Post-dose 
WK 
3 
WK 
5 
WK 
9 
WK 
13 
WK 
17 
WK 
21 
WK 
25 
WK 
29 
WK 
33 
WK 
37 
Visit Window 
  
  
  
±3 
days 
±3 
days 
±3 
days 
±3 
days 
±3 
days 
±3 
days 
±3 
days 
±3 
days 
±3 
days 
±3 
days 
  
  
Informed Consent 
X 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
Inclusion/Exclusion Criteria 
X 
Xo 
  
 
  
  
  
  
  
  
  
  
  
  
  
Randomization 
  
X 
  
 
  
  
  
  
  
  
  
  
  
  
  
Height 
X 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
Weight 
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full physical examination  
X 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
Medical History 
X 
 
  
 
  
  
  
  
  
  
  
  
  
  
  
Abbreviated physical examination 
  
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
  
  
 
  
  
  
  
  
  
  
  
X 
  
(X)a  
Vital Signs 
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysisb 
X 
  
  
 
  
  
  
  
  
  
  
  
 X 
X  
(X)a 
Hep B and C, HIV, & QuantiFERON-
TB Gold or Quantiferon-TB Gold 
Plus or TB-Spot 
X 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
Pregnancy testc 
X 
X 
  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Skin biopsyd 
X 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
Hematology, coagulation, and serum 
chemistrye 
X 
X 
  
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
(X)a  
HbA1c and LDLe (fasting) 
  
X 
  
 
  
  
X 
  
  
X 
  
  
X 
X 
  
FSHf 
X 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
PK sample 
  
X 
Xg 
Xh 
Xh 
Xh 
Xh 
  
  
Xh 
  
  
 Xh 
Xh 
(X)a   
PD: anti-desmoglein-1 and -3 
autoantibody titers by ELISA 
X 
X 
  
 
  
  
X 
  
  
X 
  
  
X 
X 
(X)a   
PDAI 
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ABQOL, TABQOL  
X 
X 
  
X 
X 
  
X 
  
 
X 
  
  
X 
X 
X 
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e Hematology will include the following: hemoglobin, hematocrit, erythrocyte count (red blood cell [RBC] count), thrombocyte count (platelets), leukocyte count (white blood cell [WBC] count) with differential in 
absolute counts (including neutrophils, eosinophils, basophils, lymphocytes, and monocytes). Serum chemistry will include the following: aspartate aminotransferase (AST); alanine aminotransferase (ALT); total, 
direct, and indirect bilirubin levels; alkaline phosphatase (ALP); albumin; creatinine; urea; total protein; sodium; chloride; calcium; phosphate; potassium; and glucose (random). Creatine phosphokinase (CPK) is to 
be performed at Screening only. Coagulation will include: PT/INR, thrombin time, aPTT, and fibrinogen level and will be collected at Screening, Day 1 Week 1 Pre-dose, and Weeks 3, 5, 9, 13, 25, & 37. HbA1c 
and LDL level (fasting) will be collected every 3 months with GTI assessment. 
f 
Any woman of age ≥55 years with amenorrhea for >1 year, will be considered as having confirmed menopause and will not need FSH or pregnancy testing. 
Postmenopausal females <55 years of age (defined as amenorrhea >1 year) should have menopause confirmed by follicle-stimulating hormone (FSH) and serum pregnancy testing at screening. Surgically sterile 
females do not require any further confirmation of menopause and will not be considered to have reproductive potential. 
g Two hours post-dose (±15 minutes). 
h PK sample should be taken at random timepoints during the patient visits with as much variation in time since last dose as practicable. Time of draw will be captured as well as time of the last two rilzabrutinib or 
placebo doses, and time of the patient’s last meal. 
i 
Pemphigus Clinical Response Definitions for CDA, CR, ECP, relapse/flare (refer to protocol Section 3). 
j 
For CS management, refer to Appendix 1. At any point if CS needs to be adjusted between required visits, the patient may return for an unscheduled visit and additional CS may be dispensed via IWRS if required. 
CS doses taken will be recorded by the patient on a dosing diary. Patients should bring their diary and used and unused CS containers with them at every visit.  
k Rituximab may be administered intravenously during the Blinded Treatment Period, unless contraindicated, after a second “qualifying relapse/flare” occurs at or after Day 29 Visit. See Appendix 1. Any rituximab 
dispensed will undergo drug accountability. 
l 
Photography of lesions allowed at selected centers at the discretion of the Investigator and as per local regulations. 
m AEs occurring after Screening and before baseline dosing are recorded as treatment AEs unrelated to rilzabrutinib or placebo. 
n As described in Section 8.3.1, laboratory assessments delayed due to logistic considerations may be performed with an extended Screening window (up to 7 additional business days), upon Sponsor review and 
approval. Patients may be re-screened once. Any labs completed in prior Screening, within 2 weeks of re-screening will remain valid and should not be repeated. Labs performed for a previous screening within 
6 weeks, may be considered for determination of eligibility on approval of the Medical Monitor. In the specific cases of QuantiFERON-TB, anti desmoglein antibodies and hepatitis/HIV testing, tests may be 
considered for determination of eligibility if performed in a previous screen within the last 12 weeks, with the approval of the Medical Monitor. However, pregnancy tests should be repeated at re-screening. 
o To determine a patient’s eligibility, Screening laboratory results will be used, not Day 1. 
p The last rilzabrutinib/placebo blinded dose should be taken on the morning of the Week 37 Visit. At the Week 37 Visit, open-label rilzabrutinib will be dispensed and used for the Week 37 evening dose. 
q Subjects are required to bring all used and unused study drug supplies with them to every clinic visit.  
r 
Patients will be encouraged to provide vaccination plans for any vaccines which are in line with the participants’age-appropriate local medical practice or guidelines (live attenuated vaccines are excluded) during 
the study. Participants planning to receive any vaccines during the study may optionally consent for collection of 2 blood samples for assay of vaccine IgG in serum for each vaccine dose regimen. 
s Vaccination data will be reported when possible (see Section 12.11, Appendix 11). Additionally, optional collection of blood for assay of vaccine IgG in serum for each vaccine: the first sample should be collected 
within 6 weeks prior to each vaccine dose regimen, and the second should be collected within approximately 3 to 6 weeks after the vaccine regimen is complete. Vaccinations should preferably occur after 
completion of at least 6 weeks of any treatment of rilzabrutinib/placebo (Blinded Treatment Period) or rilzabrutinib (OLE or LTE), while remaining in compliance with the patient’s recommended immunization 
schedule. Blood collections should be conducted at regularly scheduled study visits but, if this is not feasible, could also be done at unscheduled visits. 
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Table 3: 
Schedule of Assessments - Open-Label Extension Period  
 
 
Open-Label Extension Period 
Follow-up Period 
Early  
Termination 
(ET) a 
 
Unscheduled 
Visit 
Week 
37k 
Week 
39 
Week 
41 
Week 
45 
Week 
49 
Week 
53 
Week 
57 
Week 
61l 
EOT/ 
Week 65 
4 wk FU Visit 
 
Visit Windows 
±3  
days 
±3  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Abbreviated physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
12-lead ECG  
X 
 
 
 
 
 
 
X 
 
(X)b 
 
(X)b 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Urinalysisc 
X 
 
 
 
 
 
 
X 
X 
X 
 
(X)b 
Urine pregnancy testd 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology, coagulation, and serum 
chemistryc 
X 
X 
 
 
X 
 
 
X 
X 
X 
 
(X)b 
HbA1c and LDLc (fasting) 
X 
 
 
 
 
 
 
 
 
 
 
 
PK Samplee 
X 
X 
 
 
X 
 
 
X 
 
X 
 
(X)b 
PD: anti-desmoglein-1 and -3 
autoantibody titers by ELISA 
X 
 
 
 
X 
 
 
X 
 
X 
 
(X)b 
PDAI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
ABQOL and TABQOL 
X 
X 
 
 
X 
 
 
X 
X 
X 
 
X 
EQ-5D-5L 
X 
X 
 
 
X 
 
 
X 
X 
X 
 
X 
GTI Index 
X 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Outcome Assessmentf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Photographyg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Rilzabrutinib dispensed 
Xj 
 
X 
X 
X 
X 
X 
Xl 
 
 
 
 
TBNK Panel 
Xm 
 
 
 
 
 
 
 
 
 
 
 
Drug reconciliationh 
(rilzabrutinib/CS Dosing 
Documentation) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
CS Daily Dosingi 
 
X (See Appendix 1) 
 
X 
Vaccine IgG 
Xn 
Xo 
Xo 
Xo 
Xo 
Xo 
Xo 
Xo 
Xo 
Xo 
 
Xo 
SARS-CoV-2 (for participants in 
Germany only, see specific 
instructions in Appendix 10) 
X 
 
X 
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ABQOL = Autoimmune Bullous Disease Quality of Life; CDA = control of disease activity; CR = complete remission; CS = corticosteroids; ECG = electrocardiogram; ECP = End of consolidation phase; ELISA = 
enzyme-linked immunosorbent assay; EOT = End of Trial; EQ-5D-5L = EuroQOL-5 Dimension 5 Level; FU = follow-up; HgbA1c = hemoglobin A1c; LDL = low-density lipoprotein; PD = pharmacodynamics; PDAI = 
Pemphigus Disease Area Index; PK = pharmacokinetic(s); TABQOL = Treatment of Autoimmune Bullous Disease Quality of Life; wk = week. 
a The early termination (ET) Visit should be performed for patients who are not able to complete the Open Label Extension period including Week 65 Visit and discontinue from the trial early.  
b Only if clinically indicated.  
c Hematology will include the following: hemoglobin, hematocrit, erythrocyte count (red blood cell [RBC] count), thrombocyte count (platelets), leukocyte count (white blood cell [WBC] count) with differential in 
absolute counts (including neutrophils, eosinophils, basophils, lymphocytes, and monocytes). Serum chemistry will include the following: aspartate aminotransferase (AST); alanine aminotransferase (ALT); total, 
direct, and indirect bilirubin levels; alkaline phosphatase (ALP); albumin; creatinine; urea; total protein; sodium; chloride; calcium; phosphate; potassium; and glucose (random). Creatine phosphokinase (CPK) is to 
be performed at Screening only. Coagulation will include: PT/INR, thrombin time, aPTT, and fibrinogen level and will be collected at Weeks 39, 49, 61, ET, and EOT (if applicable). Urinalysis will include: pH, 
specific gravity, protein, glucose, ketones, bilirubin, blood, nitrites, urobilinogen, leukocytes and reflex microscopy. At Week 37, the HbA1c and LDL level (fasting) will be collected with GTI assessment. 
d For women of childbearing potential only. 
e PK sample should be taken at random timepoints during the patient visits with as much variation in time since last dose as practicable. Time of draw will be captured as well as time of the last two rilzabrutinib 
doses, and time since the patient’s last meal. 
f 
Pemphigus Clinical Response Definitions for CDA, CR, ECP, relapse/flare (refer to protocol Section 3).  
g Photography of lesions allowed at selected centers at the discretion of the Investigator and as per local regulations.  
h Subjects are required to bring all used and unused study drug supplies with them to every clinic visit. 
i 
For CS management, refer to Appendix 1. At any point if CS needs to be adjusted between required visits, the patient may return for an unscheduled visit and additional CS may be dispensed via IWRS if required. 
CS doses taken will be recorded by the patient on a dosing diary. Patients should bring their diary and used and unused CS containers with them at every visit. Patients entering the LTE will receive Sponsor-
provided CS, following CS Management Guidelines (Appendix 1). 
j 
The last rilzabrutinib/placebo blinded dose should be taken on the morning of the Week 37 visit. At the Week 37 visit, open-label rilzabrutinib will be dispensed and used for the Week 37 evening dose. 
k Assessments performed at the Week 37 Visit of the Blinded Treatment Period should not be repeated at this visit.  
l 
If patient is eligible for the Long Term Extension Period at Week 61 they will continue to receive rilzabrutinib per Table 4. If the patient is not eligible for the Long Term Extension Period at Week 61 they will 
discontinue rilzabrutinib and complete the EOT visit at Week 65. 
m Patients that received rituximab during the Blinded Treatment Period and are continuing in the study, TBNK panel will be drawn at their Week 37 visit. 
n Patients will be encouraged to provide vaccination plans for any vaccines which are in line with the participants’age-appropriate local medical practice or guidelines (live attenuated vaccines are excluded) during 
the study. Participants planning to receive any vaccines during the study may optionally consent for collection of 2 blood samples for assay of vaccine IgG in serum for each vaccine dose regimen. 
o Vaccination data will be reported when possible (see Section 12.11, Appendix 11 ). Additionally, optional collection of blood for assay of vaccine IgG in serum for each vaccine: the first sample should be collected 
within 6 weeks prior to each vaccine dose regimen, and the second should be collected within approximately 3 to 6 weeks after the vaccine dose regimen is complete. Vaccinations should preferably occur after 
completion of at least 6 weeks of any treatment of rilzabrutinib/placebo (Blinded Treatment Period) or rilzabrutinib (OLE or LTE), while remaining in compliance with the patient’s recommended immunization 
schedule. Blood collections should be conducted at regularly scheduled study visits but, if this is not feasible, could also be done at unscheduled visits. 
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Table 4: 
Schedule of Assessments - Long Term Extension Period  
Visit Windows 
Long Term Extension Period 
Early  
Termination 
(ET)a 
 
Unscheduled 
Visit 
Week 
61j 
Week 
65 
Week 
69 
Week 
73 
Week 
85 
Week 97 
Week 
109 
EOT/Week 113 
4 wk FU Visit 
 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±10  
days 
±10  
days 
±10  
days 
±5  
days 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Abbreviated physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
12-lead ECG  
X 
 
 
 
 
 
X 
 
(X)b 
 
(X)b 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Urinalysisc 
X 
 
 
 
 
 
X 
X 
X 
 
(X)b 
Urine pregnancy testd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology, coagulation, and serum 
chemistryc 
X 
 
 
 
X 
X 
X 
X  
X 
 
(X)b 
PK Samplee 
X 
 
 
 
 
 
 
 
 
 
(X)b 
PD: anti-desmoglein-1 and -3 autoantibody 
titers by ELISA 
X 
 
 
X 
X 
X 
X 
 
X 
 
(X)b 
PDAI 
X 
 
 
 
 
 
X 
 
X 
 
 
ABQOL and TABQOL 
X 
 
 
 
 
 
X 
 
X 
 
 
EQ-5D-5L 
X 
 
 
 
 
 
X 
 
X 
 
 
Efficacy Outcome Assessmentf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Adverse events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Photographyg 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Rilzabrutinib dispensed 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Drug reconciliationh 
(rilzabrutinib/CS Dosing Documentation) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
CS Daily Dosingi 
X      See Appendix 1 
 
X 
Vaccine IgG 
Xk 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
 
Xl 
SARS-CoV-2 (for participants in Germany 
only, see specific instructions in 
Appendix 10) 
X 
 
X 
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ABQOL = Autoimmune Bullous Disease Quality of Life; CDA = control of disease activity; CR = complete remission; CS = corticosteroids; ECG = electrocardiogram; ECP = End of consolidation phase; ELISA = 
enzyme-linked immunosorbent assay; EOT = End of Trial; EQ-5D-5L = EuroQOL-5 Dimension 5 Level; FU = follow-up; 
HgbA1c = hemoglobin A1c; LDL = low-density lipoprotein; PD = pharmacodynamics; PDAI = Pemphigus Disease Area Index; PK = pharmacokinetic(s); TABQOL = Treatment of Autoimmune Bullous Disease Quality 
of Life; wk = week 
a The early termination (ET) Visit should also be performed for patients who are not able to complete the Long-Term Extension period including Week 113 Visit and discontinue from the trial early.  
b Only if clinically indicated.  
c Hematology will include the following: hemoglobin, hematocrit, erythrocyte count (red blood cell [RBC] count), thrombocyte count (platelets), leukocyte count (white blood cell [WBC] count) with differential in 
absolute counts (including neutrophils, eosinophils, basophils, lymphocytes, and monocytes). Serum chemistry will include the following: aspartate aminotransferase (AST); alanine aminotransferase (ALT); total, 
direct, and indirect bilirubin levels; alkaline phosphatase (ALP); albumin; creatinine; urea; total protein; sodium; chloride; calcium; phosphate; potassium; and glucose (random). Coagulation will include: PT/INR, 
thrombin time, aPTT, and fibrinogen level and will be collected at Weeks 61, 85, 97, 109, ET, and EOT. Urinalysis will include: pH, specific gravity, protein, glucose, ketones, bilirubin, blood, nitrites, urobilinogen, 
leukocytes and reflex microscopy.  
d For women of childbearing potential only. May be performed monthly between Week 73 and Week 113 if required by local regulations. 
e PK sample required at Week 61; and after Week 61 only if the patient experiences relapse/flare. Time of draw will be captured as well as time of the last two rilzabrutinib doses, and time since the patient’s last 
meal. 
f 
Pemphigus Clinical Response Definitions for CDA, CR, ECP, relapse/flare (refer to protocol Section 3).  
g Any photos should be taken and stored in accordance with local regulations (Week 61 only). 
h Subjects are required to bring all used and unused rilzabrutinib study drug supplies with them to every clinic visit. 
i 
For CS management, refer to Appendix 1. Patients entering the LTE will receive Sponsor-provided CS. At any point if CS needs to be adjusted between required visits, the patient may return for an unscheduled 
visit and additional CS may be dispensed.  
j 
Assessments performed at the Week 61 Visit of the Open-Label Period should not be repeated at this visit.  
k Patients will be encouraged to provide vaccination plans for any vaccines which are in line with the participants’age-appropriate local medical practice or guidelines (live attenuated vaccines are excluded) during 
the study. Participants planning to receive any vaccines during the study may optionally consent for collection of 2 blood samples for assay of vaccine IgG in serum for each vaccine dose regimen. 
l 
Vaccination data will be reported when possible (see Section 12.11, Appendix 11). Additionally, optional collection of blood for assay of vaccine IgG in serum for each vaccine: the first sample should be collected 
within 6 weeks prior to each vaccine dose regimen, and the second should be collected within approximately 3 to 6 weeks after the vaccine dose regimen is complete. Vaccinations should preferably occur after 
completion of at least 6 weeks of any treatment of rilzabrutinib/placebo (Blinded Treatment Period) or rilzabrutinib (OLE or LTE), while remaining in compliance with the patient’s recommended immunization 
schedule. Blood collections should be conducted at regularly scheduled study visits but, if this is not feasible, could also be done at unscheduled visits. 
 
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2 
INTRODUCTION  
2.1 
STUDY RATIONALE  
Study PRN1008-012 is a randomized, parallel-group, double-blind, placebo-controlled trial over 
36 weeks (Blinded Treatment Period) followed by an Open-Label Extension Period of 24 weeks, 
Long Term Extension Period of 48 weeks, and a Follow-up Period of 4 weeks, which is intended 
to evaluate the efficacy and safety of oral PRN1008 (Rilzabrutinib) in moderate to severe 
pemphigus. 
The primary purpose of the 24-week, Open-Label Extension Period (OLE) is to allow access to 
study drug who were on placebo medication as well as to evaluate durability of clinical response 
and accrue additional long term data on the safety and efficacy of rilzabrutinib.  
The primary purpose of the 48-week, Long Term Extension Period (LTE) is to provide extended 
access to rilzabrutinib for patients who are receiving clinical benefit and to accrue additional 
long-term data on the safety and efficacy of rilzabrutinib. 
2.2 
BACKGROUND  
2.2.1 Overview of pemphigus  
Pemphigus is a group of rare autoimmune diseases that causes painful blistering of the skin 
and mucous membranes (mouth, nose, throat, eyes, and genitals). Pemphigus is associated with 
autoantibodies to the epithelial protein, desmoglein, in about 90% of cases. Pemphigus vulgaris 
(PV) and pemphigus foliaceus (PF) are the main subtypes of pemphigus with PV being the most 
common in most parts of the world (5, 6). Pemphigus can occur at any age, but often strikes 
people in middle or older age. Studies have shown that some populations may be at greater risk 
for certain types of pemphigus. For instance, people of Jewish descent and those from India, 
Southeast Europe, and the Middle East are at greater risk for PV, while PF is common in South 
America.  
PV typically begins with blisters (bullae) in the mouth, which are often mistaken for aphthous 
ulcers. The blisters are flaccid and are easily broken, leading to often-painful lesions or erosions. 
Blistering can also affect the esophagus, rectum, nose, or the lining of the eyelids. Skin lesions 
appear several weeks or months after the onset of mucosal erosions. PV is associated with 
circulating antibodies to desmoglein 3 in most cases. 
PF affects the skin only, without mucosal involvement. Antibodies to desmoglein 1 are commonly 
detected. The natural history is chronic, and treatment is identical to that for PV. 
In both types of pemphigus, Nikolsky's sign (shear force displacement of skin) can appear on 
perilesional skin or, in some cases, even on healthy skin. The diagnosis can be confirmed by 
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standard histopathological analysis and direct immunofluorescence test on affected skin. 
The presence of elevated anti-desmoglein antibodies is confirmatory. 
Presently, there are few effective treatment options for pemphigus. Current treatments include 
corticosteroids (CS) to reduce inflammation and antibiotics to treat associated infections. Agents 
such as mycofenolate mofetil are often used and rituximab has been reported to be effective. 
Mycofenolate mofetil has not been approved for this indication in any country and rituximab 
to treat pemphigus vulgaris has not been globally approved. The beneficial effects of these 
2 products take weeks to months. Current day practice guidelines recommend first-line therapy 
with relatively high doses of CS initially (0.5 to 1.5 mg/kg/day of prednisone or equivalent CS), 
with rituximab also for consideration as first line therapy in combination with CS (1). The long-
term use of CS has many adverse effects including serious infections, osteoporosis, decreased 
bone density, hypertension, and iatrogenic Cushing’s syndrome. Therefore, there is a significant 
unmet medical need for new therapeutics that can rapidly achieve and maintain disease remission 
while obviating or minimizing the need for CS therapy.  
2.2.2 BTK inhibitor (rilzabrutinib)  
Bruton tyrosine kinase (BTK) is expressed in cells of the B-cell lineage, including 
marrow-derived hematopoietic stem cells, common lymphoid progenitor cells and developing 
B and myeloid lineages. Bruton tyrosine kinase is also expressed in other cells of hematopoietic 
lineage with the exception of T cells, natural killer cells and plasma cells (7). 
A BTK inhibitor such as rilzabrutinib has the potential to target multiple pathways and cell types 
involved in inflammation and autoimmunity. These include: B cell receptor (BCR)-mediated 
B cell pathways, FcγR-induced cytokine release from monocytes and macrophages, FcεR-induced 
mast cell degranulation and granulocyte migration and mediator release. 
2.2.3 Nonclinical experience  
Rilzabrutinib has been evaluated in various pharmacology, pharmacokinetic, and toxicology 
studies in mice, rats, and dogs primarily by the intended oral route of administration. Rilzabrutinib 
demonstrated blockade of the rat arthus reaction, full disease reversal of a rat collagen-induced 
arthritis model, and reduction in platelet loss in a mouse model of immune thrombocytopenia. The 
therapeutic effects of rilzabrutinib in pemphigus was studied in dogs with newly diagnosed, 
naturally occurring PF in an outpatient clinical trial. The drug safely controlled disease without 
the need for CS in 4 of 4 cases. 
Please refer to the Investigator Brochure (IB) for more details. 
2.2.4 Clinical experience  
In clinical studies to date, Rilzabrutinib has been administered to more than 200 people, including 
healthy volunteers and patients with pemphigus and idiopathic thrombocytopenia. Twenty-seven 
patients with PV in a Phase 2 study (NCT02704429) used a starting dose of 400 mg BID which 
was shown to produce adequate BTK occupancies in all but one patient. One patient dose-escalated 
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to 500 mg BID and two to 600 mg BID, with all other patients using the 400 mg BID dose. The 
primary endpoint of the study, “control of disease activity by the Week 5 Visit on ≤0.5 mg/kg/day 
of prednisone (or equivalent CS)” was met by 54% (14/26) of patients. Complete remission (CR) 
on ≤0.5 mg/kg/day of CS was achieved by 25% (5/20) of patients completing 12 weeks treatment. 
Treatment-emergent adverse events (TEAEs) in the pemphigus study related to rilzabrutinib in 
≥10% of patients were nausea (15%), abdominal pain (11%) and headache (11%). One serious 
adverse event (AE) of Grade 3 “cellulitis” considered related to rilzabrutinib therapy occurred, 
resulting in a three day interruption of rilzabrutinib therapy. This patient continued therapy for 
two further months without recurrence of the event. 
Overall, results from Phase 1 and Phase 2 studies demonstrate that rilzabrutinib has an acceptable 
safety profile and is well tolerated in healthy subjects and patients with pemphigus. Please refer to 
the IB, for more details. 
2.3 
BENEFIT/RISK ASSESSMENT  
Phase 1 and Phase 2 studies have demonstrated an encouraging safety profile and a clinically 
meaningful treatment effect with Rilzabrutinib in mild to moderate pemphigus. In particular, the 
ability of rilzabrutinib to rapidly induce control of disease on doses of CS between 0 and 30 mg 
per day suggests that the drug may have a major CS-sparing effect. No risks other than those 
previously mentioned in the IB or in the summary of rilzabrutinib clinical experience, or in the 
rituximab and CS prescribing information are known at this time. Given this profile, there is 
equipoise in the proposed randomized, controlled trial of rilzabrutinib versus placebo on a 
background of usual care with CS. The risks of combination of rituximab and rilzabrutinib, should 
this occur, are justified as the combination will only be used in a multiple relapse/flare setting 
which requires more intensive immunosuppression. Furthermore, a similar rate of TEAEs has 
been reported in a randomized trial comparing the combination of rituximab and ibrutinib, a BTK/ 
interleukin-2-inducible T-cell kinase (ITK)/ epidermal growth factor receptor (EGFR) inhibitor to 
ibrutinib alone (8). 
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3 
OBJECTIVES AND ENDPOINTS  
Table 5: 
Objectives and endpoints  
Objectives 
Endpoints 
Efficacy 
• 
To evaluate the efficacy of rilzabrutinib in 
achieving durable CR on low to zero doses 
of oral corticosteroid (CS) and on the 
timecourse of quantitative disease activity 
scores 
• 
To assess the ability of rilzabrutinib to 
reduce CS exposure and the adverse 
effects of CS 
• 
To evaluate the time to specified clinical 
endpoints  
• 
To assess the longer term durability of CR 
 
Primary Efficacy Endpoint 
• 
The proportion of patients who are in CR from Week 29 to 
Week 37 with a CS dose of ≤10 mg/day 
Key Secondary Efficacy Endpoints 
• 
Cumulative CS dose from Baseline to Week 37 
• 
Cumulative duration of CR with a CS dose ≤10 mg/day, from 
Baseline to Week 37 
• 
Time to first CR with a CS dose ≤10 mg/day, from Baseline to 
Week 37 
Other Secondary Endpoints 
• 
The proportion of patients who are in CR from Week 29 to 
Week 37 with a CS dose of ≤5 mg/day 
• 
The proportion of patients who have a PDAI score <3 from 
Week 29 to Week 37 with a CS dose ≤10 mg/day 
• 
Cumulative duration of CR with a CS dose ≤10 mg/day from 
Baseline to Weeks 61 and 109 
• 
Cumulative duration of CR with a CS dose = 0 mg/day from 
Baseline to Weeks 61 and 109 
• 
GTI score at Week 37 
• 
Change in PDAI score from Baseline to Weeks 5, 13, 25, 37, 
61, and 109 
• 
Change in Autoimmune Bullous Disease Quality of Life 
(ABQOL) score from Baseline to Weeks 5, 13, 25, 37, 61, and 
109 
• 
Proportion of patients with ABQOL Score of zero at Weeks 5, 
13, 25, 37, 61, and 109 
• 
Change in EuroQOL-5 Dimension 5 Level (EQ-5D-5L) results 
(visual analog scale [VAS] results and individual dimension) 
scores from Baseline to Weeks 5, 13, 25, 37, 61, and 109 
• 
Time to first CR with a CS dose ≤10 mg/day, from Baseline to 
Weeks 61 and 109 
• 
Total number of disease relapses/flares from initial CDA to 
Week 37 
• 
Time to initial relapse/flare from initial CDA to Week 37 
• 
Proportion of patients with 3 or more new lesions within 
1 month that do not heal spontaneously within 1 week, or with 
extension of established lesions, from Baseline to Week 37 
• 
Proportion of patients with at least one disease relapse/flare 
from initial control of disease activity (CDA) to Week 37 
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Objectives 
Endpoints 
• 
Cumulative duration of CR with a CS dose ≤10 mg/day, from 
Week 37 to Week 61 
• 
Cumulative duration of CR with a CS dose = 0 mg/day, from 
Week 37 to Week 61 
Safety 
• 
To evaluate the safety of rilzabrutinib 
• 
To evaluate differences in potentially CS-related 
adverse events 
 
• 
Nature, frequency, and severity of adverse events, including 
serious adverse events, adverse events leading to 
discontinuation and possible corticosteroid-related adverse 
effects 
• 
Change from Baseline in vital signs and clinical laboratory 
test results (including complete blood count and blood 
chemistry) 
PK/PD Objectives 
• 
To evaluate the pharmacokinetics (PK) of 
rilzabrutinib 
• 
To evaluate pharmacodynamic (PD) effects 
of rilzabrutinib on anti-desmoglein (anti-dsg) 
autoantibody titers (anti-dsg1 and anti-dsg3) 
 
Pharmacokinetic Endpoints 
• 
Plasma concentrations of rilzabrutinib at approximately the 
time of maximum concentration at Day 1 and at varied 
subsequent timepoints (refer to Table 2 and Table 3) 
Pharmacodynamic Endpoints 
• 
Change from Baseline in anti-dsg1 and anti-dsg3 
autoantibody levels by enzyme-linked immunosorbent 
assay (ELISA) at Weeks 13, 25, 37, 49, 61, and 109 
Exploratory Objectives 
• 
To evaluate the PK of rilzabrutinib 
metabolites 
• 
To examine the effects of rilzabrutinib if 
any, of the baseline covariates on PK 
and/or PD, and the relationship between 
PK, PD, and efficacy  
• 
To explore association of vaccine response 
with rilzabrutinib 
• 
To examine the effect of rilzabrutinib on the 
costs of hospitalizations, outpatient medical 
visits, adverse events, concomitant 
medication use, and other relevant health 
economic outcomes 
• 
To examine the temporal relationship of 
change from baseline in Pemphigus 
Disease Area Index (PDAI) total activity 
score and quality of life and health 
economic measures 
 
Exploratory Endpoints 
• 
Plasma concentrations of rilzabrutinib metabolites 
• 
Exploratory PK/PD analysis will examine the effects, if any, 
of covariates on PK and/or PD, and the relationship 
between PK, PD, and efficacy in this population 
• 
Cost utilities based on the number and type of 
hospitalizations, outpatient medical visits, concomitant 
medication use, adverse events and other relevant 
outcomes 
• 
Change from Baseline in PDAI by visit and the temporal 
relationship to changes in quality of life and health 
economic variables 
• 
Proportion of patients with relapse/flare after achievement of 
CR between Baseline and Weeks 61 and 109 
• 
Proportion of patients initially randomized to rilzabrutinib that 
are in CR with a zero CS dose, from Week 53 to Week 61 
(no randomized treatment comparison) 
• 
Proportion of patients initially randomized to placebo that 
are in CR with a zero CS dose, from Week 53 to Week 61 
(no randomized treatment comparison) 
• 
Change in Treatment of Autoimmune Bullous Disease 
Quality of Life (TABQOL) score from Baseline to Weeks 5, 
13, 25, 37, 61, and 109 
• 
Total number of disease relapses/flares from Week 37 to 
Weeks 61 and 109 
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Objectives 
Endpoints 
• 
(Optional) Blood samples for exploratory analysis of vaccine 
IgG response during treatment. 
Long Term Extension Objective 
• 
To evaluate the long-term safety and 
efficacy of rilzabrutinib 
Long Term Extension Endpoints 
• 
Nature, frequency, and severity of adverse events, including 
serious adverse events, adverse events leading to 
discontinuation and possible corticosteroid-related adverse 
effects during the LTE from Week 61 to Week 113 
• 
Average daily dose of CS from Week 61 to Week 113 
• 
Time to initial relapse/flare from initial CDA to Week 109. 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
Outcome Assessment Definitions 
Control of Disease Activity (CDA): 
Control of disease activity (disease control) is defined as the visit at which new lesions cease to 
form and established lesions begin to heal. This is also considered the beginning of the 
consolidation phase. The expected interval of time to reach the control of disease activity is on the 
order of weeks, although it may be shorter.  
End of Consolidation Phase (ECP): 
The end of the consolidation phase is defined as the visit at which no new lesions have developed 
for a minimum of 2 weeks and the majority (approximately 80%) of established lesions have 
healed. Therefore, in order to achieve ECP, CDA must be confirmed at a visit ≥2 weeks later and 
80% of the lesions seen previously must have healed.   
Complete Remission (CR): 
Complete remission is defined as the absence of new and established lesions and is intended to 
mean “no disease activity”. Various qualifying statements are added to this definition for 
endpoints in this protocol.  
Relapse/Flare: 
A relapse of disease and a flare of disease are synonymous. They are defined by the appearance of 
3 or more new lesions after CDA and within a month that do not heal spontaneously within 
1 week, or by the extension of established lesions, in a patient who has achieved CDA. 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a randomized, phase 3, parallel-group, double-blind, placebo-controlled trial with 
36 weeks of treatment during a Blinded Treatment Period followed by an Open-Label Extension 
Period of 24 weeks. After completing the Open-Label Extension Period, eligible patients may 
continue in the Long Term Extension Period of 48 weeks. Patients will continue to have a 4 week 
follow-up visit after the patient’s last dose of rilzabrutinib as detailed in the Figure 1. This study 
will be conducted at approximately 100 global sites.  
Duration of Trial Participation 
For each patient, the trial will last approximately 68 weeks including Screening Period (up to 
4 weeks), the Blinded Treatment Period (Week 1 through Week 37), the Open-Label Extension 
Period (Week 37 to Week 61), and a 4-week end of treatment follow-up (up to Week 65). 
Blinded Treatment Period (Weeks 1 to 37) 
After informed consent is obtained, patients with moderate to severe pemphigus (PV and PF) will 
be screened and if eligible will be randomized in a 1:1 allocation ratio to receive either 
rilzabrutinib 400 mg twice daily (bid) (n ~ 60) or placebo bid (n ~ 60) during the Blinded 
Treatment Period (Week 1 to Week 37). 
At Screening, patients will begin to take Sponsor-provided CS according to the minimum dose 
requirements, shown in Table 1, and as required to adequately treat the disease. CS doses may be 
adjusted per Investigator discretion during the Screening period (Appendix 1 Section 12.1) but the 
dose should not be reduced below the required minimum initial dose levels (Table 1). CS taper 
below the required minimum dose level should not begin until ECP has been achieved. 
Rilzabrutinib (400 mg tablet) or placebo will be taken twice daily by mouth starting on Day 1. 
Tablets may be taken with or without food.  
If a patient achieves CDA (no new lesions and established lesions begin to heal), a follow-up visit 
≥2 weeks later must confirm the finding of no new lesions prior to declaring ECP and tapering 
CS. ECP is achieved with the confirmation of CDA (no new lesions for ≥2 weeks) with 
approximately 80% of the established lesions epithelialized (healed). If needed, confirmation of 
CDA and achievement of ECP may be documented at an Unscheduled Visit, prior to the next 
scheduled study visit. See Table 2 for all required assessments for an Unscheduled Visit, which 
also includes Efficacy Outcome Assessment and PDAI. 
While continuing on rilzabrutinib or placebo, following the achievement of ECP, patients will 
undergo a moderately rapid CS taper regimen as recommended by recently published consensus 
guidelines (1) with the goal to reduce the CS dose to 5 mg/day by no later than Study Week 29, 
with CS dose-adjustment as clinically indicated to control disease (CS and Rituximab 
Management protocol, Appendix 1 Section 12.1).  
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CS taper should not begin until ECP has been achieved.  
If the first documentation of CDA coincides with no disease activity (PDAI = 0), a follow-up visit 
≥2 weeks later must still confirm that no new lesions are seen and PDAI = 0. At this time the 
patient is deemed to have confirmed CDA, ECP, and CR and therefore CS tapering can begin. If 
new lesion(s) are seen, the patient is no longer in CDA and therefore CS tapering should not 
begin. If a patient has not achieved CDA or new lesions emerge or existing lesions worsen but do 
not meet definition of relapse/flare, refer to Appendix 1 Section 12.1 regarding increasing steroid 
dosage. 
Throughout the Blinded Treatment Period, patients who fail to respond to treatment or experience 
a worsening of disease should have their CS dose increased per CS Management Guidelines 
(Appendix 1 Section 12.1) until CDA is obtained. If ECP is not achieved in a timely manner, it is 
encouraged that CS dose be further increased unless clinically contraindicated. The Principal 
Investigator (PI) should consult with the Medical Monitor in such cases.  
Efficacy Outcome Assessment should be performed per the Efficacy Outcome Assessment 
Flowchart, Appendix 8 Section 12.8. 
Once patients achieve CR on a dose of 5 mg/day of CS, that dose should be maintained 
(not tapered further) until Study Week 37 (time of primary endpoint). 
Rituximab treatment may be administered during the Blinded Treatment Period at or after the 
Week 5 Visit, only after a second “qualifying relapse/flare” occurs, unless contraindicated 
(Appendix 1 Section 12.1). 
If rituximab is administered, patients should continue to take rilzabrutinib/placebo, remain on trial 
and blinded to treatment assignment. After completing the Blinded Treatment Period, patients will 
enter the Open-Label Extension Period to receive active treatment with rilzabrutinib described 
below. A patient in the Blinded Treatment Period requiring an additional “top up” dose of 
rituximab after their initial rituximab course of treatment must be discontinued from the trial.  
Open-Label Extension Period (Weeks 37 to 61) 
From Week 37, all patients will receive active drug in the Open-Label Extension Period for 
24 weeks per Table 3. Patients who received placebo will thus receive active treatment with 
rilzabrutinib 400 mg bid. Patients requiring treatment by rituximab or other immunosuppressants 
(other than CS) for relapse/flare during this period, must be discontinued from the study. If a 
patient has a qualifying relapse/flare during the Blinded Treatment Period and the second infusion 
from the rituximab course of treatment occurs during the Open-Label Extension period, the 
patient may continue in the trial. 
Patients that received rituximab during the Blinded Treatment Period and are continuing in the 
study, will complete TBNK testing (T and B and Natural Killer Lymphocyte Panel) at their 
Week 37 Visit. 
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From Week 37 (time of primary endpoint), further tapering to 0 mg CS should be attempted in 
patients with CR unless medically contraindicated. Patients who fail to respond to treatment 
or experience worsening of disease should have their CS dose increased per CS management 
guidelines (Appendix 1 Section 12.1) until CDA is obtained. If ECP is not achieved in a timely 
manner, it is encouraged that CS dose be further increased unless clinically contraindicated. The 
PI should consult with the Medical Monitor in such cases. 
Long Term Extension (LTE) Period (Week 61 to Week 109): 
After completing the Open-Label Extension Period, patients who are responding to rilzabrutinib 
treatment will be eligible to enter the Long Term Extension Period and will continue to receive 
open-label rilzabrutinib 400 mg bid for 48 weeks per Table 4.  
Patients are eligible to participate in the LTE if: 
a) 
they have achieved and/or maintained an ECP with ≤10 mg/day CS at any time 
between 37 and 61 weeks in the study. 
Patients are not eligible to participate in the LTE if: 
a) 
they have more than one relapse/flare following ECP requiring treatment with 
>10 mg/day CS (excluding CS taken short-term for dental work or surgery), or  
b) 
have failed to adequately recover after a relapse/flare despite maximal tolerated CS 
dose. 
Failure to adequately recover is defined as: <25% decrease from peak PDAI despite treatment 
with maximal steroid doses (minimum of 1.5 mg/kg/day unless there is a specific documented 
medical contraindication) for at least 2 weeks.  
CS doses above refer to doses of prednisone or its equivalent. 
Patients may continue in the LTE until: 
a) 
they have had more than one relapse/flare following ECP that requires >10 mg/day CS 
(excluding CS taken short-term for dental work or surgery) or have failed to 
adequately recover after a relapse/flare despite maximal tolerated CS dose 
(per definition of failure to adequately recover above);  
b) 
the drug is no longer being developed by the Sponsor for this indication;  
c) 
the program is stopped for safety reasons. 
Patients who have previously completed the Open-Label Extension Period prior to this 
amendment and were responders per the LTE requirement may enroll into the LTE.   
Patients entering the LTE will receive Sponsor-provided CS, following CS Management 
Guidelines (Appendix 1 Section 12.1). 
Patients requiring rituximab during the Long Term Extension Period will be discontinued from 
the trial. 
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Study Population 
Approximately 120 male or female patients with newly diagnosed or relapsing moderate to severe 
pemphigus (pemphigus vulgaris [PV] or pemphigus foliaceus [PF]) will be enrolled with a 
targeted minimum of 90 patients with PV, and a target maximum of 22 patients with PF. 
Study Assessments Overview 
See Figure 1 for a diagram of the study design and the Schedules of Assessments (Table 2, 
Table 3, and Table 4) and for description of the assessments. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
Study PRN1008-012 is a randomized, parallel-group, double-blind, placebo-controlled trial over 
36 weeks (Blinded Treatment Period) followed by an Open-Label Extension Period of 24 weeks, 
Long Term Extension Period of 48 weeks, and a Follow-up Period of 4 weeks, which is intended 
to evaluate the efficacy and safety of oral PRN1008 (Rilzabrutinib) in moderate to severe 
pemphigus. 
Placebo has been selected as the comparator to rilzabrutinib, as there are no globally approved 
medicinal products, other than CS (approved in European Union [EU] but not US) that could 
serve as a suitably rapid-acting and active comparator. While azathioprine is approved in the EU 
for pemphigus, it is regarded as minimally effective by expert dermatologists (6) and takes 
9 months to demonstrate any CS-sparing effects (9); therefore, it is not a suitable comparator to a 
fast acting agent like rilzabrutinib. Use of placebo is ethical in this context, since all patients in the 
trial will receive concomitant flexible dosing of CS therapy in accordance with standard of care, 
and rituximab rescue therapy may be used after a second “qualifying relapse/flare” (defined in 
Appendix 1 Section 12.1). 
All patients will undergo a standard CS taper as soon as possible, commencing at the ECP, with 
the goal of achieving a reduction of CS dose to 5 mg/day by no later than Week 29, so that the 
“durable CR” primary endpoint at Week 37 can be met. From Week 37, further tapering to 0 mg 
CS should be attempted in patients with CR unless medically contraindicated. Please refer to 
Appendix 1 Section 12.1 (Corticosteroid and Rituximab Management) and Section 3 (Response 
Definitions). A CS dose of 5 mg/day has been recommended by a European task force of experts 
as the level for long-term use associated with a low risk of harm (10).  
The marketed tyrosine kinase (BTK) inhibitor, ibrutinib, has been studied in combination with 
rituximab in the treatment of chronic lymphocytic leukemia without evidence of increased 
drug-related adverse events (8). There is no a priori drug interaction potential between anti-CD20 
biologic drugs and the small molecule rilzabrutinib apart from the theoretic on-target effects of 
combined immunosuppression. 
The primary purpose of the 24-week, Open-Label Extension Period (OLE) is to allow access to 
study drug who were on placebo medication as well as to evaluate durability of clinical response 
and accrue additional long term data on the safety and efficacy of rilzabrutinib.  
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The primary purpose of the 48-week, Long Term Extension Period (LTE) is to provide extended 
access to rilzabrutinib for patients who are receiving clinical benefit and to accrue additional 
long-term data on the safety and efficacy of rilzabrutinib. 
During the Coronavirus disease 2019 (COVID-19) pandemic, measures to ensure continued drug 
supply and safety monitoring for patients are described in the “Updated Guidelines to Sites for 
Delayed Patient Visits or Missed Visits Due to Travel Restrictions and Any Foreseeable Impacts 
of COVID-19” (Appendix 9 Section 12.9). These measures include remote study visits, 
enrollment procedures, direct to patient delivery of study medication and approved urine 
pregnancy tests, and handling of protocol deviations. 
4.3 
JUSTIFICATION FOR DOSE  
Based on dose-ranging in the Phase 1 program using the BTK occupancy of rilzabrutinib in 
circulating white blood cells, a 400 mg bid dosing regimen with the tablet formulation was 
selected because this dose was predicted to produce >70% BTK occupancy predose (or >85% 
average occupancy over the day). BTK occupancy data from Study PRN1008-005 of patients with 
pemphigus confirms adequacy of this dose with an average Day 1 2-hour and Day 2 predose BTK 
occupancy of approximately 85%. Twice a day dosing has been more efficacious in both the rat 
collagen induced arthritis model and naturally occurring PF in dogs, and was confirmed to have a 
promising efficacy and safety profile in Study PRN1008-005. 
The exposures from a 400 mg bid dose in humans have adequate safety factors to exposures in 
chronic rat and dog Good Laboratory Practices (GLP) safety toxicology studies. Please refer to 
the IB for more details. 
Rituximab and Possible Combination with rilzabrutinib 
Rituximab is a chimeric anti-CD20 antibody authorized for the treatment of rheumatoid arthritis, 
non-Hodgkin’s lymphoma, chronic lymphocytic leukemia (CLL), and granulomatosis with 
polyangiitis (granulomatosis with polyangiitis [GPA] also known as Wegener’s granulomatosis) 
and microscopic polyangiitis (MPA) in combination with CS. An open-label, randomized study 
comparing rituximab with 0.5 to 1 mg/kg/day of prednisone with 1 to 1.5 mg/kg/day of 
prednisone found a CR rate of 89% could be achieved by two years compared with 34% for CS 
alone. The study used a regimen of treatment at Month 0 of two 1 g infusions, two weeks apart, 
and 500 mg each at Month 12 and 18 (11). Although it is approved for the treatment of pemphigus 
only in the US at this time, it is recommended as a possible first-line therapy in combination with 
CS in newly updated consensus guidelines (1). 
RITUXAN, MabThera or other approved, biosimilar agents may be used in this clinical trial per 
protocol. Instructions for administration of the intravenous infusion will be provided in the 
Pharmacy Manual. For detailed safety information on rituximab or other biosimilar agents 
investigators should refer to the current, locally applicable, approved product information. 
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4.4 
END OF STUDY DEFINITION  
End of Trial (Follow-up Period, 4 Weeks after last Trial Dose):  
End of Trial (EOT) for the overall clinical trial is defined as the point at which the last patient has 
completed the last visit of the study. 
For patients eligible for the Long Term Extension, the EOT is defined as the point at which the 
patient has completed their Week 113 Visit (4 weeks after the patient’s last dose of rilzabrutinib).  
For patients that are not eligible for the Long Term Extension, the EOT is defined as the point at 
which the patient has completed their Week 65 Visit (4 weeks after the patient’s last dose of 
rilzabrutinib).  
Patients who are not able to complete the Blinded Treatment Period, Open-Label Extension 
Period or Long Term Extension Period as planned and discontinue the study early should be 
encouraged to come back for an Early Termination (ET) Visit as soon as possible. Patients that 
discontinue early will have the ET assessments completed as outlined in the Schedule of 
Assessments based upon from which phase treatment they are terminating, Table 2 (Blinded 
Treatment Period), Table 3 (Open-Label Extension Period), or Table 4 (Long-Term Extension 
Period). 
In addition to the ET Visit, patients should return for the EOT Visit 4 weeks following their last 
dose of rilzabrutinib/placebo or rilzabrutinib. 
In the event the ET Visit occurs ≥4 weeks after their last dose of rilzabrutinib/placebo or 
rilzabrutinib, this will be recorded as the ET Visit and there is no need for the 4-week safety 
follow-up (EOT) visit. 
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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA  
Patients may be included in the study if ALL of the following criteria are met: 
Type of participant and disease characteristics 
I 01. Male or female patients, aged 18 to 80 years old with moderate to severe, newly diagnosed 
or relapsing PV or PF, with a clinical presentation and histopathology consistent with PV 
or PF (see Section 8.4.3).  
I 02. Positive circulating anti-dsg1 or 3 autoantibody titer. 
I 03. At Screening, PDAI score of at least 9 points for relapsing patients (diagnosed >6 months 
prior to Screening) or at least 15 points for newly diagnosed patients (diagnosed ≤6 months 
prior to Screening). 
I 04. Adequate hematologic, hepatic, and renal function (including but not limited to absolute 
neutrophil count ≥1.5 × 109/L, hemoglobin [Hgb] >9 g/dL, platelet count ≥100 × 109/L, 
aspartate aminotransferase [AST] and/or alanine aminotransferase [ALT] ≤1.5 × upper 
limit of normal [ULN], albumin ≥3 g/dL, creatinine ≤1.5 × ULN). 
Sex, contraceptive/barrier method and pregnancy testing requirements 
I 05. Female patients who are of reproductive potential must agree for the duration of the study 
to use an effective means of contraception (eg, hormonal contraception methods that 
inhibit ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal 
ligation, vasectomized partner or condoms).  
For females considered not to have reproductive potential:  
Any woman of age ≥55 years with amenorrhea for >1 year, will be considered as having 
confirmed menopause and follicle-stimulating hormone (FSH) or pregnancy testing will 
not be needed. Postmenopausal females <55 years of age (defined as amenorrhea >1 year) 
must have menopause confirmed by elevated FSH levels at screening. Surgically sterile 
females do not require any further confirmation of menopause and will not be considered 
to have reproductive potential. 
For participants in Germany, please see specific instructions in 
Appendix 10 Section 12.10. 
Informed Consent 
I 06. Able to provide written informed consent and agreeable to the schedule of assessments. 
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5.2 
EXCLUSION CRITERIA  
Patients will be excluded from the trial if any of the following criteria are met: 
Medical conditions 
E 01. Suspected paraneoplastic pemphigus and other forms of pemphigus that are not pemphigus 
vulgaris or pemphigus foliaceus. 
E 02. Previous use of a Bruton tyrosine kinase (BTK) inhibitor. 
E 03. Pregnant or lactating women. 
E 04. Electrocardiogram (ECG) findings of QT corrected for heart rate (QTc) >450 msec (males) 
or >470 msec (females), poorly controlled atrial fibrillation (ie, symptomatic patients or a 
ventricular rate above 100 beats/min on ECG), or other clinically significant abnormalities. 
E 05. A history of malignancy of any type within 5 years before Day 1, other than surgically 
excised non-melanoma skin cancers or in situ cervical cancer.  
Prior/concomitant therapy 
E 06. Use of immunologic response modifiers as concomitant medication and with the following 
washout periods: A) stop at least 2 weeks prior to Screening: mycophenolate mofetil, 
azathioprine, methotrexate, cyclosporine, dapsone, intravenous immunoglobulin (IVIG), 
Kinaret (anakinra), Enbrel (etanercept), or any other immunosuppressant not mentioned in 
this exclusion criterion; B) 12 weeks prior to Screening: Remicade (infliximab), Humira 
(adalimumab), Simponi (golimumab), Orencia (abatercept), Actemra (tocilizumab), 
Cimzia (certolizumab), Cosentyx (secukinumab), plasmapheresis; C) 6 months prior to 
Screening (or shorter if there is documented B cell reconstitution for anti-CD20 drugs): 
anti-CD20 drugs such as rituximab, ofatumumab, other long-acting biologics. 
E 07. Use of proton pump inhibitor drugs such as omeprazole and esomeprazole within 3 days of 
Day 1 (it is acceptable to change patient to H2 receptor blocking drugs prior to Day 1). 
E 08. Concomitant use of known strong-to-moderate inducers or inhibitors of CYP3A within 
3 days or 5 half-lives (whichever is longer) of Day 1 (Appendix 7 Section 12.7). 
E 09. Use of CYP3A-sensitive substrate drugs with a narrow therapeutic index within 3 days or 
5 half-lives (whichever is longer) of Day 1 and for the remainder of the trial including, but 
not limited to alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus (topical and oral), or 
terfenadine.  
E 10. Has received any investigational drug (or is currently using an investigational device) 
within the 30 days before Day 1, or at least 5 times the respective elimination half-life time 
(whichever is longer). 
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E 11. History of drug abuse within the previous 12 months. 
E 12. Alcoholism or excessive alcohol use, defined as regular consumption of more than 
approximately 3 standard drinks per day. 
Other exclusions 
E 13. Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel 
resection that would preclude adequate rilzabrutinib/placebo absorption. 
E 14. Donation of a unit or more of blood or blood products within 4 weeks prior to Day 1. 
E 15. History of solid organ transplant. 
E 16. Positive at Screening for human immunodeficiency virus (HIV), hepatitis B (surface 
antigen and/or core antibodies), or hepatitis C (anti-HCV antibody confirmed with Hep C 
RNA). 
E 17. Positive interferon-gamma release assay (IGRA) (eg, T-spot TB Test, QuantiFERON®-TB 
Gold, or QuantiFERON®-TB Gold Plus (QFT Plus), at Screening. Unless, the patient has 
latent tuberculosis (TB) and all of the following 3 conditions are true: 
a) Chest X-ray does not show evidence suggestive of active TB disease 
b) There are no clinical signs and symptoms of pulmonary and/or extra-pulmonary TB 
disease 
c) Documented receipt of one of the following prophylactic treatment regimens: 
i. Oral daily Isoniazid for 6 months 
or 
ii. Oral daily Rifampin (RIF) for 4 months 
or 
iii. Isoniazid and Rifapentine weekly for 3 months (3HP). 
On a case by case basis, after discussion and approval by the Sponsor, a local TB test that 
is negative and is considered equivalent to 1 of the above tests may be used for eligibility. 
For example, if a QuantiFERON®-TB Gold, or QuantiFERON-TB Gold Plus (QFT Plus) 
is indeterminate for any reason and a local blood test or T-Spot TB test is negative, the 
patient may be enrolled using the local result upon approval of the Sponsor. 
E 18. History of serious infections requiring intravenous therapy with the potential for recurrence 
or currently active moderate to severe infection at Screening (Grade 2 or higher). 
E 19. Live vaccine within 28 days prior to Day 1 or plan to receive one during the trial. 
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E 20. Any other clinically significant disease, condition (including contraindication to CS and/or 
inability to follow CS dosing as outlined in the protocol [see Table 1 for more details]), or 
medical history that, in the opinion of the Investigator, would interfere with patient safety, 
trial evaluations, and/or trial procedures. In areas endemic for Chagas disease, screening is 
recommended prior to enrollment. 
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6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
6.1.1 Rilzabrutinib/Placebo  
Each PRN1008 (Rilzabrutinib) film-coated tablet contains 400 mg of rilzabrutinib drug substance 
and is 
 in color. In addition, the tablet contains 
 
 
.  
The placebo treatment is also film-coated tablets that are identical in appearance and contain the 
same inactive ingredients as that of the rilzabrutinib trial medication, but do not contain 
rilzabrutinib. In addition, the inactive ingredient mannitol has been added as a filler to replace 
rilzabrutinib. 
6.1.1.1 Packaging  
PRN1008 (Rilzabrutinib) drug product or placebo will be supplied to the clinical sites in blister 
cards. Each blister card will contain 14 tablets of rilzabrutinib or placebo with day and night 
designation to provide guidance to the subject on which tablet to ingest. Subjects will receive 
rilzabrutinib or placebo tablets in a kit containing 5 blister cards or 5-week supply of rilzabrutinib 
or placebo (70 tablets). 
6.1.2 Corticosteroids  
Oral corticosteroids (prednisone or prednisolone) will be provided during the Blinded 
Treatment Period and Open-Label Extension Period. Patients entering the LTE will receive 
Sponsor-provided CS. 
6.1.2.1 Corticosteroid starting doses and management during screening and at Day 1  
Required initial doses of CS for the duration of Screening are ≥0.2 mg/kg/day of CS for patients 
with relapsing disease (diagnosed >6 months prior to Screening) and ≥0.5 mg/kg/day for patients 
with newly diagnosed disease (diagnosed ≤6 months prior to Screening). At Screening, patients 
will begin to take Sponsor-provided CS according to the minimum dose requirements, and as 
required to adequately treat the disease during the Screening period. CS doses may be adjusted per 
Investigator discretion during the Screening period (Appendix 1 Section 12.1) but the dose should 
not be reduced below the required minimum initial dose levels (Table 1). CS taper below the 
required minimum dose level should not begin until ECP has been achieved. 
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If disease significantly (Investigator judgment) worsens during the Screening period, up titration 
of CS dose by 50-100% should occur, as often as every 5-7 days if needed (4).  
6.1.2.2 Corticosteroid management during blinded treatment period, open-label 
extension period, and long term extension period  
6.1.2.2.1 
Corticosteroid-Tapering (Consensus Guidelines)  
CS will be tapered from ECP towards a goal of 5 mg/day by ≤Week 29. Once the 5 mg level is 
achieved it will be kept at 5 mg/day until the time of the primary endpoint at Week 37 is reached. 
From Week 37, further tapering to 0 mg CS should be attempted in patients with CR unless 
medically contraindicated. At Investigator discretion, the CS may be switched to equivalent doses 
of oral hydrocortisone instead of prednisone or prednisolone when tapering from 5 mg to 0 mg 
CS. 
CS tapering should follow the modified dosing guidelines below (1). Adjustment of the dosing 
guideline protocol by investigators is permitted for safety reasons, based on assessment and 
documentation of clinical need.  
• 
Start tapering CS as soon as ECP is confirmed. 
• 
Decrease CS by 25% every two weeks, until 20 mg per day 
• 
Once at 20 mg per day, decrease CS by 2.5 mg per week 
• 
Once at 10 mg/day, decrease CS by 1 mg per week. 
Note, because 1 mg will be the smallest CS dosage provided and tablet splitting is not allowed, 
the Investigator must round up or down to the nearest whole milligram for CS dose after 
calculation of the new dose level. 
6.1.2.2.2 
Corticosteroid-Up-Titration  
Patients who fail to respond to treatment or experience a worsening of disease should have their 
CS dose increased per CS Management Guidelines (Appendix 1 Section 12.1) until CDA is 
obtained (4). If ECP is not achieved in a timely manner, it is encouraged that CS dose be further 
increased unless clinically contraindicated. The PI should consult with the Medical Monitor in 
such cases. 
For full details of up-titration see Appendix 1 Section 12.1. 
6.1.2.3 Corticosteroids and rituximab  
Required, initial doses of CS for the duration of Screening are ≥0.2 mg/kg/day for patients with 
relapsing disease (diagnosed >6 months prior to Screening) and ≥0.5 mg/kg/day for patients with 
newly diagnosed disease (diagnosed ≤6 months prior to Screening).  
Thereafter, CS are managed per the Corticosteroid and Rituximab Management protocol 
(Appendix 1 Section 12.1). 
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Rituximab should be managed per the Corticosteroid and Rituximab Management protocol 
(Appendix 1 Section 12.1), utilizing instructions in the Pharmacy Manual for administration of the 
to-be-used rituximab product. 
6.1.3 Rituximab  
Rituximab (or biosimilar) will be provided for patients having a second qualifying relapse/flare 
(Appendix 1 Section 12.1) during the Blinded Treatment Period. However, in the event a patient 
in the Blinded Treatment Period requires an additional “top up” dose of rituximab after their 
initial rituximab course of treatment, this will not be provided because the patient must be 
discontinued. Similarly, if a patient in the Open-Label Extension Period or Long Term Extension 
Period requires rituximab, the patient must be discontinued and rituximab will not be provided. 
If a patient has a qualifying relapse/flare during the Blinded Treatment Period and the 
second infusion from the rituximab course of treatment occurs during the open label period, the 
patient may continue in the trial. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
6.2.1 Preparation, administration and storage  
6.2.1.1 Rilzabrutinib/Placebo  
No preparation of the PRN1008 (Rilzabrutinib) or placebo trial medication will be needed. 
Patients will use the trial medication directly from the dispensed blister cards.  
Treatment medication will be taken twice daily by mouth starting on Day 1. Rilzabrutinib or 
placebo may be taken with or without food. Consecutive rilzabrutinib/placebo doses should not be 
taken within 8 hours of each other. Tablets should not be broken or crushed. Further details for 
dispensation and administration of blinded treatment are provided in the Pharmacy Manual.  
PRN1008 (Rilzabrutinib) or placebo tablets are supplied in blister cards. The recommended 
storage condition is 2 to 25°C (IB). 
6.2.1.2 Corticosteroids  
No preparation of CS will be needed. 
Corticosteroids are recommended to be stored at 2 to 25°C according to product label. 
6.2.1.3 Rituximab  
Rituximab, if required, should be administered per the product information in accordance with 
this protocol and the Pharmacy Manual. 
Rituximab (or biosimilar) should be stored according to the instructions in the product label. 
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6.2.2 Drug management  
Drug management will be the responsibility of the Investigator of the medical institution. 
The Investigator, the pharmacist of the medical institution, or another designated person must 
complete, in real time, all the documents concerning treatment management. Treatment 
management will be verified on a regular basis by the trial monitor.  
The trial medication should be used only by healthcare professionals who are qualified by training 
and experience in the safe use and handling of investigational drugs.  
During the COVID-19 pandemic, drug supply can be delivered to patients when the patient is not 
able to travel to the site or the site cannot host a patient visit. Site instructions for delivery of 
supplies directly to patients and procedures for conducting remote site visits inclusive of ensuring 
drug supply maintenance are described in Appendix 9 Section 12.9 (“Updated Guidelines to Sites 
for Delayed Patient Visits or Missed Visits Due to Travel Restrictions and Any Foreseeable 
Impacts of COVID-19”), specifically in Appendix 9B for global sites and for sites in Taiwan. 
6.2.3 Drug accountability  
The Investigator or his/her designated representatives will dispense trial medication per the 
Schedule of Assessments (Table 2 and Table 3). 
The Investigator is responsible for the control of drugs under investigation. Adequate records of 
the receipt (eg, Drug Receipt Record) and disposition (eg, Investigational Drug Dispensing Log) 
of the trial medication must be maintained. The Investigational Drug Dispensing Log must be 
kept current and should contain the following information: 
• The identification of the participant to whom the trial medication was dispensed 
(for example subject identification number, participant initials, and date of birth) 
• The date(s), quantity, and lot number(s) of the trial medication dispensed to the participant 
• The identification of the person who dispensed the trial medication 
All used and unused drug supplies must be returned by the subject at every visit.  
All records and used and unused drug supplies must be available for inspection by the trial 
monitor at every monitoring visit. Reconciliation of all drug supplies (rilzabrutinib or placebo, 
rilzabrutinib open-label, CS, and rituximab) will be performed by the trial monitor. When the trial 
is completed, the Investigator will return any used and unused trial medication (eg, empty, 
partially used, and unused containers), to the Sponsor as requested. Copies of the completed Drug 
Dispensing Log and Drug Return Record(s) will be returned to the Sponsor. The Investigator's 
copy of the Drug Return Record(s) must accurately document the return of all drug supplies to the 
Sponsor. 
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6.2.4 Destruction of investigational product  
Local or institutional regulations may require immediate destruction of used investigational 
medicinal product for safety reasons. In these cases, it may be acceptable for investigational trial 
center staff to destroy dispensed investigational product before a monitoring inspection, provided 
that source document verification is performed on the remaining inventory and reconciled against 
the documentation of quantity shipped, dispensed, returned, and destroyed, and provided that 
adequate storage and integrity of drug has been confirmed. Written authorization must be obtained 
from the Sponsor or Sponsor designee after final accountability prior to destruction. 
Unused trial medication from the site that has not been stored properly should not be destroyed 
until the monitor and/or Sponsor approve the destruction. 
Written documentation of destruction must contain the following: 
• Identity of investigational product(s) destroyed 
• Quantity of investigational product(s) destroyed 
• Date of destruction 
• Method of destruction 
• Name and signature of responsible person who destroyed the investigational products 
Investigational sites that do not have a procedure for destruction and appropriate disposal of 
investigational product, or cannot dispose of investigational product locally may request 
assistance and documentation for return to the Sponsor, or assignment to a local qualified vendor 
for destruction and disposal. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
Allocation of patients to treatment groups will proceed through the use of an interactive web 
response system (IWRS) that is accessible 24 hours a day, 365 days a year. 
The pharmacist or designee will be required to enter or select information that will include, 
but not be limited to: the user ID, and password, subject number, patient year of birth, as well 
as other information (as allowed locally). The pharmacist or designee will then be provided with a 
patient randomization number and treatment assignment. Once patient numbers 
and randomization numbers have been assigned, they cannot be reassigned. The randomization 
system will also send confirmation of the randomization, by email or fax, to the user. Specific 
instructions will be provided in the IWRS trial reference guide. Access to the randomization code 
will be limited; all Sponsor personnel (and representatives), and site personnel who are directly 
involved in the conduct of the trial will be blinded to randomization codes. 
The treatment each patient receives will not be disclosed to the Investigator, trial center personnel, 
patients, or the Sponsor or representatives on the clinical study team. Further details for blinding 
and dispensing of blinded treatment are provided in the Pharmacy Manual. 
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If deemed by the Investigator to be medically necessary, the Investigator can unblind a patient via 
the IWRS. 
6.4 
STUDY INTERVENTION COMPLIANCE  
Accountability and participant compliance will be assessed by maintaining adequate trial 
medication dispensing records and medication counts. The Investigator is responsible for ensuring 
that dosing is administered in compliance with the protocol. See Section 6.2.3 for instructions on 
Drug Accountability procedures. 
6.5 
CONCOMITANT THERAPY  
6.5.1 Prohibited medications  
The following medications are prohibited for use during the trial: 
• Concomitant use of any immunosuppressant medication, other than CS and rituximab as 
described in this protocol. Patients who need other immunosuppressant therapy during the 
trial should be withdrawn. See E 06, Section 5.2 for washout periods. 
• Concomitant use of known strong to moderate inducers or inhibitors of cytochrome P450 
(CYP) 3A (Appendix 7 Section 12.7) within 3 days or 5 half-lives (whichever is longer) of 
Day 1. 
• Use of CYP3A-sensitive substrate drugs with a narrow therapeutic index (within 3 days 
or 5 half-lives (whichever is longer) of Day 1 including, but not limited to, alfentanil, 
astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus (topical and oral), or terfenadine. 
• Proton pump inhibitors are not permitted. Esomeprazole was shown to reduce the 
exposure of rilzabrutinib by approximately 50%, presumably due to the effects of a lack of 
an acidic environment on tablet dissolution. Subjects who are on proton pump inhibitors 
should be changed to histamine (H2) receptor blocking drugs if possible or not enroll in 
the trial. Details of H2 receptor blocker administration is provided in Section 6.5.2. 
• Intralesional steroids are not permitted within 3 months prior to Screening, during 
Screening and for the duration of the study. 
• Warfarin use is not permitted within 1 week or 5 half-lives (whichever is longer) of Day 1 
and for the duration of the study. 
• Live vaccines. 
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6.5.2 Particular permissible medications  
The following medications are permitted for use during the trial: 
• Local use of topical corticosteroids and oral corticosteroid rinses (mouth washes) are 
allowed.  
• Use of short, defined courses of intravenous corticosteroids are allowed, if deemed 
clinically necessary and at doses consistent with the oral regimen, after consultation with 
Medical Monitor. Sites should make all attempts to use Sponsor-provided oral 
prednisolone during the Blinded Treatment Period. 
• Bisphosphonate drugs for osteoporosis prophylaxis. 
• Clinically relevant cytochrome P450 (CYP)3A substrate drugs that are not narrow 
therapeutic index (eg, “sensitive substrate” listed in Appendix 7 Section 12.7). These 
drugs should be managed by administering rilzabrutinib or placebo on a time schedule 
such that CYP3A substrate drugs can be given 2 hours or more after rilzabrutinib or 
placebo. 
• Histamine 2 (H2) receptor blocking drugs (ranitidine or famotidine) and antacids are 
permitted provided they can be given 2 hours or more after administration of rilzabrutinib 
or placebo. 
 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
7.1.1 Permanent discontinuation  
The trial will be terminated if major safety concerns related to rilzabrutinib or placebo emerge. 
Trial safety stopping criteria are: 
1. More than one rilzabrutinib-related death 
2. Three or more life-threatening (Common Terminology Criteria for Adverse Events 
[CTCAE], Grade 4) rilzabrutinib-related TEAEs 
3. Sponsor chooses to terminate the study (see Section 7.1.2) 
4. If the Data Safety Monitoring Board (DSMB) recommends trial termination due to safety 
reasons. 
For participants in Germany, please see specific instructions in Appendix 10 Section 12.10. 
7.1.2 Sponsor trial termination  
The Sponsor has the right to terminate this study at any time for any reason. Reasons for 
terminating the study may include but are not necessarily limited to the following: 
• The incidence or severity of AEs indicates a potential health hazard to patients. 
• Patient enrollment is unsatisfactory, and the Sponsor wishes to stop the study. 
• New scientific knowledge or other conditions place study patients at undue risk by 
continuing in the study. 
• If the DSMB recommends trial termination due to safety reasons. 
After having informed the Investigators and the coordinators, the Sponsor may terminate the study 
before its scheduled term. The Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and regulatory authorities will be informed according to local regulations. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
7.2.1 Patient Discontinuation and Stopping Rules  
The Investigator in conjunction with the Sponsor may also, at their discretion, discontinue the 
patient from participation in the study at any time if discontinuation would be in the patient’s best 
interest. If a patient meets any of the criteria listed below, the patient should complete the 
assessments for the ET Visit (see Table 2 and Table 3). 
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Reasons for discontinuing a patient may include, but are not necessarily limited to, the following: 
• Severe and life-threatening pemphigus disease activity 
• Grade 4 rilzabrutinib-related TEAE 
• Serious allergic reaction to rilzabrutinib or placebo including anaphylactic reaction 
• A patient in the Blinded Treatment Period requiring an additional “top up” dose of 
rituximab after their initial rituximab course of treatment or a patient in the Open-Label 
Extension Period or Long Term Extension Period requiring rituximab 
• Human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), 
viral hepatitis (B and C) infection occurring during the study 
• Pregnancy 
• Any medical condition or personal circumstance that, in the opinion of the Investigator, 
exposes the patient to risk if the patient continues with rilzabrutinib or placebo or that 
prevents the patient’s adherence to the protocol 
• If in the Investigator’s or the Sponsor’s judgment, discontinuation is in the patient’s best 
interest 
• Violation of protocol inclusion or exclusion criteria, if, in the opinion of the Investigator 
and the Sponsor, the violation would significantly compromise data interpretation 
• Discontinuation of the study by the Sponsor. 
For participants in Germany, please see specific instructions in Appendix 10 Section 12.10. 
No follow-up or additional procedures will be performed on patients who discontinue before 
receiving rilzabrutinib or placebo. For patients who discontinue after receiving any amount of 
rilzabrutinib or placebo, the reason for a patient’s discontinuation from the study must be clearly 
documented in the patient’s medical records and on the appropriate page of the eCRF, 
and patients will be asked to complete the ET assessments (see Table 2 and Table 3). 
7.2.2 Patient withdrawal  
All patients have the right to withdraw consent and discontinue participation without prejudice 
at any time during the trial. Every effort should be made to comply with the protocol; however, 
patients will be withdrawn from the trial entirely with no further trial visits if any of the following 
situation arise: 
• Withdrawal of patient’s consent or patient’s request to discontinue from the trial for any 
reason. 
• The patient is unwilling or unable to comply with the protocol. 
Patients who are withdrawn from the trial will not be replaced. The reason for the patient’s 
withdrawal from the trial should be recorded on the electronic case report form (eCRF).  
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7.3 
LOST TO FOLLOW-UP  
At the start of the study, the Investigator should try to obtain all relevant contact details for the 
patient to facilitate making contact with the patient, if necessary. In addition, each patient should 
be encouraged to attend all trial visits for which the patient is scheduled. 
If a patient discontinues the study without notifying the Investigator, the Investigator must make 
every effort to contact the patient to identify the reason for the patient’s discontinuation and to 
encourage the patient to complete the applicable ET visit assessments (see Table 2 and Table 3). 
If documented attempts to contact the patient fail, and a reason for the patient’s discontinuation is 
undiscoverable, the Investigator can declare the patient as “lost to follow-up” at the end of the 
study. The Investigator should document in the corresponding medical record all efforts to contact 
the patient. 
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8 
STUDY ASSESSMENTS AND PROCEDURES  
8.1 
TRIAL RECRUITMENT PROCEDURES  
Participants will be identified for potential recruitment by the Investigator using a recruitment 
plan agreed upon with Principia, possibly including, but not limited to, a listing from a trial center, 
volunteer database, newspaper/radio/internet advertisement, or mailing list. 
8.2 
TRIAL ENROLLMENT PROCEDURES  
Participants eligible for Screening cannot commence enrollment study procedures until the 
informed consent process and form (including voluntary participation/future use of blood 
samples/optional collection of blood pre-and post-vaccination) has been properly administered 
and signed. Screening tests are then administered, including blood tests sent for laboratory testing. 
Where the clinical significance of an abnormal Screening test result (lab or any other tests) is 
considered uncertain, the test may be repeated once. 
The Investigator or designee will enter data for each enrolled participant in the trial electronic 
case report form (eCRF) and enter the corresponding patient identification number in the 
appropriate place on each participant’s eCRF. Screening eCRFs must be completed in order to 
verify patient eligibility and should be completed as soon as assessments are performed. 
A participant enrollment and Identification Code List must be maintained by the Investigator 
or pharmacist, or designee. 
Under no circumstances will participants who enroll in this trial and complete treatment as 
specified be permitted to re-enroll in the trial unless in the rare case where Sponsor approval is 
granted (eg, for a subject who completed and exited the OLE that is eligible to participate in the 
LTE).  
During the COVID-19 pandemic, there is a need to assess the feasibility of implementing a plan 
for patient access to study drug and any additional measures required to monitor patient safety on 
an ongoing basis. Investigators should notify Principia and their contract research organization 
(CRO) study monitor if their site suspend patient enrollment (Appendix 9 Section 12.9). 
8.3 
VISIT OVERVIEW  
During the trial, patients will return at specified times on an outpatient basis for assessment 
of vital signs, physical examination, assessment of AEs and concomitant medication use, 
assessment of clinical benefit and for provision of blood samples for clinical safety, PK, and PD 
assessment. For participants in Germany, please see specific instructions for SARS-CoV-2 testing 
in Appendix 10 Section 12.10. 
Trial procedures and activities will occur at each visit as specified in Table 2 and Table 3.  
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During the COVID-19 pandemic, remote (eg, telephone call, video call) study visits may be 
performed when a patient is not able to travel to the site or the site cannot host a patient visit. 
Procedures to be performed during remote site visits are described in Appendix 9A of “Updated 
Guidelines to Sites for Delayed Patient Visits or Missed Visits Due to Travel Restrictions 
and Any Foreseeable Impacts of COVID-19” (Appendix 9 Section 12.9). 
8.3.1 Screening (Day -29 to Day -1)  
Informed consent will be obtained at Screening before performing any trial procedures. 
Patients will undergo Screening assessments, including, but not limited to; blood sampling, ECG, 
clinical assessment and various quality of life assessments. Please refer to Table 2. 
In cases where laboratory assessments are delayed due to logistic considerations, the Sponsor may 
permit an extension of the Screening Period for laboratory assessments up to 7 business days in 
order to determine eligibility. Week 1 Day 1 should occur as soon as possible upon evaluation of 
the delayed assessments and no later than 35 days after the initial Screening Visit. 
Medical history and demographic data, including sex, age, race, body weight (kg), height (cm), 
and body mass index (BMI), will be recorded. 
Patients not already on the mandated CS doses for the commencement of the Screening Period 
will commence the protocol-mandated CS doses. 
Patients may be re-screened once following a Screen failure. Any labs performed in prior 
screening, within 2 weeks of re-screening will remain valid and should not be repeated. Labs 
performed for a previous screening within 6 weeks, may be considered for determination of 
eligibility on approval of the Medical Monitor. In the specific cases of QuantiFERON-TB, anti 
desmoglein antibodies and hepatitis/HIV testing, tests may be considered for determination of 
eligibility if performed in a previous screen within the last 12 weeks, with the approval of the 
Medical Monitor. However, pregnancy tests should be repeated at re-screening. Please see 
Schedule of Assessments Table 2. 
When approaching the season appropriate for influenza vaccination, patients will be reminded to 
inform the clinic staff about vaccination plans. Similarly, when approaching the planned date of 
any vaccine dose regimen (during all study periods), patients will be reminded about the related 
pre- and post-vaccination blood sampling for vaccine IgG testing. Those who have not yet 
consented for collection of blood pre-vaccination (eg, those who make mid-study decisions about 
vaccinations) may do so just prior to blood collection. Additional details are provided in 
Appendix 11 Section 12.11. 
8.3.2 Baseline (Day 1)  
Patients will undergo baseline assessments shown in Table 2. The first dose of rilzabrutinib 
or placebo will be administered after all pre-dose procedures on Day 1 have been completed. 
Patients will remain in the clinic for 2 hours post-dose for a 2 hour blood collection. 
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8.3.3 Blinded treatment period (Weeks 1 to 37)  
Please refer to Table 2 for specific assessments at each visit. CS dosing, and use of rituximab for a 
second qualifying relapse/flare, are detailed in Appendix 1 Section 12.1. The Efficacy Outcome 
Assessment Flowchart is detailed in Appendix 8 Section 12.8. 
8.3.4 Open-label extension period (Weeks 37 to 61)  
Please refer to Table 3 for specific assessments at each visit. CS dosing is detailed in Appendix 1 
Section 12.1. Rituximab therapy is not allowed during this period unless the patient is withdrawn 
from the trial. 
8.3.5 Long term extension period (Beginning Week 61)  
Please refer to Table 4 for specific assessments at each visit. CS dosing is detailed in Appendix 1 
Section 12.1. Rituximab therapy is not allowed during this period unless the patient is withdrawn 
from the trial. Please refer to Appendix 11 Section 12.11 for optional collection of blood pre-and 
post-vaccination. 
8.3.6 OLE EOT/Week 65 and LTE EOT/Week 113 visits (follow-up period, 4 weeks after 
last trial dose)  
Please refer to Table 3 and Table 4 for specific assessments at the EOT Visit for safety follow-up 
procedures performed 4 weeks after the last dose of study drug. 
8.3.7 Early termination visit  
Please refer to Table 2 (if terminating during double-blind treatment), Table 3 (if terminating 
during Open-Label Extension), or Table 4 (if terminating during Long Term Extension) for 
specific ET assessments. An attempt should be made to have the patient return for the ET Visit as 
soon as possible after the last dose of rilzabrutinib or placebo. 
Patients in the OLE or LTE who are required to discontinue the study early per the rituximab 
receipt rules (Section 6.2.1.3) should have their ET Visit completed prior to rituximab infusion. 
8.4 
TRIAL ASSESSMENTS  
All trial assessments will be collected as outlined at the visits noted in Table 2, Table 3, 
and Table 4. 
8.4.1 Body height and weight  
Body weight should be measured after checking for accurate zero calibration. Weight is recorded 
in kg to one decimal place. 
Height is only assessed at Screening and is recorded in cm. 
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8.4.2 Physical examination  
A full physical examination includes, at a minimum, assessment of the following: skin, eyes, ears, 
nose, throat, heart, chest/breast, abdomen, neurological system (briefly), lymph nodes, spine and 
extremities (skeletal). 
An abbreviated physical examination is inclusive of general appearance, cardiac, gastrointestinal, 
and pulmonary assessments. 
A licensed physician or nurse practitioner (or equivalent) will examine each patient. 
Physical examination may be performed at various unscheduled time points if deemed necessary 
by the Investigator. 
8.4.3 Biopsies  
A new biopsy (cutaneous and/or mucosal) is not required if there is a prior and available biopsy 
report documenting histopathologic findings diagnostic for PV or PF. A new biopsy should be 
performed if an archival biopsy report is not available. 
New biopsies should include local hematoxylin and eosin (H&E) histopathological review 
and direct immunofluorescence (DIF) for the characteristic pattern diagnostic of pemphigus. 
Histopathology on biopsies is evaluated for consistency with a diagnosis of PV or PF: 
• If DIF is positive, the patient is eligible in the presence of positive anti-desmoglein 
antibodies. 
• If DIF is negative, the patient is not eligible. In these cases, where the H&E histopathology 
is characteristic of pemphigus and anti-desmoglein antibodies are positive, the biopsy may 
be repeated at the discretion of the Investigator. 
• If DIF is not available, the patient is eligible in the presence of positive anti-desmoglein 
antibodies, and H&E histopathology characteristic of pemphigus. 
8.4.4 Medical history  
Medical history will be recorded at Screening and will include detailed pemphigus history (special 
Case Report Form), and history of all other underlying medical conditions. 
8.4.5 Vital signs  
Vital signs include body temperature, respiratory rate, blood pressure, and pulse rate. 
Vital signs may be measured at unscheduled time points, if deemed necessary by the Investigator. 
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8.4.6 Electrocardiogram monitoring  
Single 12-lead ECGs will be performed at Screening, Week 37, Week 61, and Week 109 (for 
patients in the Long Term Extension). All ECGs will be performed with the patient in a supine 
position. 
Unscheduled ECGs may be performed as deemed necessary by the Investigator. 
8.4.7 Clinical laboratory tests  
See Table 2, Table 3, and Table 4 for laboratory test panels for chemistry, hematology, urinalysis 
and pregnancy testing. Laboratory safety tests may be performed at unscheduled time points, 
if deemed necessary by the Investigator. Screening laboratory safety tests may be repeated upon 
discussion with the Sponsor/Medical Monitor. 
The Laboratory Manual will supply complete written instructions for collection, handling, 
processing, storage, and shipping of samples. 
8.4.8 Pharmacokinetic/Pharmacodynamic assessments  
Blood samples will be collected at timepoints for rilzabrutinib (and metabolites, as applicable) 
concentration levels (PK) and for anti-desmoglein-1 and -3 auto antibody titers by enzyme-linked 
immunosorbent assay (ELISA) (PD) per the Schedules of Assessments in Table 2 and Table 3.  
Details regarding the collection, handling, processing, storage, and shipping of samples are 
provided in the Laboratory Manual. 
8.4.8.1 Vaccine IgG  
To explore possible effects on vaccine response, investigators will be encouraged to request 
injectable vaccination plans in line with age-appropriate local medical practice or guidelines from 
participants who have entered the study and completed at least 6 weeks of rilzabrutinib/placebo at 
the time of scheduled vaccination for the Blinded Treatment Period, and 6 weeks of rilzabrutinib 
for the Open-label or Long-term Extension period such as vaccines for influenza, COVID-19, or 
tetanus (alone or in combination) (live attenuated vaccines are excluded).  
Participants scheduled to receive any of the aforementioned vaccines during the study periods 
may volunteer, after documenting informed consent, to provide 2 blood samples for vaccine-
specific IgG in serum. The first blood sample should be collected within 6 weeks prior to each 
vaccine dose regimen and the second blood sample should be collected within approximately 3 to 
6 weeks after the vaccine dose regimen is complete. Whenever possible, blood for vaccine-
specific IgG should be collected at a scheduled visit; but may also be collected during an 
Unscheduled Visit. Dates of vaccination, disease, brand name of vaccine product and antigenic 
strain should be recorded. Additional details are provided in Appendix 11 Section 12.11. 
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8.4.9 Pemphigus disease area index (PDAI)  
The PDAI total activity score is a clinical assessment with a possible rater score ranging from 0 to 
250, consisting of ≤120 points for skin activity, ≤10 points for scalp activity, and ≤120 points for 
mucosal activity (Appendix 2 Section 12.2). The rater examines each body area with scores 
assigned according to the number and maximum size of lesions in that area. When a score of 1 is 
given for a score of 1-3 lesions and none are more than 2 cm, the scorer records the actual number 
from 1 to 3. There is also a damage component to the score to reflect the non-active lesions such 
as post-inflammatory hyperpigmentation, but this is not counted in the assessment of disease 
activity. The PDAI is sensitive to low number of lesions which improves the consistency of score 
values between physician raters. The PDAI does not use body surface area (BSA) which can be 
difficult to estimate or lesion type as a scoring variable, both of which can exaggerate small 
differences between raters (12). 
8.4.10 Autoimmune bullous disease quality of life (ABQOL)  
The Autoimmune Bullous Disease Quality of Life (ABQOL) questionnaire was developed in 
Australia as a patient-based measure to determine quality of life in patients with autoimmune 
bullous disease (Appendix 3 Section 12.3). The ABQOL was found to be more sensitive than both 
the 36-Item Short Form Health Survey (p = 0.01) and the Dermatology Life Quality Index 
(p = 0.02). It was also found to be a reliable instrument evaluated by internal consistency with a 
Cronbach α coefficient of 0.84 (13). 
8.4.11 Treatment autoimmune bullous disease quality of life (TABQOL)  
The TABQOL questionnaire is a patient-based tool that measures the subjective element of 
disease progression and burden attributable to the side effects of autoimmune bullous disease 
(AIBD) treatment, with higher scores indicating worse quality of life (QOL) (14). Refer to 
Appendix 4 Section 12.4 for the scale. 
8.4.12 EuroQOL (EQ-5D-5L)  
The EuroQOL-5 Dimension 5 Level (EQ-5D-5L) is a copyrighted, patient-based instrument for 
a standardized measure of health status developed by the EuroQoL Group in order to provide 
a simple and generic measure of health for clinical and economic appraisal (15). The health status 
measured with EQ-5D-5L is used for estimating preference weight for that health status, then by 
combining the weight with time, quality-adjusted life-year can be computed. Quality-adjusted 
life-years gained is used as an outcome in cost-utility analysis which is a type of economic 
evaluation of healthcare programs and intervention. Refer to Appendix 5 Section 12.5 for an 
example of the copyrighted scale.  
8.4.13 Glucocorticoid toxicity index (GTI)  
The GTI is a copyrighted instrument for measurement of CS toxicity (16). Refer to Appendix 6 
Section 12.6. 
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8.4.14 Photography  
Photography of lesions may be performed at selected sites, at the Investigator’s discretion as 
allowed by country and local regulations.  
8.4.15 SARS-CoV-2 testing requirement (for German participants only)  
For participants in Germany, please see specific instructions for SARS-CoV-2 testing in 
Appendix 10 Section 12.10. 
8.5 
ASSESSMENT OF EFFICACY  
8.5.1 Specification of the efficacy parameters  
Efficacy will be evaluated using a combination of lesion assessments, corticosteroid usage, and 
validated instruments for assessing disease activity and patient quality of life.  
A comprehensive list of all the secondary endpoints can be found in Section 3. In summary:  
• The primary endpoint requires patients to have no new or established lesions at the 
Week 29, 33 and 37 Visits, while on a daily corticosteroid dose ≤10 mg/day.  
• The first key secondary endpoint is an analysis of the cumulative CS dose from baseline to 
Week 37. 
• The other secondary or exploratory endpoints include analyses of the following 
instruments: PDAI, ABQOL, TABQOL, EQ-5D-5L, VAS and GTI. Descriptions of the 
instruments can be found in Section 8.4.9 - Section 8.4.13. 
8.5.2 Methods and timing for assessing, recording and analyzing of efficacy parameters  
Lesion assessments, the Pemphigus Disease Area Index (PDAI) and prescribed corticosteroid 
doses are recorded at every visit. The quality of life instruments are administered at the visits 
specified in the schedule of assessments (Table 2), and the ET Visit and Unscheduled visits. 
Further assessment details can be found in Section 8. 
Descriptions of the analysis of the primary and secondary endpoints can be found in Section 9.3.5 
and Section 9.3.6.  
8.6 
ASSESSMENT OF SAFETY  
8.6.1 Overview  
After a comprehensive baseline evaluation, the safety of the patients will be monitored by 
assessment of vital signs, laboratory tests (hematology, and chemistry), disease assessments, 
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and abbreviated physical examinations. Concomitant medications and TEAEs will be monitored 
and tracked. 
The Investigator should take appropriate and prompt remedial measures for AEs, including 
clinically significant laboratory result abnormalities, while trying to elucidate the etiology of the 
condition. The patient should then be followed-up until the condition resolves or becomes chronic 
or stable. 
Trial stopping criteria are discussed in Section 7.1.1 and individual stopping criteria in 
Section 7.2.  
8.6.2 Data safety monitoring board (DSMB) and interim analysis  
An independent DSMB will regularly review and evaluate unblinded patient safety data including 
reported serious adverse events (SAEs), tabulations of all AEs, and safety laboratory results. The 
DSMB will agree on the DSMB charter and an initial frequency of meetings. Subsequently, 
meeting frequency will be determined as appropriate by the DSMB.  
Documentation of the patient data reviewed at each meeting, including the individual DSMB 
member’s confirmation of data review and the findings and actions of the DSMB, will be included 
in the Trial Master File. DSMB findings that impact the safety of patients in this trial will be 
immediately reported to the local competent authority (CA) and IEC. Details of unblinding 
procedures, DSMB composition and responsibilities, and other DSMB information will be 
provided in a separate DSMB charter. 
Detailed methodology for summary and evaluation of data to be reviewed by the DSMB will be 
documented in a Statistical Analysis Plan (SAP) and DSMB charter. These documents may 
modify the plans outlined in the protocol; however, any major modification of the outcome 
measures and/or its analysis will also be reflected in a protocol amendment. 
8.6.3 Adverse Events  
8.6.3.1 Adverse event collection period  
The AE Collection Period begins at the time of the first Screening/eligibility assessment and ends 
at the EOT for each patient. 
During the COVID-19 pandemic, AEs will be collected during phone or video calls and recorded 
by electronic data capture (EDC) as described in Appendix 9A of the “Updated Guidelines to 
Sites for Delayed Patient Visits or Missed Visits Due to Travel Restrictions and Any Foreseeable 
Impacts of COVID-19” (Appendix 9 Section 12.9). 
8.6.3.2 Clinical adverse events  
An AE is any untoward medical occurrence in a participant or clinical investigation participant 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with the intervention. An AE can therefore be any unfavorable and unintended sign 
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(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of an investigational product, whether or not considered related to the 
product. All AEs encountered during the clinical study will be reported in detail in the source 
documents and documented in the case report form (CRF), from the date of participant consent 
throughout the follow-up visit. Pre-existing conditions that worsen during a study are to be 
reported as AEs, with the exception of expected variation in pemphigus disease activity itself. 
The below guidelines should be followed when recording AEs: 
• Medical terms: Whenever possible, use recognized medical terms when recording AEs on 
the AE CRF. Do not use colloquialisms or abbreviations. 
• Diagnosis: If known or suspected, record the diagnosis (except for hypoglycemia) rather 
than component signs and symptoms on the AE CRF and SAE form (eg, record congestive 
heart failure rather than dyspnea, rales, and cyanosis). However, signs and symptoms that 
are considered unrelated to an encountered syndrome or disease should be recorded as 
individual AEs on the AE CRF and SAE form. 
• Death: Death is an outcome of an event. The event that resulted in the death should be 
recorded and reported on the AE CRF and SAE form (except for sudden, unexplained 
death). 
• Surgical or diagnostic procedures: For medical or surgical procedures (eg, colonoscopy, 
biopsy), the medical condition that led to the procedure is an AE. Elective procedures 
(eg, vasectomy), planned hospitalizations, and procedures for treatment of conditions 
noted in the patient’s medical history that have not worsened (eg, hernia repair) are not 
considered AEs. 
• Chronic disease: In the case of disease (excluding disease under study) that is progressing 
by episodes (chronic disease), if the disease is known when the participant enters the trial, 
only worsening (increased frequency or intensity of the episodes or attacks) will be 
documented as an AE. If the disease is detected during the trial, and if repeated episodes 
enable diagnosis of a chronic disease, the episodes will be grouped together in the CRF, 
and the diagnosis will be clearly described. 
• Underlying disease conditions: Unchanged (stable), chronic conditions, or those related to 
the underlying disease that are consistent with the disease’s natural progression are not 
AEs and are not to be recorded on the AE page of the CRF. These conditions are 
considered part of the patient’s medical history and must be adequately documented on the 
appropriate page of the CRF. Day-to-day fluctuations of pre-existing disease should not be 
recorded as an AE on the AE CRF. 
• Disease under study (Pemphigus): Unexpected progression, signs, or symptoms of the 
disease under study are not AEs and are not to be recorded on the AE page of the CRF 
unless the event meets the definition of an SAE or is not consistent with the typical clinical 
course of the patient’s disease as established by the patient’s medical history. Worsening 
of the disease under study or other disease-related symptoms should be recorded as 
an AE only if the event meets the definition of an SAE or is not consistent with the 
typical clinical course of the disease. 
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• Laboratory abnormalities: An isolated, out-of-range laboratory result in the absence of any 
associated, clinical finding may or may not be considered an AE; the Investigator’s 
evaluation should be based on a consideration of the overall clinical context.  
• An out-of-range laboratory result will be considered clinically significant and recorded as 
an AE when it is part of a clinical abnormality requiring specific medical intervention or 
follow-up. The test will be repeated, and the patient will be followed-up until the test value 
has returned to the normal range or baseline, or the Investigator has determined that the 
abnormality is chronic or stable. The Investigator will exercise medical judgment in 
deciding whether out-of-range values are clinically significant and document the 
assessment in the source records. 
8.6.3.3 Adverse event intensity grading  
All clinical AEs encountered during the clinical study will be reported on the AE page of the 
CRF. Intensity of AEs will be graded based on the National Cancer Institute (NCI) CTCAE, 
Version 4.0 or higher and reported in detail as indicated on the CRF. For any AEs not found in the 
CTCAE, a description of intensity grading can be found below: 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2: 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living. 
Grade 3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care activities of daily living. 
Grade 4: 
Life-threatening consequences; urgent intervention indicated: by definition also 
a SAE. 
Death will not be recorded as Grade 5 severity - rather, the underlying condition will be recorded 
and its severity graded, with death regarded as an outcome. 
8.6.3.4 Adverse event relationship to trial medication  
Investigators should use their knowledge of the study participant, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or not an AE 
is considered to be related to the rilzabrutinib or placebo, indicating "yes" or "no" accordingly. 
The following guidance should be taken into consideration: 
• Temporal relationship of event onset to the initiation of rilzabrutinib or placebo 
• Course of the event, considering especially the effects of dose reduction, discontinuation 
of trial medication, or reintroduction of rilzabrutinib or placebo (if applicable) 
• Known association of the event with the rilzabrutinib or placebo or with similar treatments 
• Known association of the event with the disease under study 
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• Presence of risk factors in the study participant or use of concomitant medications known 
to increase the occurrence of the event 
• Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event. 
8.6.3.5 Treatment and follow-up of adverse events  
Adverse events (AEs), especially those for which the relationship to the rilzabrutinib or placebo is 
“related”, should be followed up until they have returned to baseline status or stabilized. 
If after follow-up, return to baseline status or stabilization cannot be established an explanation 
should be recorded on the CRF. 
8.6.3.6 Laboratory and ECG abnormalities  
Laboratory test results will be recorded on the laboratory results pages of the CRF, or appear on 
electronically produced laboratory reports, if applicable. 
Any treatment-emergent abnormal laboratory or ECG result which is clinically significant 
(ie, meeting one or more of the following conditions) should be recorded as a single diagnosis on 
the AE page in the CRF: 
• Accompanied by clinical symptoms 
• Leading to a change in rilzabrutinib or placebo (eg, dose modification, interruption, 
or permanent discontinuation) 
• Requiring a change in concomitant therapy (eg, addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or treatment) 
Note: Any laboratory or ECG result abnormality fulfilling the criteria for an SAE should be 
reported as such, in addition to being recorded as an AE in the CRF. 
8.6.3.6.1 Follow-up of abnormal laboratory test values  
In the event of unexplained clinically significant abnormal laboratory test values, the tests should 
be repeated as soon as possible and followed up until they have returned to the normal range 
and/or an adequate explanation of the abnormality is found. If a clear explanation is established, it 
should be recorded on the CRF. 
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8.6.3.7 Serious adverse event reporting  
8.6.3.7.1 Definitions  
An SAE is any experience (clinical AE or abnormal laboratory test) that suggests a significant 
hazard, contraindication, side effect, or precaution. An SAE must fulfill at least one of the 
following criteria at any dose level: 
• is fatal (results in the outcome death)* 
• is life-threatening 
• requires in-patient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
• is medically significant or requires intervention to prevent one or other of the outcomes 
listed above 
* Note that the term "sudden death" should only be used when the cause is of a cardiac origin as 
per standard definition. The terms "death" and "sudden death" are clearly distinct and must not be 
used interchangeably. 
8.6.3.7.2 Serious Adverse Event Reporting  
Any clinical adverse event or abnormal laboratory test value that is serious and which occurs 
during the course of the study (as defined above), occurring from the enrollment visit (start of 
study Screening procedures), including long term follow-up must be reported to: 
• The Local Sponsor (or designee) and trial monitor within 24 hours of the Investigator 
becoming aware of the event (expedited reporting). 
• The investigational site’s IRB by the Investigator in accordance with their regulations. 
Initial notification of an SAE  
Pharmacovigilance (PVG) must be informed in writing 24 hours from the time the site 
investigational team first become aware of the event using the EDC system, if possible. Paper 
SAE report forms should only to be used when the EDC system is not accessible, and SAEs 
should be transferred into EDC once the system is available. 
If EDC is not accessible, a paper SAE form including a written, narrative description of any SAE 
must be emailed to
 within 24 hours after awareness of the 
event. 
If paper SAE forms are used, copies of the initial and follow-up SAE report forms must be made 
and the paper originals of all information that has been emailed must be retained in the 
Investigator Site File. 
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In addition to reporting the SAE in the EDC or via email, the local clinical research associate 
(CRA) and the Global Medical Monitor must be alerted via phone (refer to Site Manual). 
As further information regarding the SAE becomes available, such follow-up information should 
be documented as an update in the EDC system, or if EDC is not accessible, on a new SAE report 
form, marked as a follow-up report and emailed to 
. 
Starting after informed consent, SAEs must be reported within 24 hours (eg, SAEs related to 
invasive Screening procedures such as biopsies, or SAEs related to corticosteroid treatment during 
Screening).  
Related SAEs MUST be collected and reported regardless of the time elapsed from the last 
administration of rilzabrutinib or placebo, even if the study has been closed. 
Unrelated SAEs must be collected and reported during the study and for up to 30 days after the 
last dose of study medication. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) are reported to Investigators at each 
site and associated IRB when the following conditions occur: 
• The event is a SAE. 
• There is a reasonable possibility that the event is an adverse reaction caused by the 
administered drug. 
• The adverse reaction is unexpected, that is to say, not foreseen in the Investigator 
Brochure. 
• When all participants at a particular site are off treatment, as defined by the protocol, 
individual SUSAR reports will be forwarded to the site and its associated IRB on 
an expedited basis. 
Individual SUSARs considered to be a significant safety issue and/or which result in a change to 
the informed consent form will be reported in an expedited manner to all Investigators and IRBs. 
Reporting of any SAEs to applicable regulatory authorities will be the responsibility of the Local 
Sponsor in compliance with local regulations. 
8.6.3.7.3 Other Safety Findings Requiring Expedited Reporting  
Significant safety findings will be reported to the Investigator by Principia or designee as 
obtained. The Investigator is responsible for reporting to the investigational site’s IRB in 
accordance with their regulations. Reporting to applicable regulatory authorities will be the 
responsibility of Principia (or designee) in compliance with local regulations. 
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8.6.4 Pregnancy  
Pregnancy in a Female Clinical Trial Participant: If a female clinical trial participant becomes 
pregnant during the study, she must be instructed to stop taking rilzabrutinib or placebo 
and immediately inform the Investigator. Pregnancies occurring up to 4 weeks after the last dose 
of rilzabrutinib or placebo must also be reported to the Investigator. The participant should be 
counseled by a specialist, to discuss the risks of continuing with the pregnancy and the possible 
effects on the fetus. Monitoring of the participant should continue until the outcome of the 
pregnancy is known. The Investigator should report all pregnancies in clinical trial participants to 
the Sponsor within 24 hours of becoming aware of them, using the Clinical Trial Pregnancy 
Reporting Form. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy for medical reasons will be reported as an AE or 
SAE.  
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor. 
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9 
STATISTICAL CONSIDERATIONS  
Detailed methodology for summary of the data will be documented prior to database lock 
and unblinding in a SAP. This document may modify the plans outlined in the protocol; however, 
any major modification of the outcome measures and/or its analysis will also be reflected in the 
clinical trial (study) report. Additional statistical analyses other than those described in this 
section may be performed, if deemed appropriate, and included in the SAP. 
Descriptive summaries of variables by treatment will be provided where appropriate. Continuous 
variables will be summarized using the following descriptive statistics: mean, standard deviation 
(SD), number of observations, median, minimum and maximum. Summaries will also be 
presented for the change from baseline, when appropriate. For categorical variables, the counts 
and proportions of each value will be tabulated by treatment. For time to event variables, point 
estimates (25th, 50th, and 75th percentiles) along with 95% confidence intervals will be tabulated 
by treatment using Kaplan-Meier methods. Survival estimates will also be shown graphically for 
each treatment. In general, all data will be listed, sorted by patient and, when appropriate, by 
study day and study timepoint for each patient. 
All statistical tests will be two-sided unless otherwise noted. 
9.1 
SAMPLE SIZE DETERMINATION  
The primary efficacy endpoint is the percent of patients who are in CR from Week 29 (Visit) to 
Week 37 (Visit) with a CS dose of ≤10 mg/day. 
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9.2 
POPULATIONS FOR ANALYSES  
Four populations will be defined for data analysis: the Safety Population, the Intent-to-Treat (ITT) 
Population, Modified Intent-to-Treat (mITT) (efficacy) Population, and the Pharmacokinetic 
Population. 
Safety Population: 
All patients who receive at least one dose of study medication will be included in the Safety 
Population. The Safety Population is the primary analysis population for safety. Patients will be 
analysed according to the treatment they actually received, not necessarily the treatment they were 
allocated to at randomization. Results will be presented “as treated.” 
Intent-to-Treat (ITT) Population: 
All patients who are randomized will be included in the ITT Population. Patients will be analyzed 
according to the treatment they were allocated to at randomization; not necessarily the treatment 
they actually received. Results will be presented “as randomized.” 
Modified Intent-to-Treat (mITT) Population: 
All patients who are randomized and receive at least one dose of study medication will be 
included in the mITT Population. The mITT Population is the primary analysis population for 
efficacy. Patients will be analyzed according to the treatment they were allocated to at 
randomization; not necessarily the treatment they actually received. Results will be presented 
“as randomized.”  
Pharmacokinetic (PK) and Pharmacodynamic (PD) Populations: 
All patients who receive at least one dose of study medication and have sufficient data for PK 
and/or PD analysis will be included in the PK and/or PD populations. 
9.3 
STATISTICAL ANALYSES  
9.3.1 Disposition of the trial patients  
The disposition of patients will be described with summaries of the number of patients treated and 
discontinued from the trial, including the primary reason for premature discontinuation. 
9.3.2 Demographic and baseline characteristics  
Summaries of patient disposition, demographics, and baseline characteristics will be provided by 
treatment group.  
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9.3.3 Exposure to study treatment  
The number of received doses will be summarized by treatment group. Treatment duration 
and compliance for all patients will be described. 
9.3.4 Safety and tolerability analysis (safety population)  
The nature, frequency, and severity of AEs, including SAEs, AEs leading to discontinuation and 
possible corticosteroid-related adverse effects will be summarized descriptively by treatment 
group. Adverse events (AEs) prespecified as possibly related to CS will be grouped and analyzed 
separately in addition to the above. 
A by-patient TEAE data listing, including verbatim term, preferred term and system organ class 
(SOC), treatment, severity, and relationship to cohort, will be provided. 
The number of patients experiencing AEs and number of AEs will be summarized by treatment 
group using frequency counts. 
Safety data, including laboratory evaluations and vital signs assessments, will be summarized by 
treatment group and time point of collection. 
Descriptive statistics (arithmetic mean, SD, sample size [N], median, minimum, and maximum) 
will be calculated for quantitative safety data and frequency counts will be compiled for 
classification of qualitative safety data. 
A change-from-baseline table will be provided for vital signs and clinical laboratory results by 
treatment group.  
A shift table describing out-of-normal range shifts will be provided for clinical laboratory results, 
as appropriate.  
Adverse events will be coded using the most current Medical Dictionary for Regulatory Activities 
(MedDRA®) available at the time of entry and the version will not change through completion of 
trial data available at the Sponsor or designee.  
Concomitant medications will be listed by treatment and coded using the most current World 
Health Organization (WHO) drug dictionary and the version will not change through completion 
of trial data available at the Sponsor or designee. 
Medical history will be listed by patient and treatment assignment. 
No formal inferential statistics will be applied to safety assessments. 
Additional analyses will be performed as appropriate. 
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9.3.5 Efficacy analysis (mITT Population)  
In general, the need for rituximab rescue will be considered “treatment failure” for the analysis of 
efficacy endpoints except cumulative CS and composite GTI score. 
The analyses for efficacy endpoints involving clinical assessment of CR during the blinded 
treatment period will be performed based on data collected during on-site visits (i.e., not including 
data collected from remote visits) as the primary analyses. 
Primary: 
The proportion of patients who are in CR from Week 29 (Visit) to Week 37 (Visit) with a CS dose 
of ≤10 mg/day. 
• A Cochran-Mantel-Haenszel (CMH) general association test stratified by disease type (PV 
or PF) and disease history (newly diagnosed or relapsing) will be used to compare 
rilzabrutinib with placebo. Newly diagnosed pemphigus is defined as patients diagnosed 
≤6 months prior to Screening. Relapsing, chronic pemphigus is defined as patients 
diagnosed >6 months prior to Screening. 
Patients who drop out of the trial, withdraw, or who receive a rituximab dose prior to Week 37 
will count as non-responders in the analysis.   
The primary efficacy analysis will be performed using a CMH general association test stratified 
by disease history (newly diagnosed or relapsing) to compare rilzabrutinib with placebo.  
Key Secondary: 
The cumulative oral corticosteroid dose over the first 36 weeks will be summarized descriptively 
and will be compared across treatment groups using pairwise comparisons from an analysis of 
variance (ANOVA) model. The ANOVA model will include effects for treatment, and disease 
history. 
Cumulative duration of CR with CS dose ≤ 10mg/day from Baseline to Week 37will be analyzed 
using a zero-inflated negative binomial model with terms for treatment group and disease history.   
Time to first CR with a CS dose ≤10 mg/day, from Baseline to Week 37, will be analyzed using 
Kaplan Meier method. The median event time (and other quartiles) and 2-sided 95% confidence 
intervals will be presented. The endpoint will be evaluated based on a p-value from a log-rank test 
stratified by disease history for treatment group comparison.  
Further details of the key secondary endpoints analysis and additional sensitivity analyses will be 
described in the SAP. 
9.3.6 Key secondary efficacy sequential testing  
After testing the primary endpoint in the PV mITT population and the mITT population (i.e. 
PV+PF population), key secondary efficacy endpoints will be tested sequentially, first on the PV 
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mITT population in the order specified below, and then on the mITT population in the same 
order: 
• 
Cumulative CS dose from Baseline to Week 37 
• 
Cumulative duration of CR with a CS dose ≤10 mg/day, from Baseline to Week 37 
• 
Time to first CR with a CS dose ≤10 mg/day, from Baseline to Week 37  
All other analyses will be performed at the 0.05 level and will not be corrected for multiple 
comparisons, as they will be viewed and handled in the perspective of not testing a formal 
hypothesis. 
Other secondary:  
The other secondary endpoints will be primarily analyzed descriptively.  
The change from baseline in GTI, ABQOL, PDAI, and EQ-5D-5L overall visual analogue scale 
(VAS) scores to each visit will also be analyzed using restricted maximum likelihood (REML)-
based mixed models for repeated measures (MMRM) with fixed effects for treatment, week, 
Screening score, and the treatment-by-week interaction.  
The proportion of patients who are in CR from Week 29 to Week 37 with a CS dose of ≤5 mg/day 
of CS at any time will be compared using the same method as the primary endpoint. 
The difference in the proportion of patients with 3 or more lesions within 1 month that do not heal 
spontaneously within 1 week, or with extension of established lesions, from Baseline to Week 37, 
will be tested in the same manner as the primary endpoint. 
Proportion of patients with at least one disease relapse/flare from initial CDA to Week 37 will be 
tested in the same manner as the primary endpoint. 
9.3.7 Pharmacokinetic and pharmacodynamic analysis  
Individual and group PK and PD data will be summarized, displayed graphically, and by 
descriptive statistics for each visit where measured. Data may be summarized by descriptive 
statistics and related to clinical responses for each patient and as a group. 
9.3.8 Exploratory analysis  
Other subgroup and exploratory analyses not specified in the protocol may be performed. Health 
economic utility data related to the costs of AEs and hospitalizations may be explored. If 
collected, vaccine response parameters may be summarized by treatment group and, by disease 
and antigenic strain of the vaccine dose regimen. The change from baseline in TABQOL score to 
each visit (Weeks 5, 13, 25, 37, 61, and 109) will also be analyzed using REML-based MMRM 
with fixed effects for treatment, week, Screening score, and the treatment-by-week interaction. 
Full details will be provided in the SAP. 
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9.3.9 Long term extension analysis  
The long term extension endpoints will be summarized descriptively in general. Summaries of 
patient disposition, demographics, and baseline characteristics will be provided. Safety data 
including AEs, laboratory evaluations and vital signs assessments will also be summarized. More 
details will be provided in the SAP. 
9.3.10 Missing data  
Missing data will not be imputed except for the situations described in the SAP. Details on the 
handling of missing data, including missing data due to the COVID-19 pandemic, will be 
described in the SAP. 
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10 
INVESTIGATOR RESPONSIBILITIES  
By signing the separate protocol and amended protocol agreement form, the Investigator agrees to 
do the following: 
1. Conduct the trial in accordance with the relevant current protocol and make changes only 
after notifying the Sponsor, except when immediate changes are necessary to protect the 
safety, rights, or welfare of the patients 
2. Comply with the currently endorsed E6 International Council for Harmonisation Tripartite 
Guideline on Good Clinical Practice and applicable Food and Drug Administration (FDA) 
Code of Federal Regulations (CFRs) 
3. Personally conduct or supervise the described investigation 
4. Inform any patients, or any persons used as controls, that the drugs are being used for 
investigational purposes 
5. Ensure that the requirements relating to obtaining informed consent and IRB/IEC review 
and approval have been met 
6. Report to the Sponsor adverse experiences that occur in the course of the investigation as 
speciﬁed in 21 CFR 312.64 and the E6 International Council for Harmonisation Tripartite 
Guideline on Good Clinical Practice and any local regulations 
7. Have read and understood the IB, including potential risks and side effects of the drug 
8. Ensure that all associates, colleagues, and employees assisting in the conduct of the trial 
are informed about their obligations in meeting the above commitments 
9. Maintain adequate and accurate records and make these available for inspection by the 
Sponsor, its designee, the FDA, the IRB/IEC, and other applicable national or local health 
authorities or agency authorized by law, as deﬁned in 21 CFR 312.68 and currently 
endorsed E6 International Council for Harmonisation Tripartite Guideline on Good 
Clinical Practice 
10. Ensure that an IRB/IEC that complies with the requirements of 21 CFR Part 56 
and applicable country-speciﬁc regulations will be responsible for the initial 
and continuing review and approval of the clinical investigation 
11. Promptly report to the IRB/IEC all changes in the research activity and all unanticipated 
problems involving risks to human patients or others 
12. Not make any changes in the research without IRB/IEC approval, except where necessary 
to eliminate apparent immediate hazards to human patients 
13. Comply with all other requirements regarding the obligations of Investigators and all other 
pertinent requirements. 
10.1 
DATA QUALITY ASSURANCE  
The overall procedures for quality assurance of clinical trial data, including data collection 
and management, will be described in the Data Management Plan. 
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Accurate and reliable data collection will be assured by verification and cross-check of the eCRF 
against the Investigator’s records by the trial monitor (source document verification), and the 
maintenance of Drug Accountability (see Section 6.2.3) by the Investigator. 
Data for this trial will be recorded in the trial EDC eCRFs. The data will be entered by the trial 
center from the source documents into the eCRF or will be loaded from other files (eg, safety lab 
data). In no case is the CRF to be considered as source data for this trial. 
A comprehensive validation check program will verify the data and discrepancy reports will be 
generated accordingly for resolution by the Investigator. All discrepant data will be resolved in 
the EDC database and data entered in the database will be independently compared with the 
original Investigator’s records. 
For classification purposes, preferred terms will be assigned to the original terms recorded on the 
eCRF, using MedDRA for AEs, diseases and surgical and medical procedures, and the WHO drug 
dictionary for drug and herbal treatments.  
10.2 
PROTOCOL AMENDMENTS AND TRIAL COMPLETION  
Protocol amendments must be made only with the prior approval of the Sponsor or its designees. 
The IRB/IEC must be informed of all amendments and give approval for all amendments. For 
studies conducted outside of the US, approval of substantial amendments must be obtained from 
the relevant Competent Regulatory Authority before implementation. The Investigator must send 
a copy of the approval letter from the IRB/IEC to the Sponsor and/or the Sponsor’s designee. 
Approval must be obtained before any changes can be implemented, except for changes necessary 
to eliminate an immediate hazard to trial participants, or when the change(s) involves only 
logistical or administrative aspects of the trial (eg, change in monitor[s], change of telephone 
number[s]). 
The Sponsor and the Investigator reserve the right to terminate the trial, according to the Clinical 
Trial Agreement. The Investigator should notify the IRB/IEC in writing of the trial’s completion 
or ET and send a copy of the notiﬁcation to the Sponsor and/or the Sponsor’s designee. 
Trial completion is deﬁned as the date when all patients have completed the ﬁnal study visit, 
and the trial database has been locked. 
10.3 
INFORMED CONSENT  
The Investigator and Sponsor must agree upon the format and content of the informed consent 
form (ICF) before it is submitted to the IRB/IEC for approval. A copy of the IRB/IEC approved 
copy of the ICF will be forwarded to the Sponsor. Written IRB/IEC-approved informed consent 
and Health Insurance Portability and Accountability Act (HIPAA) release (or other privacy 
protection release, as governed by local regulations) must be obtained from each patient, before 
any trial related activities are conducted. The Investigator must retain all original signed and dated 
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ICFs (together with any subsequent IRB/IEC-approved amended versions) in the patient’s ﬁle. A 
copy of the signed and dated ICF (and any amendments) must be given to the patient. 
The ICF documents the trial-speciﬁc information the Investigator provides to the patient the 
patient’s agreement to participate. Among other things, the Investigator or his/her designee will 
fully explain in layman’s terms the nature of the trial, along with the aims, methods, anticipated 
beneﬁts, potential risks, and any discomfort participation may entail. The ICF/patient information 
sheet must be appropriately signed and dated before the patient enters the trial. 
Patients will be informed of ﬁndings from earlier or concurrent clinical studies (including AEs), if 
it is considered that such information could potentially affect patient’s willingness to participate 
or continue in the trial. Depending on the nature, severity, and seriousness of these AEs, the ICF 
may be amended as deemed appropriate. The original and any amended signed and dated ICF(s) 
and patient information sheet(s) must be retained in the patient’s ﬁle at the trial site; and a copy 
must be given to the patient. 
In this study, the optional procedures (eg, photographs and vaccine IgG sample collection) are 
listed separately at the end of the consent. Each option is subject to an independent consent and 
must be confirmed by ticking a checkbox in the main consent. The Investigator or authorized 
designee will explain to each participant the objectives of the exploratory research and why data 
and samples are important for future research. Participants will be told that they are free to refuse 
to participate and may withdraw their consent at any time and for any reason during the storage 
period. 
10.4 
PATIENT CONFIDENTIALITY AND DISCLOSURE OF DATA  
The Investigator must ensure that each patient’s anonymity is maintained as described below. 
On the eCRFs or other documents submitted to the Sponsor and/or its designee, patients must only 
be identiﬁed by trial, Patient Identification Number, and demographics, and pertinent restrictions 
of local regulations. No other personal identifiers will be used, and data will be de-identified in a 
manner compliant with Privacy Laws and, for US patients, the HIPAA regulations. Documents 
that are not for submission to the Sponsor and/or its designee (eg, signed ICFs and Patient 
Information Sheets) should be kept in strict conﬁdence by the Investigator in compliance with 
Federal regulations or other applicable laws or International Council for Harmonization (ICH) and 
Good Clinical Practice (GCP) Guidelines. The Investigator and institution must permit authorized 
representatives of the Sponsor and/or its designee, by representatives of the FDA, national and 
local health authorities, and the IRB/IEC direct access to review the patient’s original medical 
records for veriﬁcation of trial-related procedures and data. Direct access includes examining, 
analyzing, verifying, and reproducing any records and reports that are needed for the evaluation of 
the trial. The Investigator is obligated to inform the patient in the ICF that his/her trial-related 
records will be reviewed, by the above-named representatives. 
Patients will be informed that data will be held on ﬁle, by the Sponsor, and that these data may be 
viewed by staff including the trial monitor and by external auditors on behalf of the Sponsor and 
appropriate regulatory authorities. Participants will also be informed that a (trial) study report will 
be prepared and may be submitted to regulatory authorities and for publication. However, 
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participants will be identiﬁed in such reports only by Patient Identiﬁcation Number and 
demographics, pertinent to restrictions of local regulations. All patient data will be held in strict 
conﬁdence, as allowed by law. 
Upon the patient’s permission, medical information may be given to the patient’s personal 
physician or other appropriate medical personnel responsible for the patient’s welfare. 
10.5 
ELECTRONIC CASE REPORT FORMS  
The data collected in the source documents for this trial will be entered into the trial EDC eCRF. 
An audit trail will maintain a record of initial entries and changes made; time and date of entry; 
and name of person making entry or change. For each participant enrolled, an eCRF must be 
completed and signed by the Principal Investigator or authorized delegate from the trial staff. 
If a participant withdraws from the trial, the reason must be noted in the eCRF. If a participant is 
withdrawn from the trial because of a treatment-limiting adverse event, thorough efforts should be 
made to clearly document the outcome. 
The Investigator should ensure the accuracy, completeness and timeliness of the data reported to 
the Sponsor in the CRFs and in all required reports. 
10.6 
RETENTION AND AVAILABILITY OF RECORDS  
The Investigator is required to retain the trial records and reports until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. If no marketing 
application is to be filed, or an application is not approved for the drug, the Investigator will retain 
the study (trial) records for 2 years after shipment and delivery of the drug for investigational use 
is discontinued and the Sponsor has so notified the FDA, per 21 CFR 312.57. Study (trial) records 
should, however, be retained longer if required by the applicable national and/or local regulatory 
requirements or by agreement with the Sponsor. 
The Investigator must make study (trial) data accessible to the monitor, other authorized 
representatives of the Sponsor, and regulatory agency inspectors upon request. A ﬁle for each 
patient must be maintained that includes the signed ICF and the Investigator’s copies of all source 
documentation related to that patient. The Investigator must ensure the reliability and availability 
of source documents from which the information on the CRF was transcribed. 
10.7 
AUDITS AND INSPECTIONS  
In accordance with ICH, GCP and the Sponsor and/or its designee audit plans, this trial may be 
selected for audit. Inspection of site facilities (eg, pharmacy, drug storage areas, laboratories) and 
review of trial-related records will occur to evaluate the trial conduct and compliance with the 
protocol, ICH, GCP, and applicable regulatory requirements. The Investigator/ institution should 
make available for direct access all requested trial-related records (ICH GCP 4.9.7) to 
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appropriately qualified personnel from the Sponsor or its designees, or to health authority 
inspectors after appropriate notification. The verification of the CRF data must be by direct 
inspection of source documents. The Investigator/institution should take measures to prevent 
accidental or premature destruction of these documents (ie, completed CRFs, Investigator site 
files, and any source documents should be stored in a protected secure location [ICH GCP 4.9.4]). 
If for any reason the study trial) records are moved to another location, the Investigator should 
notify the Sponsor of the new location. 
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11 
ETHICAL ASPECTS  
This section provides information for the Investigator on the ethics requirements for the trial, 
including subject informed consent, IRB/IEC review of the study and study materials, 
and conditions for modifying or terminating the study. Requirements for financial disclosure 
for the Investigator are also described. 
11.1 
LOCAL REGULATIONS/DECLARATION OF HELSINKI  
The Investigator will ensure that this trial is conducted in full conformance with the ethical 
principles that have their origin in the “Declaration of Helsinki”, and that are consistent with the 
principles outlined in the current “Guideline for Good Clinical Practice” ICH Tripartite Guideline 
GCP E6 or with the laws and regulations of the country in which the research is conducted (eg, 
Directive 2001/20/EC and 2005/28/EC, and the Title 21 Code of Federal Regulations Parts 50, 54, 
56, 312, and 314, where appropriate), whichever affords the greater protection to the individual. 
11.2 
INSTITUTIONAL REVIEW BOARD REVIEW  
This protocol and any accompanying material provided to the participant (such as participant 
information sheets or descriptions of the trial used to obtain informed consent), as well as any 
advertising or compensation given to the participant, will be submitted by the Principal 
Investigator or coordinating Investigator to the relevant institutional IRB/IEC responsible for the 
investigational trial.  
An approval letter or certificate (specifying the protocol number and title) from the IRB/IEC must 
be obtained before starting the trial (initiation). The approval letter to the Investigator should 
specify the date on which the committee met and granted the approval. The Local Sponsor must 
also obtain relevant competent authority approvals before starting the trial. 
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12 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
12.1 
APPENDIX 1 
CORTICOSTEROID AND RITUXIMAB MANAGEMENT  
Corticosteroid Starting Doses and Management During Screening and at Day 1: 
Topical corticosteroid and oral corticosteroid rinses (mouth washes) are allowed. 
Required, initial doses of oral CS (prednisone or prednisolone) for the duration of Screening are 
≥0.2 mg/kg/day of CS for patients with relapsing disease (diagnosed >6 months prior to 
Screening) and ≥0.5 mg/kg/day for patients with newly diagnosed disease (diagnosed ≤6 months 
prior to Screening). At Screening, patients will begin to take Sponsor-provided CS according to 
the minimum dose requirements, and as required to adequately treat the disease during the 
Screening period. CS doses may be adjusted per Investigator discretion during the Screening 
period but should not be reduced below the required minimum CS dose levels (≥0.2 mg/kg/day 
for patients with relapsing disease and ≥0.5 mg/kg/day for patients with newly diagnosed 
diseases. CS taper below the required minimum dose level should not begin until ECP has been 
achieved. 
If disease significantly (Investigator judgment) worsens during the Screening period, up-titration 
of CS dose by 50-100% should occur, as often as every 5-7 days if needed (4).  
Corticosteroid Management during Blinded Treatment Period, Open-Label Extension 
Period, and Long Term Extension Period 
Corticosteroid-Tapering (Consensus Guidelines) (1) 
CS will be tapered upon confirmation of ECP towards a goal of 5 mg/day by ≤Week 29. ECP is 
defined as the visit at which no new lesions have developed for a minimum of 2 weeks and the 
majority (approximately 80%) of established lesions have healed. Once the 5 mg/day level is 
achieved it will be kept at 5 mg/day until the time of the primary endpoint at Week 37 is reached.  
From Week 37, further tapering to 0 mg CS should be attempted in patients with CR unless 
medically contraindicated. At Investigator discretion, the CS may be switched to equivalent doses 
of oral hydrocortisone instead of prednisone or prednisolone when tapering from 5 mg to 0 mg 
CS. 
CS tapering should follow the modified dosing guideline below, based upon (1). Adjustment of 
the dosing guideline protocol by investigators is permitted for safety reasons, based on assessment 
and documentation of clinical need. 
• 
Start tapering CS as soon as ECP is confirmed 
• 
Decrease CS by 25% every two weeks, until 20 mg per day 
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• 
Once at 20 mg per day, decrease CS by 2.5 mg per week 
• 
Once at 10 mg/day, decrease CS by 1 mg per week to 5 mg 
Note, because 1 mg will be the smallest CS dosage provided and tablet splitting is not allowed, 
the Investigator must round up or down to the nearest whole milligram for CS dose after 
calculation of the new dose level. 
Table 6: 
Example Taper for a 60 mg Dose of CS  
Current Dose Level 
(prednisone equivalent) 
Size of Dose Reductions 
(prednisone equivalent) 
Example (Note: dosages 
rounded to nearest mg) 
Frequency of 
Dose Reductions 
60 mg down to ~20 mg 
Approximate 25% decrease  
60 mg, 45 mg, 34 mg, 26 mg, 
20 mg 
Every two weeks 
~20 mg to ~10 mg 
~2.5 mg decrease  
20 mg, 18 mg, 15 mg, 13 mg, 
10 mg 
Weekly 
~10 mg to 5 mg 
1 mg  
10 mg, 9 mg, 8 mg, 7 mg, 6 mg, 
5 mg until Week 37 then further 
titration to 0 mg 
Weeklya 
a Per guidelines (1) has a typographical error mistakenly saying “daily” when “weekly” was intended. 
CS dose up-titration for worsening disease: 
1. Severe relapse/flare or worsening disease at any time, which, in the opinion of the 
Investigator, is potentially life threatening 
Commence conventional immunosuppressive therapy and discontinue rilzabrutinib/placebo. 
2. Non life-theatening worsening of disease during taper of CS prior to confirmation of 
ECP 
During Screening or the treatment periods of the trial, where an initial induction of CDA has not 
been achieved and blistering continues without improvement, CS should be increased by 50 to 
100% every 5 to 7 days until confirmation of ECP. After ECP is confirmed CS taper should 
commence. Rituximab therapy may not be used in this situation. Patients who have been treated 
with a minimum of 1.5 mg/kg/day of corticosteroids for 2 weeks and have not achieved control 
of disease activity may be eligible after discussion with Principia to receive rituximab. For 
patients who are unable to escalate CS up to 1.5 mg/kg/day due to documented AEs related to CS 
and cannot achieve CDA following 2 weeks of treatment with their maximally tolerated CS dose, 
rescue with rituximab therapy may be offered. Please consult with the Medical Monitor. 
3. Non life-theatening worsening of disease during taper of CS after confirmation of 
ECP 
• 
Go back to last CS dose level if >3 lesions reappear during the tapering of oral 
corticosteroid therapy (where relapse/flare, as defined below, has not occurred) 
• 
If a more severe full relapse/flare occurs (ie, the appearance of ≥3 new lesions within 
a month that do not heal spontaneously within 1 week, or there is extension of established 
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lesions), increase the CS dose by going back to the second to last dose until control of the 
lesions is achieved within 2 weeks, then resume taper 
• 
If disease control is still not reached despite this, go back to initial dose or higher as 
necessary, and resume taper when ECP is confirmed again 
It is recommended to follow the CS Guidelines during the Long Term Extension. 
Rituximab Management during Blinded Treatment Period  
Rituximab for second “qualifying relapse/flare”: 
• “Qualifying relapse/flare” for this purpose is defined as a relapse/flare occurring after 
CDA is achieved, ECP has been confirmed and CS taper has begun, that is not life-
threatening (when a patient should be withdrawn) but is severe enough such that the PDAI 
total activity score is equal to or greater than the Screening or Day 1 baseline PDAI score 
(whichever is higher) for that patient. For example, if the Screening PDAI was 25, the Day 
1 baseline was 21, and the relapse/flare PDAI 23, the relapse/flare would not be severe 
enough to be “qualifying”. Whereas if the relapse/flare PDAI was ≥25 it would be 
“qualifying”. 
• Where a second qualifying relapse/flare occurs meeting the above definition, and it is at 
or after the Week 5 Visit, then one course of rituximab, which consists of two intravenous 
doses of 1 gram two weeks apart, may be administered, unless contraindicated.  
• Oral CS doses should be managed as indicated for the patient at the time of the 2nd 
qualifying relapse/flare 
• Rituximab should be administered as recommended in the Pharmacy Manual.  
• Patients should not be unblinded to treatment assignment and should continue in the trial. 
Rituximab Management during Open-Label Extension Period and Long Term Extension 
Period 
Patients requiring treatment by rituximab or other immunosuppressants (other than CS) 
for relapse/flare during these study periods, must be discontinued from the study. If a patient has 
a qualifying relapse/flare during the Blinded Treatment Period and the second infusion from the 
rituximab course of treatment occurs during the Open-Label Extension period the patient may 
continue in the trial. 
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12.2 
APPENDIX 2 
PEMPHIGUS DISEASE ACTIVITY: PDAI  
Pemphigus Disease Area Index (PDAI) (1, 18)  
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12.4 
APPENDIX 4 
PEMPHIGUS QUALITY OF LIFE EVALUATION: TABQOL  
Treatment of Autoimmune Bullous Diseases Quality of Life Assessment (TABQOL) (19) 
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12.5 
APPENDIX 5 
GENERAL QUALITY OF LIFE EVALUATION: EQ-5D-5L  
EuroQOL-5 Dimension 5 Level (EQ-5D-5L) (20) 
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12.6 
APPENDIX 6 
GLUCOCORTICOID TOXICITY INDEX (GTI)  
The Glucocorticoid Toxicity Index (GTI) is a proprietary licensed instrument from Massachusetts 
General Hospital (16). It was developed to assess glucocorticoid (GC)-related morbidity and GC-
sparing ability of other therapies. The scale collects information about known steroid toxicities 
and uses a weighted scoring system to assesses toxicity. The instrument calculates a composite 
index score from data captured related to the following domains: body mass index, glucose 
tolerance, blood pressure, lipids, steroid myopathy, skin toxicity, neuropsychiatric toxicity, and 
infection. In addition, reports of any of the following toxicities are included in the index: 
endocrine (adrenal insufficiency), gastrointestinal (perforation, peptic ulcer disease), 
musculoskeletal (ruptured tendon, avascular necrosis) and ocular (retinopathy, increase in ocular 
pressure, posterior subcapsular cataract). 
12.7 
APPENDIX 7 
STRONG TO MODERATE CYP3A INHIBITORS AND INDUCERS AND 
SENSITIVE CYP3A SUBSTRATES  
 
Strong 
Moderate 
3A Inducers 
Avasimibe, carbamazepine, phenytoin, 
rifampin, St. John’s wort 
Bosentan, efavirenz, etravirine, 
modafinil, nafcillin 
3A Inhibitors 
Boceprevir, 
clarithromycin, conivaptan, 
grapefruit juice, indinavir, 
itraconazole, ketoconazole,  
lopinavir/ritonavir, 
mibefradil,  
nefazodone, nelfinavir, 
posaconazole, ritonavir,  
saquinavir,  
telaprevir, 
telithromycin, 
voriconazole 
Amprenavir, aprepitant, 
atazanavir, ciprofloxacin, 
darunavir/ritonavir, diltiazem, 
erythromycin, fluconazole, 
fosamprenavir, Seville orange juice,  
imatinib, verapamil 
From: Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. U.S. Food and Drug 
Administration.  
CYP3A Sensitive Substrate 
Subset with Narrow Therapeutic Index 
Alfentanil, aprepitant, budesonide, buspirone, 
conivaptan, darifenacin, darunavir, dasatinib, 
dronedarone, eletriptan, eplerenone, 
everolimus, felodipine, indinavir, fluticasone, 
lopinavir, lovastatin, lurasidone, maraviroc, 
midazolam, nisoldipine, quetiapine, 
saquinavir, sildenafil, simvastatin, sirolimus, 
tolvaptan, tipranavir, triazolam, vardenafil 
Alfentanil, astemizole, cisapride, cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus, tacrolimus 
(topical and oral), terfenadine 
From: Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. U.S. Food and Drug 
Administration.  
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12.8 
APPENDIX 8 
EFFICACY OUTCOME ASSESSMENT FLOWCHART  
 
 
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12.9 
APPENDIX 9 
UPDATED GUIDELINES TO SITES FOR DELAYED PATIENT VISITS 
OR MISSED VISITS DUE TO TRAVEL RESTRICTIONS AND ANY FORESEEABLE 
IMPACTS OF COVID-19  
Principia Biopharma understands that many study institutions have implemented restrictions to 
minimize in-person activities due to the rapidly evolving concerns and risks related to the 
COVID-19 outbreak. 
The safety data to date and the unique mechanism of action of Rilzabrutinib continues to support a 
favorable benefit/risk profile for pemphigus patients experiencing active disease manifestations. 
Principia intends to continue to enroll patients, provide investigational study drug to randomized 
patients, and to perform protocol assessments as possible during the pandemic whilst following 
the recent guidance issued from the United States Food and Drug Administration (FDA) 
and European Medicines Agency (EMA) in March 2020. For FDA, the Guidance is dated 
18 March 2020 entitled “FDA Guidance on the Conduct of Clinical Trials of Medical Products 
During COVID-19 Pandemic” and for EMA is dated 27 March 2020 entitled “Guidance on the 
Management of Clinical Trials during the COVID-19 (Coronavirus) Pandemic; Version 2” for the 
management of trials and subject safety under these circumstances. In addition, with the advent of 
the COVID-19 pandemic, and in consideration of the recently issued guidance by the EMA 
referenced above, Principia is committed to provide measures that assure continued drug supply 
and safety monitoring for patients, and is working in collaboration with sites and their respective 
Institutional Review Boards/Independent Ethics Committees to implement novel ways that 
support social distancing and stay at home measures while maintaining access to study drug and 
safety oversight. 
Precautions regarding COVID-19 and management of patients should be followed as there is 
no data regarding the impact of rilzabrutinib on COVID-19. Please refer to the current version of 
the Investigator Brochure (IB Edition v11.0) for further information on the potential risks 
and benefits of treatment with rilzabrutinib. 
Since rilzabrutinib is an oral medication, maintaining drug supply for patients during these 
restrictive times is feasible, especially as drug can be administered at home, and Principia is 
committed to making drug supply to patients a top priority. This is important because patients 
with pemphigus require uninterrupted treatment to maintain treatment response. 
Recommendations from the CDC and World Health Organization (WHO) for minimizing the risk 
of exposure to COVID-19 should be followed at all times, and the Investigator should make an 
assessment of the patient’s benefit/risk profile for inclusion and continuation in the Pegasus trial 
on a case-by-case basis. 
Principia is committed to keeping investigative sites informed in writing if there are any new 
significant safety findings that emerge affecting a patient’s willingness to participate or pose 
additional risk. For sites affected by restrictions due to COVID-19, Principia will implement the 
following changes in research plans in order to eliminate apparent immediate hazards to research 
participants in PRN1008-012: 
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Remote Study Visits for Active Patients 
It is expected that if your site is not affected and the patient is able to travel to the site for their 
regular scheduled protocol visit, that the visit occurs per schedule. It is important to discuss all 
upcoming visits in the next month with all patients to provide sufficient time to plan for their 
visits. 
In the circumstance that the patient is not able to travel to the site, or the site is quarantined 
and cannot host a patient visit - please following these guidelines below for allowing continued 
safety monitoring of the patient and continued supply of corticosteroids and rilzabrutinib/placebo. 
The priority is to ensure that the patient has continued supply of rilzabrutinib/placebo 
and corticosteroids to last them through to the next scheduled protocol visit. If the patient has 
enough supply until their next scheduled protocol visit, then no additional supply needs to be sent. 
Please remind the patient to bring all medication with them at their next in-clinic visit, and to 
continue to complete their patient corticosteroid diary. 
In-clinic study visits, as outlined in the protocol schedule of assessments, may be changed to 
a remote visit (eg, telephone call, video call) as needed to address the COVID-19 restrictions. We 
are mindful that your site resources may be restrictive during this time, so please inform your 
study monitor of any concerns so we can address any specific needs at your site as well as 
understand your internet and source documentation access. Please let us know if you have the 
capability to perform a video teleconference with your currently active enrolled patients via smart 
phone or computer. Refer to Appendix 9A “Remote Study Visits for Active Patients” on how to 
perform and document these remote visits. 
Enrollment 
Please notify Principia and your CRO study monitor of your Institution policy on enrollment 
during the pandemic prior to enrolling new patients. We need to ensure patient safety can be 
adequately monitored, access to study drug is feasible, and a plan is in place for each enrolled 
patient to determine how this will be implemented. 
Investigational Product (IP) Delivery Direct to Research Patients 
Where patients are self-isolating or in quarantine, sites are requested to obtain and document 
a patient’s verbal consent for IP delivery and in the case of shipment consent to provide address 
details for transport purposes. 
Options for IP Transport 
1. No change from current practice in protocol: a patient may obtain dispensed study drug 
during an in-clinic visit. 
2. Study drug may be delivered directly from the site to the patient at the address provided by 
the patient for the shipment of IP: 
a. Global - using Principia’s 
 account, insulated shipper, 
and temperature monitor. Please see Appendix 9B for instructions. 
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b. Taiwan only - a site member such as a study coordinator may deliver dispensed study 
drug from site/hospital to the patient’s home. Please see Appendix 9B for instructions. 
3. If you are not able to use Principia’s 
 vendor for shipping supplies and delivery of drug 
to the patient, you will need to provide the information to Principia regarding which local 
courier will be used, what kind of insulated shipper you will use, and brand and model 
number of the temperature monitoring device. Principia will need to approve the material 
and courier prior to shipment to the patient. Upon approval by Principia in writing, the site 
may arrange the shipment with the local courier. 
Urine Pregnancy Testing (UPT) for Women of Childbearing Potential 
It is important to confirm pregnancy status for women of childbearing potential. Please send 
2 urine pregnancy tests to the subject with each shipment of investigational product. If the UPT 
has a package insert with instructions on collection, include this in the shipment. During 
the follow up phone call with the patient, confirm pregnancy status (negative or positive) 
and document the result in the source notes. The subject may confirm the result by showing 
the test over the video or provide a photo of the test to site staff. A positive test result will need to 
be reconfirmed with a second test.  
Protocol Deviations 
Where the change to remote visits is being implemented due to COVID-19 to protect the 
safety and well-being of subjects, failing to obtain assessments will need to be documented 
(eg, identifying the specific limitation imposed by COVID-19 leading to the inability to perform 
the protocol-specified assessments). Please continue to document in your source documents all 
protocol deviations and inform your local site monitor. Notify your IRB/IEC as required locally. 
Remote Site Monitoring Visits, If Applicable 
As you know, the Sponsor is required to monitor the safety and benefit/risk for continued conduct 
of the study. In accordance with the FDA and EMA Guidance, the change in process required for 
monitoring due to COVID-19 must be documented and agreed upon by the investigative sites. To 
meet our Sponsor oversight obligations while study monitors are not allowed onsite, we ask that 
you continue to enter data into the EDC as soon as possible after a subject’s visit. Additionally, 
your study monitor may perform a remote (telephone) monitoring visit, in which they will ask you 
questions related to subject visit status, disease status, and any adverse events (AEs) or 
concomitant medications that were reported by the subject. In this event, your study monitor will 
document this discussion in an Interim Monitoring Visit report and will provide a follow-up letter 
as always. If permitted, sites are asked to provide source documents with all personal information 
REDACTED for your study monitor to perform remote source document verification. A separate 
manual will be sent to you for how this will be performed. 
Please share this information with your study site staff and inform your local IRB/IEC. 
For participants in Germany, please see specific instructions in Appendix 10 Section 12.10. 
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12.9.1 Appendix 9A - Remote Study Visits for Active Patients  
Remote visit procedures to be performed: 
1. Inform the patient that the study visit will be changed to a remote visit.  
2. Obtain rilzabrutinib/placebo and corticosteroid amounts remaining with the patient. Based on 
the anticipated next in-clinic visit, determine whether the patient requires additional 
dispensing of rilzabrutinib/placebo and corticosteroids. If additional dispensing is needed, 
obtain details on date, time, and delivery address for the patient’s home to confirm someone 
will be available to accept/sign for a home delivery. Follow options for IP transport 
instructions. 
3. Email or mail Quality of Life (QOL) questionnaires to patients. The patient should keep them 
and provide the completed questionnaires when they return to the clinic, or the site can send a 
pre-printed and labeled Airway Bill to return via courier. The questionnaires include: 
a. Autoimmune Bullous Disease Quality of Life (ABQOL) questionnaire 
b. Treatment Autoimmune Bullous Disease Quality of Life (TABQOL) questionnaire 
c. EuroQOL-5 Dimension 5 Level (EQ-5D-5L) 
4. Where possible schedule a local lab visit. If a local lab is not available, please notify your 
local study monitor. 
5. Collect the following critical study data via the phone call or video call. Document the 
conversation of the items below: 
a. At a minimum, the following assessments must be performed by phone call: 
i. New or changes in adverse events/serious adverse events 
ii. New or changes in concomitant medications 
iii. New or changes in Pemphigus concomitant medications 
iv. Confirm IP compliance (corticosteroids and rilzabrutinib/placebo) 
v. Confirm if changes in corticosteroid dosages are needed 
b. If feasible and allowable per local regulations the following assessments should be 
performed: 
i. PDAI assessment (must be done using video or photography for Investigator to 
visually review and confirm lesions) 
ii. Disease efficacy outcome assessment (ie, CDA, ECP, CR, or Relapse/flare ; must be 
done using video or photography for Investigator to visually review and confirm 
lesions) 
iii. Local labs performed (performed, yes/no, result and units) 
iv. Home monitoring of vital signs (eg, weight and blood pressure) 
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Documentation: 
1. Source documents: Continue to observe good documentation practice and record all details 
of the remote study visit, including: 
a. Patient Study ID 
b. Date and method of remote visit 
c. Site staff who performed remote visit 
d. All remote data collected 
2. CRFs: Enter all data collected within 5 days of the remote visit. Any data not collected should 
be entered as ‘Not done’ in the applicable CRF. 
3. For the QOL questionnaires, after the patient completes the questionnaire, the patient can read 
their answers to the coordinator over the phone with the coordinator recording the verbal 
conversation in a telephone report noting the test name, question number, and the subject 
verbal answer. This telephone report will reside with the source data and be entered into 
the EDC. The data will then later be verified against the original questionnaire supplied by the 
patient. This deviation in the process will be noted by the Study Coordinator and documented. 
Dispensing of CS and rilzabrutinib/placebo in Suvoda: 
1. Corticosteroids may be dispensed at any time using Corticosteroid Dispensing Visit 
Transaction in the IWRS. Reference page 17 of IWRS Site User Manual to dispense 
additional CS. 
Complete the paper Drug Accountability Log with corticosteroids dispensed. 
2. Rilzabrutinib/placebo may only be dispensed at a regular scheduled visit. Select the next 
scheduled patient visit. Respond “Yes” when asked if the visit was performed. A kit will be 
dispensed. If you select ”No”, the visit will be skipped and no kit will be dispensed. If the visit 
occurs outside the protocol specified window, you will be prompted to confirm that you would 
like to continue with registering the visit out of window. Respond ”Yes.” 
Scheduled Visit 
This function should be used to perform a scheduled dosing visit. 
Steps: 
1. Confirm Subject 
2. Confirm Visit 
3. Confirm Visit Performed 
a) In the case of a skipped visit, select “No” when asked if the visit was performed 
and the system will prompt you to confirm your selection. 
→ Scheduled visit complete. Kit Number assigned. 
  
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Complete the paper Drug Accountability Log with rilzabrutinib/placebo kit dispensed. 
Visit Scheduling: 
The goal is to complete the visit with all associated assessments in its entirety, even if this occurs 
late and out of window. If the visit is delayed for multiple weeks and rolls over into the next 
scheduled visit period, the previous visit will be considered missed and the subject should 
continue with that next scheduled protocol visit. 
Aim to return the patient to the original visit schedule, based on the randomization date 
and Suvoda visit schedule. 
Example Scenario 1 
Patient had the baseline visit on 06-Feb-2020 and are due for the Week 9 visit between 
16-Mar-2020 and 22-Mar-2020. Patient is unable to travel to site until 30-Mar-2020. 
Aim is to perform the Week 9 visit in its entirety on 30-Mar-2020, even if performed out of 
window. 
Document in source that dispensing of Week 9 IP occurred on dd-mmm-2020 (earlier) 
and visit assessments occurred late on dd-mmm-2020, “due to…” and then provide the reason. 
Example Scenario 2 
Patient had the baseline visit on 06-Feb-2020 and are due for the Week 9 visit between 
16-Mar-2020 and 22-Mar-2020. Patient is unable to travel to site until 12-Apr-2020. As the 
next scheduled protocol visit is Week 13 with window 12-Apr to 19-Apr; Week 9 will be 
considered missed and site should proceed with conducting the Week 13 visit. 
Document in source that Week 9 was missed, “due to…” and then provide the reason. 
Data Entry in EDC: 
If a visit is missed, answer “No” to “Was this visit performed” in the Visit Status page. The 
remaining visit assessments will not load. 
If a visit occurs out of window, enter the assessments within the applicable visit folder. A query 
will be generated asking to confirm if date is correct. Answer confirmed as correct. 
Enter any adverse events and concomitant information updates in the Common folder. 
 
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12.9.2 Appendix 9B - IP Shipment/Delivery Process  
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Instructions for Taiwan Only: 
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12.9.4 Appendix 9D - 
 Ordering Process - Site to Patient Courier Services  
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12.10 APPENDIX 10 COUNTRY-SPECIFIC REQUIREMENTS  
Amendment for Germany  
Synopsis: Inclusion Criteria (see Section 1.1) and Section 5.1 Inclusion Criteria 
(see Section 5.1) 
I05. Female patients who are of childbearing potential must agree for the duration of the study 
to use a highly effective means of contraception (eg, combined estrogen-progesterone 
containing hormonal contraception methods that inhibit ovulation, (oral, intravaginal, 
transdermal), progesterone-only hormonal contraception methods that inhibit ovulation 
(oral, injectable, implantable), intrauterine device, intrauterine hormone-releasing system, 
bilateral tubal ligation, vasectomized partner or sexual abstinence (only if it is the preferred 
and usual lifestyle of the patient). A woman is considered of childbearing potential 
(WOCBP), ie fertile, following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral 
salpingectomy and bilateral oophorectomy. A post-menopausal state is defined as no 
menses for 12 months without an alternative medical cause. A high follicle stimulating 
hormone (FSH) level in the postmenopausal range may be used to confirm a post-
menopausal state in women not using hormonal contraception or hormonal replacement 
therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement 
is insufficient. 
I06. Has been informed and has given written informed consent and agreeable to the schedule 
of assessments. 
I07. Male patients should use condoms during study treatment and until 90-days after the last 
dose of Rilzabrutinib/placebo, and should not donate sperm during this same time period. 
For a non-pregnant female partner of childbearing potential, contraception 
recommendations for the female partner should also be considered. 
Synopsis: Exclusion Criteria (see Section 1.1) and Section 5.2 Exclusion Criteria 
(see Section 5.2) 
E21. Patients who have a known contraindication to Sponsor-provided corticosteroid or with a 
known sensitivity to Rilzabrutinib or its excipients 
E22. Patients who are institutionalized by order of authorities or courts.  
E23. Patients who may be unduly influenced by association with or connected to the Sponsor, 
Investigator, or Site. 
E24. Patients who have a positive test result for severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) infection per local testing standards. 
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Table 2 Schedule of Assessments - Blinded Treatment Period (see Table 2), Table 3 Schedule 
of Assessments - Open Label Extension Period (see Table 3), and Table 4 Schedule of 
Assessments - Long Term Extension Period (see Table 4) 
At each visit: 
Subjects must be tested for SARS-CoV-2 infection within one week prior to each visit or up to 
2 days after each visit. Every effort should be made to comply with local or institutional testing 
procedures. If the time required for obtaining results exceeds this testing window, an extension 
may be granted by the Medical Monitor. The requirement for the test may be waived by the 
Medical Monitor (with approval from the Ethics Committee) if the local regulations change with 
control of the pandemic. 
Section 7.1.1 Permanent discontinuation (see Section 7.1.1) 
The trial will be terminated if major safety concerns related to PRN1008 (Rilzabrutinib) or 
placebo emerge. Trial safety stopping criteria in Germany are: 
5. If the insurance cover cannot be adjusted to the maximum sum necessary in the event that 
the risk profile worsens. 
6. If the approval or the positive assessment has been revoked by the State Office for Health 
and Social Affairs; Ethics Commission of the State of Berlin.   
 
Section 7.2.1 Patient Discontinuation and Stopping Rules (see Section 7.2.1) 
Mandatory termination criteria for a patient in this study in Germany include: 
• Positive SARS-CoV-2 test at any time during the study 
Section 8.3 Visit Overview (see Section 8.3) 
Subjects must be tested for SARS-CoV-2 infection within one week prior to each visit or up to 
2 days after each visit or per local or institutional testing procedures. 
Section 8.4.15 SARS-CoV-2 Testing Requirement (see Section 8.4.15) 
Testing for infection with SARS-CoV-2 will be required and collected during screening and for 
all regular study visits. The testing for SARS-CoV-2 infection must be performed within 
one-week (7 days) prior to each visit or up to two (2) days after. SARS-CoV-2 tests can be 
performed following local or institutional guidelines in order to fulfil protocol requirements. 
Documentation of test results must be provided to the Investigator. If the time required for 
obtaining results exceeds this testing window, an extension may be granted by the Medical 
Monitor. The requirement for the test may be waived by the Medical Monitor (with approval from 
the Ethics Committee) if the local regulations change with control of the pandemic. 
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Appendix 9 UPDATED GUIDELINES TO SITES FOR DELAYED PATIENT VISITS OR 
MISSED VISITS DUE TO TRAVEL RESTRICTIONS AND ANY FORESEEABLE IMPACTS 
OF COVID-19 (see Section 12.9, Appendix 9). 
Urgent Safety Measures Initiated Due to COVID-19 Pandemic 
Each participating site, ethics committees, and the Federal Institute for Drugs and Medical 
Devices (BfArM) were informed (22 April 2020) of urgent safety measures implemented to 
ensure continued supply of study medication and safety monitoring for patients. These measures 
are described in the “Updated Guidelines to Sites for Delayed Patient Visits or Missed Visits due 
to travel restrictions and any foreseeable impacts of COVID-19” (Appendix 9). When the 
COVID-19 pandemic resolves, the measures will be repealed back to the previous state as 
government rules and benefit/risk assessment allow. 
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12.11 APPENDIX 11 VACCINE RESPONSE  
Investigators are to ask about vaccination plans of all participants treated with 
rilzabrutinib/placebo (Blinded Treatment Period) or rilzabrutinib for at least 6 weeks and expected 
to continue in the study for at least 12 weeks in either the Open-Label Period or Long-Term 
Extension period. Investigators will present an option to volunteer to provide 2 blood samples for 
vaccine-specific IgG before and after each vaccine dose regimen. Informed consent should be 
documented from interested participants prior to collecting any blood intended for vaccine 
response analysis. All pre- and post-vaccine dose regimen samples will be analyzed at a central 
laboratory. 
Before each eligible vaccination: Investigators will document any history of injection site pain, 
swelling, redness, joint pain, excessive itching, hives or other adverse effects of prior 
vaccination(s) and document dates, location, and type of vaccination in the source document and 
in the medical history CRF. 
The date and time of pre-vaccination blood draw will be recorded in the CRF. Instructions for 
labeling, collection, storage, and shipping of the sample will be provided in a separate technical 
procedure manual (ie, PPD Central Lab manual). 
Prior to scheduled vaccination, participants will be given an information card labeled with the 
participant subject ID to collect the following information from the person administering the 
vaccine dose regimen: 
• Date and time of vaccination 
• Place of vaccination and contact information to allow investigator follow-up 
• Virus and antigenic strain(s) covered by vaccine product 
• Brand name of vaccine product (or other vaccine-specific identifier for 
investigation/generic/un-branded products) 
• Manufacturer of vaccine product. 
After each eligible vaccination: Investigators will collect the vaccination information card from 
the participant at the next scheduled study visit and complete the corresponding page of the CRF.  
AEs associated with the vaccination should be documented and recorded in the CRF. 
The post-vaccination blood sample is to be collected within approximately 3 to 6 weeks after the 
vaccination regimen is complete and date and time of sample collection recorded in the CRF. 
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12.12 APPENDIX 12 
ABBREVIATIONS  
 
ABQOL 
autoimmune bullous disease quality of life 
AE 
adverse event 
AIBD 
autoimmune bullous disease 
AIDS 
acquired immune deficiency syndrome 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
anti-dsg  
anti-desmoglein 
AST 
aspartate aminotransferase 
bid/BID 
twice daily 
BMI 
body mass index 
BSA 
body surface area 
BTK 
Bruton tyrosine kinase 
CA 
competent authority 
CDA 
control of disease activity 
CLL 
chronic lymphocytic leukemia 
CMH 
Cochran-Mantel-Haenszel 
CFR 
Code of Federal Regulations 
COVID-19 
Coronavirus disease 2019 
CR 
complete remission 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
CS 
corticosteroids 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DIF 
direct immunofluorescence 
DSMB 
Data Safety Monitoring Board 
DSUR 
Development Safety Update Report 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
ECP 
end of consolidation phase 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
ELISA 
enzyme-linked immunosorbent assay 
EOT 
End of Trial 
EQ-5D-5L 
EuroQOL-5 Dimension 5 Level 
ET 
Early Termination 
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EU 
European Union 
FDA 
United States Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GPA 
granulomatosis with polyangiitis 
GTI 
Glucocorticoid Toxicity Index 
H2 
histamine 2 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
H&E 
hematoxylin and eosin 
Hgb 
hemoglobin 
HgbA1c 
hemoglobin A1c 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
IB 
Investigator Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
IGRA 
interferon-gamma release assay 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IVIG 
intravenous immunoglobulin 
ITK 
interleukin-2-inducible T-cell kinase 
ITP 
immune thrombocytopenic purpura 
IWRS 
Interactive Web Response System 
LTE 
Long Term Extension 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified Intent-to-Treat 
MMRM 
mixed models for repeated measures 
MPA 
microscopic polyangiitis 
NCI 
National Cancer Institute 
OLE 
Open-Label Extension 
PD 
pharmacodynamics 
PDAI 
Pemphigus Disease Area Index 
PF 
pemphigus foliaceus 
PK 
pharmacokinetic(s) 
PML 
progressive multifocal leukoencephalopathy 
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PV 
pemphigus vulgaris 
PVG 
pharmacovigilance 
QOL 
quality of Life 
QTc 
QT corrected for heart rate 
REML 
restricted maximum likelihood 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOC 
system organ class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TABQOL 
Treatment of Autoimmune Bullous Disease Quality of Life 
TBNK 
T and B and Natural Killer Lymphocyte Panel 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States 
VAS 
visual analogue scale 
WHO 
World Health Organization  
 
 
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12.13 APPENDIX 13 
PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
12.13.1 
Clinical Study Protocol Version 2 (12 September 2018)  
This was a local amendment to protocol Version 1 (US) and was regarded as a substantial 
amendment. 
Overall Rationale for the Amendment  
The primary reasons for this amendment to Protocol PRN1008-012, Version 2 are: 
• 
To increase the number of sites to 100, 
• 
To add new efficacy objective in order to establish the duration of the response, 
• 
To modify minimum screening CS doses based on the PDAI criteria and to match the 
disease severity (severe and moderate),  
• 
To clarify CS tapering in accordance with guidelines, 
• 
To add a new inclusion criterion #3 with a minimum PDAI requirement 
• 
To add text related to the rituximab rescue during OLE period that would lead to 
discontinuation. 
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Protocol Amendment summary of changes Table 
PRN1008-012 Protocol V2.0 (12 September 2018) 
Deleted text has strikethrough and new text is bolded. 
Section 
Amended or New Wording 
Justification of Change 
Cover Page 
Principia Biopharma Inc. 
Sponsor address change 
2.8 
Number of Study Sites 
Approximately 80100 sites worldwide. 
Increased number of sites for the 
study   
3.2.1 
Efficacy Objectives 
•To evaluate the efficacy of PRN1008 in achieving durable CR on low to zero doses of 
oral corticosteroid (CS) and on the time course of quantitative disease activity scores 
•To assess the ability of PRN1008 to reduce CS exposure and the adverse effects of CS 
•To evaluate the time to specified clinical endpoints  
•To assess the longer term durability of CR 
Objective added to establish the 
duration of the response. 
3.3.1 
Study Design - Blinded 
Treatment Period 
(Weeks 1 to 37) 
Table 1:  Definitions of Moderate to Severe Population and starting CS doses* 
 
PDAI entry 
criteria 
Required prednisone 
dose starting at 
Screening** 
Newly diagnosed (diagnosed 
≤ 6 months prior to 
Screening) 
PDAI ≥ 15 
≥ 0.5 mg/kg/day 
Relapsing, chronic (> 6 
months since diagnosis) 
PDAI ≥ 9 
≥ 0.2 mg/kg/day 
* (Shimizu 2014, Boulard 2016) 
** Doses shown above are minimum requirements. Actual doses will be determined by Investigator 
judgment 
 
Modified minimum starting CS 
doses to align with the PDAI 
criteria and to match the disease 
severity (severe and moderate).  
Minimum PDAI score and CS 
doses were also defined for newly 
diagnosed patients and relapsing 
disease patients to align with 
available disease guidelines per 
publications.   
 
Added text related to the rituximab 
rescue.  
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Section 
Amended or New Wording 
Justification of Change 
After informed consent is obtained, patients with moderate to severe pemphigus (PV and 
PF) (ie, a PDAI score ≥ 15) at Screening will be randomized in a 1:1 allocation ratio to 
receive either PRN1008 400 mg twice daily (bid) (n ~ 60) or placebo bid (n ~ 60) during 
the Blinded Treatment Period (Week 1 to Week 37).  
At Screening, patients will begin to take Sponsor-provided prednisone according to 
the minimum dose requirements, Table 1 At Screening, patients with moderate disease 
(ie, a PDAI score 15 to 45) will be initiated on a dose of 0.25 mg/kg prednisone daily; 
patients with severe disease (ie, PDAI score > 45) will be initiated on a dose of 0.5 mg/kg 
prednisone daily. If a patient responds to CS and their PDAI score falls below 15 at Day 1, 
they are still eligible to continue in the study. If a patient’s disease worsens during 
Screening, at the Day 1 visit or earlier the CS dose should be up titrated to 0.5 to 1.5 
mg/kg/day above, and as required to adequately treat the disease. Prednisone doses 
may be adjusted per Investigator discretion during the Screening period in the 
mandated range (CS and Rituximab Management, Appendix 1). 
……. 
If rituximab is administered, patients should remain on trial and blinded to treatment 
assignment, but will be considered treatment failures for all efficacy endpoints except for 
cumulative CS and composite Glucocorticoid Toxicity Index (GTI) score. After 
completing the Blinded Treatment Period, patients will enter the Open-Label Extension 
Period to receive active treatment with PRN1008 described below. If a A patient requires 
in the Blinded Treatment Period requiring an additional “top up” dosesdose of 
rituximab 6 or 12 months after thetheir initial rituximab dose, the patient should be 
discontinued from the trial. 
3.3.1 
Study Design - Follow-
up Period (Weeks 61 to 
65): 
End of Trial for each patient is defined as the point at which the patient has completed their 
Week 65 visit (4 weeks after the patient’s last dose of PRN1008). Patients who are not able 
to complete the planned Week 65 visit and discontinue the study early should be 
encouraged to come back for their last visit, and this will be recorded as the End of Trial 
(EOT) visit, which will also be denoted as an early termination (ET). Patients that 
discontinue early will have the ET assessments completed as outlined in the Schedule of 
Assessments based upon from which phase treatment phase they are terminating, Table 2 
(Blinded Treatment Period) and Table 3 (Open-Label Extension Period). 
Updated for clarity 
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Section 
Amended or New Wording 
Justification of Change 
3.4.1  
Corticosteroid Starting 
Doses at and 
Management during 
Screening and Baseline 
(at Day 1) 
3.4.1. Corticosteroid Starting Doses at and Management during Screening and Baseline 
(at Day 1) 
Required, initial doses of CS atfor the commencement duration of Screening are ≥ 0.252 
mg/kg/day of prednisone for patients with a moderate PDAI total activity score of 15 to 
45,relapsing disease (> 6 months since diagnosis) and ≥ 0.5 mg/kg/day for patients with 
a PDAI total activity score of > 45. 
During the newly diagnosed disease (diagnosis ≤ 6 months prior to Screening Period up
titration ). At Screening, patients will begin to guideline recommended (Consensus 
Guideline, ), CS doses (0.5take Sponsor-provided prednisone according to 1.5 
mg/kg/day), is recommended if initial starting doses are insufficient to prevent worsening 
disease. The choice of exact CS dosage if up titration is the minimum dose 
requirements, and as required is up to adequately treat the Investigator. 
At the baseline (Day 1) visit, if disease worsened during screening despite initial (as the 
Screening period. Prednisone doses may be adjusted upward per Investigator 
discretion during the Screening period but the dose should not be reduced below the 
initial dose levels (Table 1) CS treatment, then CS doses must be raised to guideline
recommended CS doses (0.5 to 1.5 mg/kg/day).). 
 
If disease significantly (Investigator judgment) worsens during the Screening period, 
up-titration of CS dose by 50-100% should occur, as often as every 5-7 days if needed 
(Harman 2017). 
Modified minimum starting CS 
doses to align with the PDAI 
criteria and to match the disease 
severity (severe and moderate).  
Minimum PDAI score and CS 
doses were also defined for newly 
diagnosed patients and relapsing 
disease patients to align with 
available disease guidelines per 
publications.   
 
3.4.2. 
Corticosteroid 
Management during 
Treatment Period and 
Open-Label Extension 
Period 
3.4.2. Corticosteroid Management during Treatment Period and Open-Label 
Extension Period 
 
Corticosteroid-Tapering (Consensus Guideline, Murrell 2018) 
CS will be tapered from CDA-ECP towards a goal of 5 mg/day by ≤ Week 29. Once 
the 5 mg level is achieved it will be kept at 5 mg/day until the time of the primary 
endpoint at Week 37 is reached. After that, taper towards 0 mg should commence as 
clinically indicated. 
Clarified CS administration to 
align with guidelines. 
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Section 
Amended or New Wording 
Justification of Change 
CS tapering should follow the dosing guidelines below (Murrell 2018). Adjustment of 
the tapering guideline protocol by investigators is permitted, based on assessment of 
clinical need. 
• 
Start tapering CS as soon as CDA is reached or up to the ECP  
• 
Decrease CS by 25% every two weeks, until 20 mg per day 
• 
Once at 20 mg per day, decrease CS by 2.5 mg per week 
• 
Once at 10 mg/day, decrease CS by 1 mg per week 
Note, because 1 mg will be the smallest prednisone dosage provided and tablet 
splitting is not allowed, the Investigator must round up to the nearest whole 
milligram for CS dose after calculation of the new dose level. 
 
Corticosteroid-Up-Titration (Consensus Guideline, Murrell 2018) (Harman 2017) 
CS up-titration is allowed if disease significantly worsens prior to initial CDA-ECP or 
after CDA-ECP, during prednisone taper. 
Up-titration should be a temporary increase until CDA-ECP is achieved (again), after 
which tapering can recommence. 
For full details of up-titration see Appendix 1. 
3.5 
Concomitant 
Medications 
…… 
Warfarin should be monitored carefully as there is limited experience of co-administration 
with PRN1008. Factor X inhibitors may be used. To date, two patients on chronic 
anticoagulation (rivaroxaban) have been treated without bleeding complications. 
Updated with recent clinical 
information. 
3.6  
Inclusion Criteria 
1. 
Male or female patients, aged 18 to 80 years old with moderate to severe, newly 
diagnosed or relapsing PV or PF (PDAI ≥ 15 at Screening), with a clinical presentation and 
histopathology consistent with PV or PF. Diagnosis requires confirmation with either a 
positive direct immunofluorescence (DIF) or serological detection of anti dsg 
autoantibodies (anti dsg1 or 3 or both). 
2. 
Positive circulating anti-dsg1 or 3 autoantibody titer 
23. 
PDAI score of at least 9 points for relapsing patients (> 6 months since 
diagnosis) or at least 15 points for newly diagnosed patients (diagnosed ≤ 6 months 
prior to Screening) 
Updated for clarity and removed 
redundancy to Inclusion Criterion 
#2. 
 
Updated to clarify the diagnoses 
for newly diagnosed and relapsing 
disease.   
 
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Section 
Amended or New Wording 
Justification of Change 
……. 
56. 
Female patients who are of reproductive potential must agree for the duration of 
active treatment in the study to use an effective means of contraception (eg, hormonal 
contraception methods that inhibit ovulation, intrauterine device, intrauterine hormone-
releasing system, bilateral tubal ligation, vasectomized partner or condoms). Unless 
surgically sterile, postmenopausal females should have menopause confirmed by follicle-
stimulating hormone (FSH) testing. 
3.7 
Exclusion Criteria 
1. 
Suspected paraneoplastic pemphigus and other forms of pemphigus that are 
not pemphigus vulgaris or pemphigus foliaceus 
…….. 
17. 
A potential patient with a positive Positive interferon-gamma release assay 
(IGRA) (eg, QuantiFERON®-TB Gold or T-spot TB® Test) at Screening. Unless, all of 
the following 3 conditions are true: 
a.   is eligible if her/his chest Chest X-ray does not show evidence suggestive of 
active tuberculosis (TB) disease 
b.  and thereThere are no clinical signs and symptoms of pulmonary and/or extra-
pulmonary TB disease. The patients with latent TB infection, must have already 
received  
c.  Documented receipt of a course of prophylactic TB treatment of at least 6 
months. 
Updated for execution clarity  
3.8.3 
Other Secondary 
Endpoints 
…….. 
•  Change in Treatment of Autoimmune Bullous Disease Quality of Life (TABQOL) score 
from baseline to Weeks 5, 13, 25, 37, and 61 
•  Proportion of patients in CR for ≥ 8 weeks on zero CS at Week 61 by original 
PRN1008/placebo group assignment and overall 
•  Proportion of patients in CR at Week 37 to maintain CR continuously to Week 61 
………. 
Updated for execution clarity 
3.12 
Randomization 
Patients will be randomized at Day 1, in a 1:1 allocation, using a stratification by PV/PF 
disease type, in a 1:1 allocation ratio to receive PRN1008 400 mg or placebo bid, and by 
relapsing/newly diagnosed disease history (newly diagnosed defined as within≤ 6 months 
ofprior to Screening). or by relapsing disease (> 6 months since diagnosis.) 
Updated to clarify the diagnoses 
for newly diagnosed and relapsing 
disease.  
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Section 
Amended or New Wording 
Justification of Change 
3.13 
Other Statistical 
Considerations 
….. 
There will be no interim analysis to assess efficacy. An interim analysis to possibly add 24 
more patients to the trial will be conducted by the DSMB when approximately 50% of 
patients have reached the Week 29 visit, based on an observed control group rate of CR of 
any duration at Week 29 that exceeds 20%. The additional 24 will include a minimum of 
20 patients with PV. 
…… 
Updated for clarity and to specify 
that the DSMB will be performing 
the IA. 
5.1 
Overview of Pemphigus 
…… 
Presently, there are few effective treatment options for pemphigus. Current treatments 
include corticosteroids (CS) to reduce inflammation and antibiotics to treat associated 
infections. Agents such as mycofenolate motetilmofetil are often used and rituximab has 
been reported to be effective; however, neither therapy is. Mycofenolate mofetil has not 
been approved for this indication in any country,. Rituximab to treat pemphigus 
vulgaris has only been approved to date in the US and for both of these agents, 
beneficial effects take weeks to months. ……. 
Updated for clarity 
5.4 
Clinical Experience 
In clinical studies to date, PRN1008 has been administered orally to approximately 114to 
140 healthy volunteers in six Phase 1 studies and 21 (as of January 18, 2018), 27 patients 
with pemphigus (mainly pemphigus vulgaris variant, ie, PV) and 4 patients with 
immune thrombocytopenic purpura (ITP). 
 
Patients with PV in an ongoing, open labela Phase 2 study with (NCT02704429) used a 
starting dose of 400 mg twice daily (bid). High clinical response rates have been observed. 
On a backgroundBID which was shown to produce adequate BTK occupancies in all 
but one patient. One patient dose-escalated to 500 mg BID and one to 600mg BID, 
with all other patients using the 400mg BID dose. An interim analysis of the first 27 
patients in this study found evidence of clinically significant activity in 80% of 
patients, with onset of disease control in the first 2 weeks of therapy, and an 
acceptable safety profile (DSUR 2018 and IB Section 5). The primary endpoint of the 
study, “control of disease activity by the Week 5 visit on ≤ 0.5mg/kg/day of 
prednisone equivalent corticosteroid (CS) doses of 0 to 30 mg per day, “Control of Disease 
Activity” (CDA) has been seen in the majority of patients within 4 weeks (11/18, 61%), 
with responses in patients with both PV and PF clinical/laboratory characteristics. ” was 
Updated the number of patients 
dosed across studies conducted 
with PRN1008. 
 
Updated with new available 
clinical data from Phase 2 PV 
study (23 April 2018 data cut).   
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met by 54% (14/26) of patients. Complete remission on ≤ 0.5mg/kg/day of prednisone 
was achieved by 25% (5/20) of patients completing 12 weeks treatment 
Treatment related emergent adverse events in the pemphigus study include one severe 
(Grade 3)related to PRN1008 in ≥ 10% of patients were nausea (15%), abdominal 
pain (11%) and headache (11%). One serious adverse event (SAE) of Grade 3 
“cellulitis (localized leg cellulitis associated with high fever and negative microbial 
cultures), and mild (Grade 1) headache (10%), moderate (Grade 2) upper respiratory tract 
infection (10%), and mild and moderate dry mouth (10%). No patients have discontinued 
therapy due to treatment ” considered related adverse events. No allergic reactions to 
PRN1008 have been reportedto PRN1008 therapy occurred, resulting in a three day 
interruption of PRN1008 therapy. This patient continued therapy for two further 
months without recurrence of the event. 
 
Overall, results from Phase 1 and Phase 2 studies demonstrate that PRN1008 has an 
acceptable safety profile and is well tolerated in healthy subjects and patients with 
pemphigus. Please refer to the Investigator Brochure, Edition 9.0 for more details. 
5.8 
Rituximab and Possible 
Combination with 
PRN1008 
….. 
Although it is not approved for the treatment of pemphigus only in the US at this time, it is 
recommended as a possible first-line therapy in combination with CS in newly updated 
consensus guidelines (Murrell 2018). ..... 
……. 
RITUXAN, MabThera or other approved, biosimilar agents may be used in this clinical 
trial per protocol. Instructions for administration of the intravenous infusion forwill be 
provided in the locally approved rituximab to be used should be followed if 
administeredPharmacy Manual. 
Updated with information on 
recent rituximab US approval for 
PV 
5.9.2 
Particular Permissible 
Medications 
….. 
• Anticoagulants: Anticoagulation with warfarin should be monitored actively in the first 
weeks of PRN1008 or placebo treatment (both the Blinded Treatment Period and the 
Open-Label Extension Period), as the combination has not been extensively studied. 
Factor X inhibitors may be usedTo date, two patients on chronic anticoagulation 
(rivaroxaban) have been treated without bleeding complications. 
Updated with new clinical 
information 
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5.9.3 
Corticosteroids and 
Rituximab 
InitialRequired, initial doses of CS atfor the commencementduration of Screening are 
≥ 0.252 mg/kg/day of prednisone for patients with a moderate Pemphigus Disease Area 
Index (PDAI) total activity score of 15 to 45,relapsing disease (> 6 months since 
diagnosis) and ≥ 0.5 mg/kg/day for patients with a PDAI total activity score of > 45.newly 
diagnosed disease (diagnosis ≤ 6 months prior to Screening).  
Thereafter, CS are managed per the Corticosteroid and Rituximab Management protocol 
(Appendix 1). 
Rituximab should be managed per the Corticosteroid and Rituximab Management protocol 
(Appendix 1), utilizing instructions in the locally approved Product InformationPharmacy 
Manual for administration of the to-be-used rituximab product. 
Modified minimum starting CS 
doses to align with the PDAI 
criteria and to match the disease 
severity (severe and moderate).  
Minimum PDAI score and CS 
doses were also defined for newly 
diagnosed patients and relapsing 
disease patients to align with 
available disease guidelines per 
publications.   
6.1.2 
Preparation and 
Administration 
….. 
Treatment medication will be taken twice daily by mouth starting on Day 1. PRN1008 or 
placebo may be taken with or without food. Tablets should not be broken or crushed. 
Further details for dispensation and administration of blinded treatment are provided in the 
Pharmacy Manual. 
Provided additional instruction on 
handling drug tablets. 
6.2.1 
Preparation and 
Administration 
No preparation of prednisone will be needed. Patients will use the prednisone medication 
directly from the dosing container dispensed in accordance with this protocol and the 
Pharmacy Manual. 
Updated for clarity 
6.3 
Rituximab 
Rituximab (or biosimilar) will be provided for patients having a second qualifying 
relapse (Appendix 1Rituximab will be sourced locally using locally approved product and 
reimbursed, if required, by the Sponsor.) during the Blinded Treatment Period. 
However, in the event a patient in the Blinded Treatment Period requires an 
additional “top up” dose of rituximab after their initial rituximab dose, this will not 
be provided because the patient must be discontinued. Similarly, if a patient in the 
Open-Label Extension Period requires rituximab, the patient must be discontinued 
and rituximab will not be provided. 
Added text related to the rituximab 
rescue. 
6.3.2 
Storage 
Rituximab (or biosimilar) should be stored according to the instructions forin the locally 
approved rituximab product label. 
Updated for clarity 
6.4.1  
Drug Accountability 
…. 
All used and unused drug supplies must be returned by the subject at every visit.  
Clarified the process for drug 
accountability 
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All records and used and unused drug supplies must be available for inspection by the 
trial monitor at every monitoring visit. WhenReconciliation of all drug supplies 
(PRN1008 or placebo, PRN1008 open-label, prednisone, and rituximab) will be 
performed by the trial monitor. When the trial is completed, the 
investigatorInvestigator will return any used and unused trial medication (eg,eg, empty, 
partially used, and unused containers), occluded labels (or the equivalent) to the Sponsor as 
requested. TheCopies of the completed Drug Dispensing Log and Drug Return Record(s) 
will be returned to the Sponsor. The Investigator's copy of the Drug Return Record(s) must 
accurately document the return of all drug supplies to the Sponsor. 
6.4.2 
Destruction of 
Investigational Product 
….. 
Unused trial medication from the site that has not been stored properly should not be 
destroyed until the final report has been approvedmonitor and/or Sponsor approve the 
destruction. 
…… 
Clarified the instruction for IP 
destruction  
6.6  
Treatment Blinding 
….. 
The pharmacist or designee will be required to enter or select information that will include, 
but not be limited to; the user ID, and password, subject number, patient dateyear of 
birth, as well as other information (as allowed locally). The pharmacist or designee will 
then be provided with a patient randomization number and treatment assignment. Once 
patient numbers and randomization numbers have been assigned, they cannot be 
reassigned. The randomization system will also send confirmation of the randomization, by 
email or fax, to the user. Specific instructions will be provided in the IWRS trial reference 
guide. Access to the randomization code will be limited; all Sponsor personnel (and 
representatives), and site personnel other than the nominated unblinded representative(s), 
who are directly involved in the conduct of the trial will be blinded to randomization 
codes.  
 
The pharmacist or designee will ensure that tablets dispensed for drug administration are 
prepared such that they are identical in appearance to trial patients and site personnel. The 
treatment each patient receives will not be disclosed to the investigatorInvestigator, trial 
center personnel, patients, or the Sponsor or representatives on the clinical study team. 
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Further details for blinding and dispensing of blinded treatment are provided in the 
Pharmacy Manual.  
7.4.1 
Patient Discontinuation 
and Stopping Rules 
Reasons for discontinuing a patient may include, but are not necessarily limited to, the 
following: 
•  Severe and life-threatening pemphigus disease activity•  Grade 4 PRN1008 -related 
TEAE 
•  Serious allergic reaction to PRN1008 or placebo including anaphylactic reaction 
•  A patient in the Blinded Treatment Period requiring an additional “top up” dose 
of rituximab after their initial rituximab dose or a patient in the Open-Label 
Extension Period requiring rituximab 
•  Human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), 
viral hepatitis (B and C) infection occurring during the study. 
……. 
Added a stopping rule for 
rituximab rescue patients to align 
with Sections 3.3.1. and 6.3. 
7.6.1 
Screening (Day -29 to 
Day -1)  
……. 
Patients not already on the mandated CS doses for the commencement of the Screening 
Period will continue or commence the protocol-recommendedmandated CS doses. 
Updated for clarity 
7.7.1 
Body Height and Weight 
Body weight should be measured on the same clinic scale each time after checking for 
accurate zero calibration. Weight is recorded in kg to one decimal place. 
Updated for execution clarity 
7.7.2 
Physical Examination 
…. 
An abbreviated physical examination is inclusive of general appearance, cardiac, 
gastrointestinal, and pulmonary assessments. 
Updated for execution clarity 
7.7.15 
Photography 
7.7.14.7.7.15. Photography 
Photography of lesions may be performed at selected sites, at investigator’s discretion as 
allowed by country and local regulations, and at selected centers with sufficient subjects.  
Clarified photography language 
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8.3.7.2 
Serious Adverse Event 
Reporting 
Initial notification of an SAE  
to XXX Pharmacovigilance (PVG) must be confirmedinformed in writing 24 hours from 
the time the site investigational team first become aware of the event using the XXXEDC 
system, if possible. Paper SAE report forms should only to be used when the XXXEDC 
system is not accessible, and SAEs should be transferred into XXXEDC once the system is 
available. 
If XXXEDC is not accessible, a paper SAE form including a written, narrative 
description of any SAE must be sent to XXX PVG by faxemailed to 
 within 24 hours after awareness of the event. 
If paper SAE forms are used, copies of the initial and follow-up SAE report forms must be 
made and the paper originals retained of all information faxed to XXXthat has been 
emailed must be retained in the Investigator Site File. 
 
Fax Number: 
Worldwide: TBD 
If unable to fax, any SAE must be reported immediately or no later than 24 hours after 
awareness of the event to the XXX PVG by telephone via the Safety Hotline Number. 
Safety Hotline Number: 
Worldwide: TBD 
 
In addition to reporting the SAE in the EDC or via email, the local CRA and the 
Global Medical Monitor must be alerted via phone (refer to Site Manual). 
As further information regarding the SAE becomes available, such follow-up information 
should be documented as an update in the XXXEDC system, or if XXXEDC is not 
accessible, on a new SAE report form, marked as a follow-up report and faxedemailed to 
XXX 
. 
AfterStarting after informed consent, but prior to initiation of study medications, only 
SAEs caused by a protocol mandated intervention must be reported within 24 hours (eg,eg, 
SAEs related to invasive screeningScreening procedures such as biopsies, medication 
washout, or noSAEs related to corticosteroid treatment run in). After first study 
medication, all SAEs must be reported within 24 hours.during Screening). 
Updated contact information and 
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8.4 
Pregnancy 
….. Pregnancies occurring up to 90 days4 weeks after the completionlast dose of 
PRN1008 or placebo must also be reported to the Investigator. The participant should be 
counseled by a specialist, to discuss the risks of continuing with the pregnancy and the 
possible effects on the fetus. ….. 
Updated language based on 
reproductive preclinical data  
9.4.4 
Safety and Tolerability 
Analysis (Safety 
Population) 
The nature, frequency, and severity of adverse events, including serious adverse events, 
adverse events leading to discontinuation and possible corticosteroid-related adverse 
effects will be summarized descriptively by treatment group. AEs prespecified as possibly 
related to prednisone will be grouped and analyzed separately in addition to the above. 
Vital signs and clinical laboratory test results (including complete blood count and blood 
chemistry) will be summarized using actual and change from baseline values. 
…….. 
Updated for clarity 
9.4.5 
Efficacy Analysis (ITT 
Population) 
Primary: 
The proportion of patients who are in CR from Week ≤ 29 (visit) to Week 37 (visit) with a 
daily prednisone dose of ≤ 5 mg/day. 
•  A Cochran-Mantel-Haenszel (CMH) general association test stratified by disease type 
(PV or PF),) and disease history (newly diagnosed or relapsing) will be used to compare 
PRN1008 with placebo. Newly diagnosed pemphigus is defined as newlypatients 
diagnosed within ≤ 6 months ofprior to Screening. SevereRelapsing, chronic 
pemphigus is defined as a PDAI score of > 45 at Screening. patients with > 6 months 
since diagnosis. 
 
Patients who drop out of the trial, withdraw, or who undergo rituximab therapy for a 
qualifying relapse will count as non-responders in the primary efficacy analysis. 
Additional sensitivity analyses, including adjusting for severity, will be described in the 
SAP. 
 
The US primary efficacy analysis will include PV subjects only. This analysis will be 
performed using a CMH general association test stratified by disease history (newly 
diagnosed or relapsing) to compare PRN1008 with placebo.  
 
Key Secondary: 
The cumulative oral corticosteroid dose over first 36 weeks will be summarized 
Updated for clarity 
 
Added the statistical modification 
to meet the FDA recommendation. 
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descriptively and will be compared across treatment groups using pairwise comparisons 
from an analysis of variance (ANOVA) model. The ANOVA model will include effects 
for treatment, disease type, disease severity, and disease history. 
 
Time to initial CR will be analyzed using competing risks methodology. The median event 
time (and other quartiles) and 2-sided 95% confidence intervals will be presented. 
Marginal survival curves will also be displayed graphically. Further details will be 
provided in the SAP. 
The difference in the proportion of patients with CR from week ≤ 29 to week 37 (≥ 8 
weeks) with a daily CS dose of ≤ 10 mg/day will be tested in the same manner as the 
primary endpoint. 
Additional sensitivity analyses, including adjusting for severity, will be described in 
the SAP. 
9.4.6 
Key Secondary Efficacy 
Sequential Testing 
Key secondary efficacy endpoints will be tested sequentially, and use the ITT population. 
Patients who drop out or withdraw early will only be included if there is sufficient data. A 
0.05 alpha level will be used for the sequential testing. Testing will stop once a p-value is 
> 0.05 for one of the secondary endpoints. The order of the secondary efficacy endpoints is 
as follows: …… 
Updated for clarity 
10.1 
Data Quality Assurance 
….. 
Accurate and reliable data collection will be assured by verification and cross-check of the 
eCRF against the investigator’sInvestigator’s records by the trial monitor (source 
document verification), and the maintenance of Drug Accountability (see Section 6.4.1a 
PRN1008/placebo dispensing log) by the investigatorInvestigator. 
….. 
Updated for clarity 
10.2  
Protocol Amendments 
and Trial Completion 
Protocol amendments must be made only with the prior approval of the Sponsor or its 
designees. Agreement from the investigator must be obtained for all protocol amendments 
and amendments to the informed consent document. The IRB/IEC must be informed of all 
amendments and give approval for all amendments. For studies conducted outside of the 
US, approval of substantial amendments must be obtained from the relevant Competent 
Regulatory Authority before implementation. The investigatorInvestigator must send a 
copy of the approval letter from the IRB/IEC to the Sponsor and/or the Sponsor’s designee. 
…… 
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Appendix 1 
Corticosteroid and 
Rituxmab Management 
Initial Corticosteroid Starting Doses:  and Management during Screening and at Day 
1: 
Required, initial doses of CS atfor the commencementduration of Screening are ≥ 0.252 
mg/kg/day of prednisone for patients with a moderate PDAI total activity score of 15 to 45, 
and relapsing disease (> 6 months since diagnosis) and ≥ 0.5 mg/kg/day for patients 
with a PDAI total activity score of > 45. 
Up titration to guideline recommended (Consensus Guideline, ), starting CS doses (0.5 to 
1.5 mg/kg/day), is recommended if these starting doses are insufficient to prevent 
worsening disease, per CS up titration paragraphs below, and as early as newly diagnosed 
disease (diagnosed ≤ 6 months prior to Screening). At Screening, patients will begin to 
take Sponsor-provided prednisone according to the minimum dose requirements, and 
as required to adequately treat the disease during the Screening period. At the Baseline 
(Day 1) visit, if disease has worsened during Screening despitePrednisone doses may be 
adjusted upward per Investigator discretion during the Screening period but should 
not be reduced below the initial (as adjusted) CS treatment, then CS doses must be raised 
to 0.5 mg/kg/day for moderate patients and 1.0 to 1.5 mg/kg/day for severe patientsdose 
levels. 
 
If disease significantly (Investigator judgment) worsens during the Screening period, 
up-titration of CS dose by 50-100% should occur, as often as every 5-7 days if needed 
(Harman 2017).  
 
Corticosteroid Management during Blinded Treatment Period and Open-Label 
Extension Period 
 
Corticosteroid-Tapering (Consensus Guideline, Murrell 2018: ) 
CS will be tapered from CDA-ECP towards a goal of ≤ 5 mg/day by ≤ Week 29. Once the 
5 mg level is achieved it will be kept at 5 mg/day until the time of the primary endpoint at 
Week 37 is reached. After that, taper towards zero0 mg should commence as clinically 
indicated. 
Modified minimum starting CS 
doses to align with the PDAI 
criteria and to match the disease 
severity (severe and moderate).  
Minimum PDAI score and CS 
doses were also defined for newly 
diagnosed patients and relapsing 
disease patients to align with 
available disease guidelines per 
publications.   
 
Updated tapering instructions for 
clarity. 
 
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CS adjustmenttapering should follow the dosing guidelines below (Murrell 2018). 
Adjustment of the dosing guideline protocol by investigators is permitted, based on 
assessment of clinical need. 
Guideline for corticosteroid tapering (Consensus Guideline, ) 
•  Start tapering CS as soon as disease controlCDA is reached or up to the end of 
consolidation phaseECP 
•  Decrease CS by 25% every two weeks, until 20 mg per day 
•  Once at 20 mg per day, decrease CS by 2.5 mg aper week 
•  AtOnce at 10 mg/day, decrease doseCS by 1 mg per week* 
Note, because 1 mg will be the smallest prednisone dosage provided and tablet 
splitting is not allowed, the Investigator must round up to the nearest whole 
milligram for CS dose after calculation of the new dose level. 
 
Table 4: 
Example Taper for a 60 mg Dose of Prednisone 
Current Dose 
Level 
(prednisone 
equivalent) 
Size of Dose 
Reductions 
(prednisone 
equivalent) 
Example (Note: 
dosages rounded up 
to nearest mg) 
Frequency of 
Dose 
Reductions 
60 mg down to 
20 mg 
Approximate 25% 
decrease e.g. to 45mg, 
then to 35mg, then to 
25mg, then 20 mg 
60 mg, 45 mg, 34 mg, 
26 mg, 20 mg 
Every two 
weeks 
20 mg to 10 mg 
2.5 mg decrease  
20 mg, 18 mg, 16 mg, 
14 mg, 12 mg, 10 
mg2.5 mg decrease 
Weekly 
10 mg to zero 
1 mg  
10 mg, 9 mg, 8 mg, 7 
mg, 6 mg, 5 mg until 
Week 37 then further 
titration to 0 mg as 
clinically indicated 
Weekly* 
 
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3.  Non life-theatening worsening of disease during taper of CS after initial CDA-ECP 
 
•Go back to last CS dose level if > 3 lesions reappear during the tapering of oral 
corticosteroid therapy (where relapse, as defined below, has not occurred) 
•If a more severe full relapse occurs (ie,ie, the appearance of ≥3 new lesions/ within a 
month that do not heal spontaneously within 1 week, or there is extension of established 
lesions), increase the oral corticosteroid dose by going back to the second to last dose until 
control of the lesions is achieved within 2 weeks, then resume taper 
……. 
Rituximab for second “qualifying relapse”:……… 
•  Where a second qualifying relapse occurs meeting the above definition, and it is ≥ after 
the Week 5 visit, then one course of rituximab, which consists of two intravenous doses of 
1 gram two weeks apart, may be may be administered, unless contraindicated.  
•  Oral CS doses should be managed as indicated for the patient at the time of the 2nd 
qualifying relapse 
•  Pre medications for rituximabRituximab should be administered as recommended in the 
locally approved Product Label InformationPharmacy Manual. 
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Appendix 7 
Glucorticoid Toxicity 
Index (GTI) 
APPENDIX 7 GLUCORTICOID TOXICITY INDEX (GTI) 
The Glucocorticoid Toxicity Index (GTI) is a proprietary licensed instrument from 
Massachusetts General Hospital (Miloslavsky 2017). It was developed to assess 
New Appendix to provide 
reference to Section 7.7.14 
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glucocorticoid (GC)-related morbidity and GC-sparing ability of other therapies. 
The scale collects information about known steroid toxicities and uses a weighted 
scoring system to assesses toxicity. The instrument calculates a composite index 
score from data captured related to the following domains: body mass index, 
glucose tolerance, blood pressure, lipids, steroid myopathy, skin toxicity, 
neuropsychiatric toxicity, and infection. In addition, reports of any of the following 
toxicities are included in the index: endocrine (adrenal insufficiency), 
gastrointestinal (perforation, peptic ulcer disease), musculoskeletal (ruptured 
tendon, avascular necrosis) and ocular (retinopathy, increase in ocular pressure, 
posterior subcapsular cataract). 
Appendix 8 
Strong to Moderate 
CYP3A Inhibitors and 
Inducers and Sensitive 
CYP3A Substrates 
 
 
Strong 
Moderate 
3A Inducers 
Avasimibe, carbamazepine, 
phenytoin, rifampin, St. John’s 
wort 
Bosentan, efavirenz, etravirine, 
modafinil, nafcillin 
3A 
Inhibitors 
Boceprevir, 
clarithromycin, conivaptan, 
grapefruit juice, indinavir, 
itraconazole, ketoconazole,  
lopinavir/ritonavir, 
mibefradil,  
nefazodone, nelfinavir, 
posaconazole, ritonavir,  
saquinavir,  
telaprevir, 
telithromycin, 
voriconazole 
Amprenavir, aprepitant, 
atazanavir, ciprofloxacin, 
darunavir/ritonavir, diltiazem, 
erythromycin, fluconazole, 
fosamprenavir, Seville orange 
juice, grapefruit juice, 
imatinib, verapamil 
 
Removed duplication of grapefruit 
juice in this table (it is a strong, not 
a moderate inhibitor)  
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12.13.2 
Clinical Study Protocol Version 3 (9 October 2018)  
This was a local amendment to protocol Version 2 and was regarded as a non-substantial 
amendment.  
Overall Rationale for the Amendment  
The primary reasons for this amendment to Protocol PRN1008-012, Version 3 are: 
• 
To clarify corticosteroid drug use that can be either prednisone or prednisolone, 
• 
To allow a permitted use of topical CS and oral CS rinses, 
• 
To add ECG at week 37 for comparison with baseline ECG, 
• 
To clarify that rituximab can be given during BTP in case a second qualifying relapse 
occurs at or after D29, 
• 
To clarify CS tapering language,  
• 
To clarify relapsing and newly diagnosed definitions throughout protocol, 
• 
To clarify PK timepoints in SoA, 
• 
To clarify control group rate of CR ≤5 mg CS, 
• 
To remove GTI and HbA1c/LDL in OLE SoA. 
 
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Protocol Amendment summary of changes Table 
PRN1008-012 Protocol V3.0 (9 October 2018) 
Deleted text has strikethrough and new text is bolded. 
Section 
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Justification of Change 
Throughout the protocol 
PrednisoneCorticosteroid (CS);  
Oral corticosteroids (prednisone or prednisolone) 
Clarified corticosteroid drug 
use can be either prednisone 
or prednisolone  
3.4.1 Corticosteroid Starting 
Doses and Management 
during Screening and at 
Day 1; 
5.9.3 Corticosteroids and 
Rituximab; 
Appendix 1 Corticosteroid 
and Rituximab Management 
Required, initial doses of CS for the duration of Screening are ≥ 0.2 mg/kg/day of 
prednisoneCS for patients with relapsing disease (diagnosed > 6 months since 
diagnosisprior to Screening) and ≥ 0.5 mg/kg/day for patients with newly diagnosed 
disease (diagnosedis ≤ 6 months prior to Screening).  
……. 
Updated to provide clarity 
3.4.2 Corticosteroid 
Management during 
Treatment Period and Open 
Label Extension Period; 
Appendix 1 Corticosteroid 
and Rituximab Management 
Corticosteroid Tapering (Consensus Guideline, Murrell 2018) 
• 
Start tapering CS as soon as CDA is reached or up to the ECP 
• 
Decrease CS by ~25% every two weeks, until ~20 mg per day 
• 
Once at ~20 mg per day, decrease CS by ~2.5 mg per week 
• 
Once at ~10 mg/day, decrease CS by 1 mg per week to 5 mg 
Note, because 1 mg will be the smallest prednisoneCS dosage provided and tablet splitting 
is not allowed, the Investigator must round up or down to the nearest whole milligram 
for CS dose after calculation of the new dose level. 
Updated to provide clarity 
3.6 Inclusion Criteria 
3.PDAI score of at least 9 points for relapsing patients (diagnosed > 6 months since 
diagnosisprior to Screening) or at least 15 points for newly diagnosed patients 
(diagnosed ≤ 6 months prior to Screening) 
Updated to provide clarity 
3.12 Randomization 
Patients will be randomized at Day 1, in a 1:1 allocation, using a stratification by PV/PF 
disease type, and by newly diagnosed disease (diagnosed ≤ 6 months prior to Screening) or 
by relapsing disease (diagnosed > 6 months since diagnosisprior to Screening.) 
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Section 
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Justification of Change 
Table 2 Schedule of 
Assessment - Blinded 
Treatment Period; 
 
Table 3 Schedule of 
Assessments - Open-Label 
Extension Period 
Footnotes:  
h (Table 2) and e (Table 3). PK sample should be taken at random timepoints during the 
patient visits with as much variation in time since last dose as practicable. Time of draw 
will be captured as well as time sinceof the last two PRN1008 or placebo dose, if 
administered with fooddoses, and time sinceof the patient’s last meal. 
 
l (Table 2) and h (Table 3).  Photography of lesions conductedallowed at selected centers 
at the discretion of the Investigator and as per local regulations. 
Updated to provide clarity 
 
 
 
 
Photography requirements 
removed to allow per 
Investigator’s discretion and 
local legislation. 
 
Table 2 Schedule of 
Assessment - Blinded 
Treatment Period 
Footnotes: 
k. Rituximab may be administered intravenously during the Blinded Treatment Period, 
unless contraindicated, after a second “qualifying relapse” occurs at or after Day 29 1 and 
the patient has completed at least Day 29 (Week 5)Visit. See Appendix 1. Any rituximab 
dispensed will undergo drug accountability. 
Updated to correct oversight 
Table 3 Schedule of 
Assessments - Open-Label 
Extension Period 
Footnotes: 
c. Hematology will include the following: hemoglobin, hematocrit, erythrocyte count (red 
blood cell [RBC] count), thrombocyte count (platelets), leukocyte count (white blood cell 
[WBC] count) with differential in absolute counts (including neutrophils, eosinophils, 
basophils, lymphocytes, and monocytes). Serum chemistry will include the following: 
aspartate aminotransferase (AST); alanine aminotransferase (ALT); total, direct, and 
indirect bilirubin levels; alkaline phosphatase (ALP); albumin; creatinine; urea; total 
protein; sodium; chloride; calcium; phosphate; potassium; and glucose (random). Creatine 
phosphokinase (CPK) is to be performed at Screening only. Coagulation will include: 
PT/INR, thrombin time, aPTT, and fibrinogen level. HbA1c and LDL levels (fasting) will 
be collected every 3 months with GTI assessment. Urinalysis will include: pH, specific 
gravity, protein, glucose, ketones, bilirubin, blood, nitrites, urobilinogen, and leukocytes at 
EOT. 
Corrected GTI assessment 
previously, inadvertently 
included in open-label 
extension period 
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5.9.2 Particular Permissible 
Medications; 
Appendix 1 Corticosteroid 
and Rituximab Management 
• Local use of topical corticosteroids and oral corticosteroid rinses (mouth washes) 
are allowed. 
Included a permitted CS use 
7.7.6 Electrocardiogram 
Monitoring 
Single 12-lead ECGs will be performed at Screening and Week 37. All ECGs will be 
performed with the patient in a supine position. 
Added ECG at week 37 for 
comparison with baseline 
ECG 
7.7.7. Clinical Laboratory 
Tests 
See Table 2 and Table 3 for laboratory test panels for chemistry, hematology, urinalysis 
and pregnancy testing. Laboratory safety tests may be performed at unscheduled time 
points, if deemed necessary by the Investigator. Screening laboratory safety tests may be 
repeated upon discussion with the Sponsor/Medical Monitor. 
Updated to provide clarity 
7.7.15 Photography 
Photography of lesions may be performed at selected sites, at the Investigator’s 
discretion as allowed by country and local regulations, and at selected centers with 
sufficient subjects. A photography manual will be provided to those sites. 
Photography requirements 
removed to allow per 
Investigator’s discretion and 
local legislation.  
3.13 Other Statistical 
Considerations; 
8.2 Data Safety Monitoring 
Board (DSMB) and interim 
Analysis  
There will be no interim analysis to assess efficacy. An interim analysis to possibly add 24 
more patients to the trial will be conducted and reviewed by the DSMB when 
approximately 50% of patients have reached the Week 29 visit, based on an observed 
control group rate of CR on ≤5 mg CS of any duration at Week 29 that exceeds 20%. The 
additional 24 patients will include a minimum of 20 patients with PV. 
Updated to correct oversight 
9.4.5 Efficacy Analysis (ITT 
Population) 
Primary: 
• A Cochran-Mantel-Haenszel (CMH) general association test stratified by disease type 
(PV or PF) and disease history (newly diagnosed or relapsing) will be used to compare 
PRN1008 with placebo. Newly diagnosed pemphigus is defined as patients diagnosed ≤ 6 
months prior to Screening. Relapsing, chronic pemphigus is defined as patients diagnosed 
with > 6 months since diagnosisprior to Screening. 
Updated to provide clarity 
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12.13.3 
Clinical Study Protocol Version 3.1 for Canada (24 April 2019)  
This was a local amendment to protocol Version 3 and was regarded as a substantial amendment. 
Overall Rationale for the Amendment  
The primary reasons for this amendment to Protocol PRN1008-012, Version 3.1 are: 
• 
To remove inclusion criterion #4 and update numbering, 
• 
To update exclusion criterion #17, 
• 
To correct Rituximab approval status globally, 
• 
To correct indication referenced to GPA. 
 
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Protocol Amendment summary of changes Table 
PRN1008-012 Protocol V3.1 Canada (24 April 2019) 
Deleted text has strikethrough and new text is bolded. 
Section #/Name 
Amended or New Wording 
Justification of Change 
Protocol Signature page 
  
 
Change in personnel. 
Page 1, 2, and 3 
3.0  
3.1 Canada  
Updated version 
3.6 Inclusion Criteria 
4. Body mass index (BMI) > 17.5  
 
Removed Inclusion Criteria 
#4 and updated the inclusion 
criteria numbering 
3.7 Exclusion Criteria  
 
History of serious infections requiring intravenous therapy with the potential for 
recurrence OR currently active moderate to severe infection at screening 
(Grade 2 or higher).  
 
5.1 Overview of pemphigus  
 
Presently, there are few effective treatment options for pemphigus. Current 
treatments include corticosteroids (CS) to reduce inflammation and antibiotics to 
treat associated infections. Agents such as mycofenolate mofetil are often used and 
rituximab has been reported to be effective. Mycofenolate mofetil has not been 
approved for this indication in any country and rituximab to treat pemphigus 
vulgaris has only been only been not been globally approved to date in the US and 
for both of these agentsto date in the US. and for both of these agents,  
The beneficial effects of these 2 products take weeks to months. Current day 
practice guidelines recommend first-line therapy with relatively high doses of CS 
initially (0.5 to 1.5 mg/kg/day of prednisone or equivalent CS), with rituximab 
also for consideration as first line therapy in combination with CS (Murrell 2018).  
Administrative change to 
correct Rituximab approval 
status 
5.8 Rituximab and Possible 
Combination with PRN1008  
Rituximab is a chimeric anti-CD20 antibody authorized approved approved for the 
treatment of rheumatoid arthritis, non-Hodgkin’s lymphoma, chronic lymphocytic 
leukemia (CLL) and granulomatosis with polyangiitis (GPA Waldenstrom’s 
macroglobulinemia ) (Waldenstrom’s macroglobulinemia also known as Wegener’s 
granulomatosis) and /microscopic polyangiitis (MPA) - GPA and MPA GPA and MPA 
in combination with CS.  
 
 
  
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12.13.4 
Clinical Study Protocol Version 3.1 for Germany (01 May 2019)  
This was a local amendment to protocol Version 3 and was regarded as a substantial amendment. 
Overall Rationale for the Amendment  
The primary reasons for this amendment to Protocol PRN1008-012, Version 3.1 are: 
• 
To update the abbreviations list, 
• 
To update the definition of WOCBP, 
• 
To update exclusion criterion #6 for male patients, 
• 
To update exclusion criterion #20 with known contraindication to provided CS or with a 
known sensitivity to PRN1008 or its excipients. 
 
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Protocol Amendment summary of changes Table 
PRN1008-012 Protocol V3.1 Germany- 
 (1 May 2019)  
Deleted text has strikethrough and new text is bolded. 
Section #/Name 
Amended or New Wording 
Justification of Change 
Headings, Page 1, 2, and 3 
9 Oct 2018 
1 May 2019 
Country specific amendment 
to existing protocol. 
Page 1, 2, and 3 
Version Number 3.0 
Version Number: 3.1 
Country specific amendment 
to existing protocol. 
Protocol Signature Page, 2 
  
  
Change in personnel. 
1. List of Abbreviations, Page 
8 
WOCBP = Woman of childbearing potential  
 
Update to abbreviation list 
based on new edits (see 
below) 
3.6 Inclusion Criteria #6 
Female patients who are of reproductive childbearing potential must agree for the 
duration of the study to use an highly effective means of contraception 
(eg, combined estrogen-progesterone containing hormonal contraception 
methods that inhibit ovulation (oral, intravaginal, transdermal), progesterone-
only hormonal contraception methods that inhibit ovulation (oral, injectable, 
implantable intrauterine device, intrauterine hormone-releasing system, bilateral 
tubal ligation, vasectomized partner or sexual abstinence (only if it is the 
preferred and usual lifestyle of the  
subject). A woman is considered of childbearing potential (WOCBP), 
ie, fertile, following menarche and until becoming post-menopausal unless  
permanently sterile). A woman is considered of childbearing potential 
(WOCBP), ie, fertile, following menarche and until becoming post-menopausal 
unless permanently sterile. Permanent sterilisation methods include 
hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A 
postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a post-menopausal state in 
Updated to provide definition 
of WOCBP
 
 
 
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Section #/Name 
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women not using hormonal contraception or hormonal replacement therapy. 
However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. Unless surgically sterile, postmenopausal females 
should have menopause confirmed by follicle stimulating hormone (FSH) testing. 
3.6 Exclusion Criteria 6 
Male patients should use condoms during study treatment and until 90-days 
after the last dose of PRN1008/placebo, and should not donate sperm during 
this same time period. For a non-pregnant female partner of childbearing 
potential, contraception recommendations for the female patients should also 
be considered.  
New text added to include 
instructions on avoidance of 
pregnancy in a partner of 
male patients. 
3.7 Exclusion Criteria #20  
Patients who have a known contraindication to sponsor-provided corticosteroid or 
with a known sensitivity to PRN1008 or its excipients.  
Updated to provide 
consistency to IB 
 
 
  
Section 6.6 Treatment 
Blinding  
Section 6.6 Treatment Blinding/Unblinding  
Edited for context  
Section 6.6, last paragraph; 
new sentence added  
See Section 8.3.5 for unblinding if required to determine best clinical course.  
Link provided for new 
section; see below.  
New section added  
8.3.5. Treatment Unblinding to Determine Clinical Course  
If deemed by the Investigator to be medically necessary in the event that a suspected 
unexpected serious adverse reaction (SUSAR) occurs, to determine appropriate 
clinical treatment, the Investigator can unblind an individual patient via the IWRS. 
Instructions for Investigators to  
unblind are located in the Suvoda IWRS Site User Manual, available both in the 
Investigator Site File as well as available for all Users to download electronically 
within the IWRS system.  
To provide additional 
instructions on unblinding for 
treatment of SUSARs  
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12.13.5 
Clinical Study Protocol Version 3.2 for Germany (22 May 2019)  
This was a local amendment to protocol Version 3.1 and was regarded as a substantial 
amendment. 
Overall Rationale for the Amendment  
The primary reasons for this amendment to Protocol PRN1008-012, Version 3.2 are: 
• To add WOCBP definition as per the CTFG recommendations on contraception  
(15 Sep 2014), 
• To clarify postmenopausal state in the protocol, 
• To introduce highly effective methods of contraception, 
• To add contraception duration in the protocol, 
• To add inclusion criterion #7 “Has been informed and has given written informed consent 
and agreeable to the schedule of assessments” 
• To add exclusion criterion #21 “Patients who have a known contraindication to Sponsor-
provided corticosteroid or with a known sensitivity to PRN1008 or its excipients” as it is 
in the IB, 
• To add exclusion criterion #22 “Patients who are institutionalized by order of authorities 
or courts” 
• To add exclusion criterion #23 “Patients who may be unduly influenced by association 
with or connected to the Sponsor, Investigator, or Site”, 
• To add “contraindication of the sponsor’s provided corticosteroid” as an exclusion 
criterion for safety reasons, 
• 
To add some clarifications to the protocol Section 6.6 for treatment unblinding. 
• 
To add Week 39 in the Open-Label Extension Period, 
• 
To add all endpoints to the body of protocol, 
• 
To add study design to body of protocol.
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Protocol Amendment summary of changes Table 
PRN1008-012 Protocol V3.2 Germany- BfArM (22 May 2019)  
Deleted text has strikethrough and new text is bolded. 
Section(s) 
Amended or New Wording 
Justification of Change 
Throughout the protocol 
01 May 2019 22 May 2019 
Administrative change to reflect new protocol date 
Throughout the protocol 
Version 3.1 Version 3.2 
Administrative change to reflect new protocol date 
List of abbreviations 
List was updated by adding WHO for World Health 
Organization. 
Change for clarity 
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Synopsis: Inclusion Criteria #6 
6. 
Female patients who are of childbearing potential 
must agree for the duration of the study to use a highly 
effective means of contraception (eg, combined estrogen-
progesterone containing hormonal contraception methods 
that inhibit ovulation, (oral, intravaginal, transdermal), 
progesterone-only hormonal contraception methods that 
inhibit ovulation (oral, injectable, implantable), intrauterine 
device, intrauterine hormone-releasing system, bilateral 
tubal ligation, vasectomized partner or sexual abstinence 
(only if it is the preferred and usual lifestyle of the subject 
patient). A woman is considered of childbearing potential 
(WOCBP), ie, fertile, following menarche and until 
becoming post-menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, 
bilateral salpingectomy and bilateral oophorectomy. A 
postmenopausal A post-menopausal state is defined as no 
menses for 12 months without an alternative medical cause. 
A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a post-
menopausal state in women not using hormonal 
contraception or hormonal replacement therapy. However, 
in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
 
[new inclusion criterion] 
As per request from the 
 
 
Synopsis: Inclusion Criteria #7 
 
 
Synopsis: Inclusion Criteria #8 
 
7. 
Has been informed and has given written informed 
consent and agreeable to the schedule of assessments 
 
[new inclusion criterion] 
8. 
Male patients should use condoms during study 
treatment and until 90-days after the last dose of 
PRN1008/placebo, and should not donate sperm during this 
 
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Section(s) 
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Justification of Change 
same time period. For a non-pregnant female patients 
partner of childbearing potential, contraception 
recommendations for the female partner should also be 
considered. 
 
[remove exclusion criterion]:  
8. Able to provide written informed consent and agreeable 
to the schedule of assessments 
 
Synopsis: Exclusion Criteria #20 
to 24 
Section 5.2 Exclusion Criteria 
[change of wording for exclusion criterion] 
 
20. Patients who have a known contraindication to sponsor
provided corticosteroid or with a known sensitivity to 
PRN1008 or its excipients. Any other clinically 
significant disease, condition, or medical history that, in 
the opinion of the Investigator, would interfere with 
patient safety, trial evaluations, and/or trial procedures. 
 
[new exclusion criteria] 
 
21. Patients who have a known contraindication to 
Sponsor-provided corticosteroid or with a known 
sensitivity to PRN1008 or its excipients 
22. Patients who are institutionalized by order of 
authorities or courts.  
23. Patients who may be unduly influenced by association 
with or connected to the Sponsor, Investigator, or Site. 
As per request from the 
 
 
Table 3 Schedule of 
Assessments - Open Label 
Extension Period 
[Column title added] 
Week 39 
[Time interval added]  Week 57 ± 5 days 
“X” added for the weight, Vital Signs, Urinalysis, Urine 
pregnancy test, PDAI at the ET Visit 
As per request from the 
 
 
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“X” added for Vital Signs, PDAI at the ET Visit and 
Unscheduled visit 
 
“X” added for the Abbreviated physical examination at the 
Unscheduled Visit 
“X” added for the Hematology, coagulation, and serum 
chemistry at Week 39, Week 49 and at the ET Visit 
“X” added for the ABQOL and TABQOL, EQ-5D-5L at 
Week 39, Week 49, the ET Visit and at the Unscheduled 
Visit 
“X” added for the PK sample, at Week 39, Week 49, at 
Week 61and at the ET Visit 
“X” added for the PD: anti-desmoglein -1 and -3 
autoantibody titers by ELISA at Week 49, at Week 61and 
at the ET Visit 
“X” added for the Efficacy Outcome Assessment, 
assessment of AEs, Photography, Concomitant medications 
at the ET Visit and at the Unscheduled Visit 
“X” added for the PRN1008 dispensed at Week 57 
“X” added for the Drug reconciliation (PRN1008 /CS 
Dosing Documentation) at Week 61, the ET Visit and at the 
Unscheduled Visit. 
 
Section 3. Objectives and 
Endpoints 
 
3. Objectives and endpoints 
3.1 Objectives 
3.1.1 Efficacy Objectives 
• 
To evaluate the efficacy of PRN1008 in 
achieving durable CR on low to zero doses of 
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oral corticosteroid (CS) and on the timecourse 
of quantitative disease activity scores.  
• 
To assess the ability of PRN1008 to reduce CS 
exposure and the adverse effects of CS 
• 
To evaluate the time to specified clinical 
endpoints  
• 
To assesss the longer term durability of CR 
3.1.2 Safety Objectives 
• 
To evaluate the safety of PRN1008 
• 
To evaluate differences in potentially CS-related 
adverse events 
3.1.3 PK/PD Objectives 
• 
To evaluate the population pharmacokinetics 
(PK) of PRN1008  
• 
To evaluate pharmacodynamic (PD) effects of 
PRN1008 on anti-desmoglein (anti-dsg) 
autoantibody titers (anti-dsg1 and anti-dsg3) 
3.1.4 Exploratory Objectives 
• 
To examine the effects of PRM1008, if any, of 
the baseline covariatets on PK and/or PD. 
3.2 Endpoints 
3.2.1 Outcome Assessment Definitions 
Pemphigus Clinical Definitions (Consensus Guideline, 
Murrel 2018) 
Control of Disease Activity (CDA): 
Control of disease activity (disease control) is defined as 
the time at which new lesions cease to form and 
established lesions begin to heal. This is also considered 
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the beginning of the consolidation phase. The expected 
interval of time to reach the control of disease activity is 
on the order of weeks, although it may be shorter.  
End of Consolidation Phase (ECP): 
The end of the consolidation phase is defined as the time 
at which no new lesions have developed for a minimum 
of 2 weeks and the majority (approximately 80%) of 
established lesions have healed. It is at this point that 
most clinicians begin to taper corticosteroid doses. 
Complete Remission (CR): 
Complete remission is defined as the absence of new and 
established lesions and is intended to mean “no disease 
activity”. Various qualifying statements are added to 
this definition for endpoints in this protocol.  
Relapse/Flare: 
A relapse of disease and a flare of disease are 
synonymous. They are defined by the appearance of 3 or 
more new lesions within 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. 
3.2.2 Primary Efficacy Endpoint 
• 
The proportion of patients who are in CR from 
Week ≤ 29 to Week 37 with a CS dose of ≤ 5 
mg/day  
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3.2.3 Key Secondary Efficacy Endpoints 
• 
Cumulative CS dose over first 36 weeks (to 
Week 37) 
• 
Time to the beginning of the CR event used to 
define success for patients reaching the primary 
endpoint 
• 
Proportion of patients with CR from Week ≤ 29 
to Week 37 with a CS dose of ≤ 10 mg/day  
3.2.4 Other Secondary Endpoints 
• 
GTI score at Week 37 
• 
Change in EuroQOL-5 Dimension 5 Level (EQ-
5D-5L) score from baseline to Week 37 
• 
Change in EQ-5D-5L score from baseline to 
Weeks 5, 13, 25, and 61 
• 
Change in Autoimmune Bullous Disease Quality 
of Life (ABQOL) score from baseline to Weeks 
5, 13, 25, 37 and 61 
• 
Change in PDAI score from baseline to Weeks 
5, 13, 25, 37 and 61 
• 
Change in Treatment of Autoimmune Bullous 
Disease Quality of Life (TABQOL) score from 
baseline to Weeks 5, 13, 25, 37, and 61 
• 
Proportion of patients in CR for ≥ 8 weeks on 
zero CS at Week 61 by original 
PRN1008/placebo group assignment and overall 
• 
Proportion of patients in CR at Week 37 to 
maintain CR continuously to Week 61 
• 
Proportion of patients not in CR at Week 37 to 
achieve CR at Week 61 
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• 
Proportion of patients to achieve CR of any 
duration at any time up to Week 37 
• 
Duration of CR  
3.2.5 Safety Endpoints 
• 
Nature, frequency, and severity of adverse 
events, including serious adverse events, adverse 
events leading to discontinuation and possible 
corticosteroid-related adverse effects 
• 
Change from baseline in vital signs and clinical 
laboratory test results (including complete blood 
count and blood chemistry) 
3.2.6 Pharmacokinetic Endpoints 
• 
Plasma concentrations of PRN1008 at 
approximately the time of maximum 
concentration at Day 1 and at varied subsequent 
timepoints (refer to Table 2 and Table 3) 
3.2.7 Pharmacodynamic Endpoints 
• 
Change from baseline in anti-dsg1 and anti-dsg3 
autoantibody levels by enzyme-linked 
immunosorbent assay (ELISA) at Weeks 13, 25, 
37, 49, and 61 
3.2.8 Exploratory Endpoints 
• 
Exploratory PK/PD analysis will examine the 
effects, if any, of covariates on PK and/or PD, 
and the relationship between PK, PD, and 
efficacy in this population. 
• 
Cost utilities based on the number and type of 
hospitalizations, outpatient medical visits, 
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concomitant medication use, adverse events and 
other relevant outcomes 
• 
Change from baseline in PDAI by visit and the 
temporal relationship to changes in quality of 
life and health economic variables and the 
relationship between PK, PD, and efficacy  
• 
To examine the effect of PRN1008 on the costs 
of hospitalizations, outpatient medical visits, 
adverse events, concomitant medication use and 
other relevant health economic outcomes 
• 
To examine the temporal relationship of change 
from baseline in Pemphigus Disease Area Index 
(PDAI) total activity score and quality of life 
and health economic measures 
Section 4. Study Design 
4. Study Design 
This is a randomized, parallel-group, double-blind, 
placebo-controlled trial with 36 weeks of treatment 
during a Blinded Treatment Period followed by an 
Open-Label Extension Period of 24 weeks and a Follow-
up Period of 4 weeks (Figure 1). This study will be 
conducted at approximately 100 global sites. 
4.1 Duration of Trial Participation 
For each patient, the trial will last approximately 68 weeks. 
This includes Screening (up to 4 weeks) through Week 37 
in the Blinded Treatment Period and from Week 37 to 
Week 61 in the Open-Label Extension Period followed by 
the 4 week post-dose follow-up at Week 65. 
4.2 Blinded Treatment Period (Weeks 1 to 37) 
 
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Table 4: 
Definitions of Moderate to Severe 
Population and starting CS doses* 
 
PDAI 
entry 
criteria 
Required CS 
dose starting 
at 
Screening** 
Newly diagnosed 
(diagnosed ≤ 6 months 
prior to Screening) 
PDAI ≥ 15 
≥ 0.5 
mg/kg/day 
Relapsing, chronic 
(diagnosed > 6 months 
prior to Screening) 
PDAI ≥ 9 
≥ 0.2 
mg/kg/day 
* (Shimizu 2014, Boulard 2016) To date, two patients 
on chronic anticoagulation (rivaroxaban) have been 
treated without bleeding complications. 
Corticosteroids and Rituximab 
Required, initial doses of CS for the duration of Screening 
are ≥ 0.2 mg/kg/day for ) 
** Doses shown above are minimum requirements. Actual 
doses will be determined by Investigator judgment. 
After informed consent is obtained, patients with moderate 
to severe pemphigus (PV and PF) at Screening will be 
randomized in a 1:1 allocation ratio to receive either 
PRN1008 400 mg twice daily (bid) (n ~ 60) or placebo bid 
(n ~ 60) during the Blinded Treatment Period (Week 1 to 
Week 37).  
At Screening, patients will begin to take Sponsor-provided 
CS according to the minimum dose requirements, shown in 
Table 4 with relapsing  above, and as required to 
adequately treat the disease (diagnosed > 6 months prior to 
Screening) and ≥ 0.5 mg/kg/day for patients with newly 
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diagnosed disease (diagnosed ≤ 6 months prior to 
Screening).  
Thereafter,. CS are managed doses may be adjusted per the 
Corticosteroid Investigator discretion during the Screening 
period in the mandated range (CS and Rituximab 
Management protocol (, Appendix 1). 
PRN1008 (400 mg tablet) or placebo will be taken twice 
daily by mouth starting on Day 1. Tablets may be taken 
with or without food.  
While continuing on PRN1008 or placebo, commencing 
during the period of achievement of CDA to approximately 
the ECP (CDA-ECP), patients will undergo a moderately 
rapid CS taper regimen as recommended by recently 
published consensus guidelines (Consensus Guidelines, 
Murrell 2018) with the goal to reduce the CS dose to 
5 mg/day by no later than Study Week 29, with CS dose-
adjustment as clinically indicated to control disease (CS 
and Rituximab Management protocol, Appendix 1).  
Once patients achieve CR on a dose of 5 mg/day of CS, 
that dose should be maintained (not tapered further) until 
Study Week 37 (time of primary endpoint). 
Throughout the Blinded Treatment Period, patients who 
fail to respond to treatment or experience a worsening of 
disease should have their CS dose increased per CS 
Management Guidelines (Appendix 1) until CDA-ECP is 
obtained and tapering of CS can (re)commence. 
Rituximab treatment may be administered during the 
Blinded Treatment Period at or after the Week 5 visit, 
unless contraindicated, after a second or subsequent, 
clinically significant “qualifying relapse” occurs 
(Appendix 1). 
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If rituximab is administered, patients should remain on trial 
and blinded to treatment assignment, but will be considered 
treatment failures for all efficacy endpoints except for 
cumulative CS and composite Glucocorticoid Toxicity 
Index (GTI) score. After completing the Blinded Treatment 
Period, patients will enter the Open-Label Extension Period 
to receive active treatment with PRN1008 described below. 
A patient in the Blinded Treatment Period requiring an 
additional “top up” dose of rituximab after their initial 
rituximab dose should be discontinued from the trial. 
4.3 Open-Label Extension Period (Weeks 37 to 61) 
From Week 37, all patients will receive active drug in the 
Open-Label Extension Period. Patients who received 
placebo will thus receive active treatment with PRN1008 
400 mg bid. Patients requiring treatment by rituximab or 
other immunosuppressants (other than CS) for relapse 
during this period, will be discontinued from the study. 
From Week 37 (time of primary endpoint), further tapering 
to 0 mg CS should be attempted in patients with CR. 
Patients who fail to respond to treatment or experience 
worsening of disease should have their CS dose increased 
per CS management guidelines (Appendix 1) until control 
of disease is obtained and tapering of CS can 
(re)commence.  
4.4 Follow-up Period (Weeks 61 to 65):  
End of Trial for the overall clinical trial is defined as the 
point at which the last patient has completed the last visit of 
the study. 
End of Trial for each patient is defined as the point at 
which the patient has completed their Week 65 visit 
(4 weeks after the patient’s last dose of PRN1008). Patients 
who are not able to complete the planned Week 65 visit and 
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discontinue the study early should be encouraged to come 
back for their last visit, and this will be recorded as the End 
of Trial (EOT) visit. Patients that discontinue early will 
have the ET assessments completed as outlined in the 
Schedule of Assessments based upon from which phase 
treatment they are terminating, Table 2 (Blinded Treatment 
Period) and Table 3 (Open-Label Extension Period). 
4.5 Study Population 
Initially, approximately 120 male or female patients with 
newly diagnosed or relapsing moderate to severe 
pemphigus (pemphigus vulgaris [PV] or pemphigus 
foliaceus [PF]) will be enrolled with a targeted minimum of 
40 patients with PV per group, and a targeted minimum of 
10 patients with PF per group. Twenty-four additional 
patients may be added after an interim analysis that will 
assess the observed complete remission (CR) rate in the 
control group. 
4.6 Study Assessments Overview 
See Figure 1 for a diagram of the study design and the 
Schedules of Assessments (Table 2 and Table 3) and for 
description of the assessments. 
5. Eligibility Criteria 
5. ELIGIBILITY CRITERIA 
5.1 Inclusion Criteria 
Patients may be included in the study if ALL of the 
following criteria are met: 
1. Male or female patients, aged 18 to 80 years old 
with moderate to severe, newly diagnosed or 
relapsing PV or PF, with a clinical presentation and 
histopathology consistent with PV or PF.  
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2. Positive circulating anti-dsg1 or 3 autoantibody 
titer 
3. PDAI score of at least 9 points for relapsing 
patients (diagnosed > 6 months prior to Screening) 
or at least 15 points for newly diagnosed patients 
(diagnosed ≤ 6 months prior to Screening) 
4. Body mass index (BMI) > 17.5 
5. Adequate hematologic, hepatic, and renal function 
(absolute neutrophil count  
≥ 1.5 × 109/L, hemoglobin (Hgb) > 9 g/dL, platelet 
count ≥ 100 × 109/L, aspartate aminotransferase 
(AST) and/or alanine aminotransferase (ALT) ≤ 
1.5 × upper limit of normal (ULN), albumin ≥ 3 
g/dL, creatinine ≤ 1.5 × ULN 
6. Female patients who are of childbearing potential 
must agree for the duration of the study to use a 
highly effective means of contraception (eg, 
combined estrogen-progresterone containing 
hormonal contraception methods that inhibit 
ovulation (oral, intravaginal, transdermal), 
progesterone-only hormonal contraception methods 
that inhibit ovulation (oral, injectable, implantable 
intrauterine device, intrauterine hormone-releasing 
system, bilateral tubal ligation, vasectomized 
partner or sexual abstinence (only if it is the 
preferred and usual lifestyle of the patient). A 
woman is considered of childbearing potential 
(WOCBP), ie, fertile, following menarche and until 
becoming post-menopausal unless permanently 
sterile. Permanent sterilisation methods include 
hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy. A postmenopausal state is defined 
as no menses for 12 months without an alternative 
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medical cause. A high follicle stimulating hormone 
(FSH) level in the postmenopausal range may be 
used to confirm a post-menopausal state in women 
not using hormonal contraception or hormonal 
replacement therapy. However in the absence of 12 
months of amenorrhea, a single FSH measurement 
is insufficient.  
7. Has been informed and has given written informed 
consent and agreeable to the schedule of 
assessments 
8. Male patients should use condoms during study 
treatment and until 90-days after the last dose of 
PRN1008/placebo, and should not donate sperm 
during this same time period. For a non-pregnant 
female partner of childbearing potential, 
contraception recommendations for the female 
partner should also be considered 
5.2 Exclusion Criteria 
Patients will be excluded from the trial if any of the 
following criteria are met: 
1. Suspected paraneoplastic pemphigus and other 
forms of pemphigus that are not pemphigus 
vulgaris or pemphigus foliaceus 
2. Previous use of a Bruton’s tyrosine kinase (BTK) 
inhibitor 
3. Pregnant or lactating women 
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4. Electrocardiogram (ECG) findings of QT corrected 
for heart rate (QTc) > 450 msec (males) or > 470 
msec (females), poorly controlled atrial fibrillation 
(ie, symptomatic patients or a ventricular rate 
above 100 beats/min on ECG), or other clinically 
significant abnormalities 
5. A history of malignancy of any type, other than 
surgically excised non-melanoma skin cancers or 
in situ cervical cancer within 5 years before Day 1 
6. Use of immunologic response modifiers as 
concomitant medication and with the following 
washout periods: A) stop at least 2 weeks prior to 
Screening: mycophenolate mofetil, azathioprine, 
methotrexate, cyclosporine, dapsone, intravenous 
immunoglobulin (IVIG), Kinaret (anakinra), 
Enbrel (etanercept) or any other 
immunosuppressant not mentioned in this 
exclusion criterion; B) 12 weeks prior to 
Screening: Remicade (infliximab), Humira 
(adalimumab), Simponi (golimumab), Orencia 
(abatercept), Actemra (tocilizumab), Cimzia 
(certolizumab), Cosentyx (secukinumab), 
plasmapheresis; C) 6 months prior to Screening 
(or shorter if there is documented B cell 
reconstitution for anti-CD20 drugs): antiCD20 
drugs such as rituximab, ofatumumab, other long-
acting biologics 
7. Use of proton pump inhibitor drugs such as 
omeprazole and esomeprazole within 3 days (It is 
acceptable to change patient to H2 receptor 
blocking drugs prior to Day 1.) 
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8. Concomitant use of known strong-to-moderate 
inducers or inhibitors of CYP3A within 3 days or 
5 half-lives (whichever is longer) of Day 1 
(Appendix 8) 
9. Use of CYP3A-sensitive substrate drugs with a 
narrow therapeutic index within 3 days or 5 half-
lives (whichever is longer) of Day 1 and for the 
remainder of the trial including, but not limited to 
alfentanil, astemizole, cisapride, cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus, tacrolimus, or 
terfenadine  
10. Has received any investigational drug (or is 
currently using an investigational device) within 
the 30 days before Day 1, or at least 5 times the 
respective elimination half-life time (whichever is 
longer) 
11. History of drug abuse within the previous 
12 months 
12. Alcoholism or excessive alcohol use, defined as 
regular consumption of more than approximately 
3 standard drinks per day 
13. Refractory nausea and vomiting, malabsorption, 
external biliary shunt, or significant bowel 
resection that would preclude adequate 
PRN1008/placebo absorption 
14. Donation of a unit or more of blood or blood 
products within 4 weeks prior to Day 1 
15. History of solid organ transplant 
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16. Positive at Screening for human immunodeficiency 
virus (HIV), hepatitis B (surface and core 
antibodies unrelated to vaccination, surface 
antigen), or hepatitis C (anti-HCV antibody 
confirmed with Hep C RNA) 
17. Positive interferon-gamma release assay (IGRA) 
(eg, QuantiFERON®-TB Gold or T-spot TB® 
Test) at Screening. Unless, all of the following 3 
conditions are true: 
a. Chest X-ray does not show evidence 
suggestive of active tuberculosis (TB) 
disease 
b. There are no clinical signs and symptoms 
of pulmonary and/or extra-pulmonary TB 
disease  
c. Documented receipt of a course of 
prophylactic TB treatment of at least 
6 months 
18. History of serious infections requiring intravenous 
therapy with the potential for recurrence 
19. Live vaccine within 28 days prior to Day 1 or plan 
to receive one during the trial 
20. Any other clinically significant disease, condition, 
or medical history that, in the opinion of the 
Investigator, would interfere with patient safety, 
trial evaluations, and/or trial procedures 
21. Patients who have a known contraindication to 
Sponsor-provided corticosteroid or with a known 
sensitivity to PRN1008 or its excipients 
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22. Patients who are institutionalized by order of 
authorities or courts.  
23. Patients who may be unduly influenced by 
association with or connected to the Sponsor, 
Investigator or Site.  
Section 6. Treatments 
6.1.1 PRN1008/Placebo 
6.1.2 Preparation and Administration Corticosteroids 
6.1.2.1 Corticosteroid Starting Doses and Management 
during Screening and at Day 1 
Required, initial doses of CS for the duration of 
Screening are ≥ 0.2 mg/kg/day of CS for patients with 
relapsing disease (diagnosed > 6 months prior to 
Screening) and ≥ 0.5 mg/kg/day for patients with newly 
diagnosed disease (diagnosed ≤ 6 months prior to 
Screening). At Screening, patients will begin to take 
Sponsor-provided CS according to the minimum dose 
requirements, and as required to adequately treat the 
disease during the Screening period. CS doses may be 
adjusted upward per Investigator discretion during the 
Screening period but the dose should not be reduced 
below the initial dose levels (Table 1). 
If disease significantly (Investigator judgment) worsens 
during the Screening period, up-titration of CS dose by 
50-100% should occur, as often as every 5-7 days if 
needed (Harman 2017).  
6.1.2.2. Corticosteroid Management during Treatment 
Period and Open-Label Extension Period 
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6.1.2.2.1. Corticosteroid-Tapering (Consensus 
Guideline, Murrell 2018) 
CS will be tapered from CDA-ECP towards a goal of 
5 mg/day by ≤ Week 29. Once the 5 mg level is 
achieved it will be kept at 5 mg/day until the time of 
the primary endpoint at Week 37 is reached. After 
that, taper towards 0 mg should commence as clinically 
indicated. 
CS tapering should follow the dosing guidelines below 
(Murrell 2018). Adjustment of the tapering guideline 
protocol by investigators is permitted, based on 
assessment of clinical need. 
• 
Start tapering CS as soon as CDA is reached or 
up to the ECP  
• 
Decrease CS by ~25% every two weeks, until 
~20 mg per day 
• 
Once at ~20 mg per day, decrease CS by ~2.5 
mg per week 
• 
Once at ~10 mg/day, decrease CS by 1 mg per 
week 
Note, because 1 mg will be the smallest CS dosage 
provided and tablet splitting is not allowed, the 
Investigator must round up or down to the nearest 
whole milligram for CS dose after calculation of the 
new dose level. 
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6.1.2.2.2. 
Corticosteroid-Up-Titration (Harman 2017) 
CS up-titration is allowed if disease significantly 
worsens prior to initial CDA-ECP or after CDA-ECP, 
during CS taper. 
Up-titration should be a temporary increase until CDA-
ECP is achieved (again), after which tapering can 
recommence. 
For full details of up-titration see Appendix 1. 
Section 7.4.1 Patient 
Discontinuation and Stopping 
Rules 
The Investigator in conjunction with the or Sponsor may 
also, at their discretion, discontinue the patient from 
participation in the study at any time if both they consider 
discontinuation to be in the patient’s best interest. If a 
patient meets any of the criteria listed below, the patient 
should complete the assessments for the Early Termination 
(ET) visit (see Table 2 and Table 3). 
Reasons Mandatory termination criteria for 
discontinuing a patient  may in this study include, but are 
not necessarily limited to, the following: 
• 
Severe and life-threatening pemphigus disease 
activity 
• 
Grade 4 PRN1008 -related TEAE 
• 
Serious allergic reaction to PRN1008 or placebo 
including anaphylactic reaction 
• 
A patient in the Blinded Treatment Period requiring 
an additional “top up” dose of rituximab after their 
initial rituximab dose or a patient in the Open-Label 
Extension Period requiring rituximab 
• 
Human immunodeficiency virus (HIV)/acquired 
immune deficiency syndrome (AIDS), viral 
hepatitis (B and C) infection occurring during the 
study 
• 
Pregnancy 
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There may be additional reasons for patient 
discontinuation, such as the following examples: 
• 
Any medical condition or personal circumstance 
that, in the opinion of the Investigator, exposes 
the patient to risk if the patient continues with 
PRN1008 or placebo or that prevents the patient’s 
adherence to the protocol 
If in the Investigator’s or the Sponsor’s judgment, 
discontinuation is in the patient’s best interest 
• 
Violation of protocol inclusion or exclusion 
criteria, if, in the opinion of the Investigator and 
the Sponsor, the violation would significantly 
compromise data interpretation 
• 
Discontinuation of the study by the Sponsor 
 
Section 8. Assessments of 
Efficacy 
8. Assessments of Efficacy 
8.1 Specification of the Efficacy Parameters 
Efficacy will be evaluated using a combination of lesion 
assessments, corticosteroid usage, and validated 
instruments for assessing disease activity and patient 
quality of life.  
A comprehensive list of all the secondary endpoints can be 
found in Sections 3.21 -3.2.3. In summary:  
• 
The primary endpoint requires patients to have no 
new or established lesions at the Week 29, 33 and 
37 visits, while on a daily corticosteroid dose ≤5 
mg/day.  
• 
The first key secondary endpoint is an analysis of 
the cumulative corticosteroid dose over the first 36 
weeks of the study (to Week 37). 
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• 
The other secondary endpoints include analyses of 
the following instruments: PDAI, ABQOL, 
TABQOL, EQ-5D-5L, VAS and GTI. Descriptions 
of the instruments can be found in Sections 7.7.9 -
7.7.14. 
8.2 Methods and timing for assessing, recording 
and analyzing of efficacy parameters 
Lesion assessments, the Pemphigus Disease Area Index 
(PDAI) and prescribed corticosteroid doses are recorded at 
every visit. The quality of life instruments are administered 
at the visits specified in the schedule of assessments (Table 
2), and the Early Termination visit and Unscheduled visits. 
Further assessment details can be found in Section 7. 
Descriptions of the analysis of the primary and secondary 
endpoints can be found in Section 10.2.10  and Section 
10.2.11 
Section 10.2 Objectives and 
Endpoints 
10.2 Objectives and Endpoints 
Please refer to Synopsis Section 4.  
Outcome Measures 
Please refer to Synopsis Section . 
Analysis Populations 
Three populations will be defined for data analysis: the 
Safety Population, the Intent-to-Treat (efficacy) Population, 
and the Pharmacokinetic Population. 
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10.2.2 Safety Population 
All patients who are randomized and receive at least one 
dose of study medication will be included in the ITT Safety 
Population. The ITT population Safety Population is the 
primary analysis population for efficacy. safety. Patients 
will be analysed according to the treatment they 
actually received, not necessarily the treatment they 
were allocated to at randomization. Results will be 
presented “as randomized treated. 
10.2.3 Intent-to-Treat (ITT) Population 
All patients who are randomized will be included in the 
ITT Population. The ITT Population will be used for 
sensitivity analyses. Patients will be analyzed according to 
the treatment they were allocated to at randomization; not 
necessarily the treatment they actually received. Results 
will be presented “as randomized.”  
10.2.4 Modified Intent-to-Treat (mITT) Population 
All patients who are randomized and receive at least one 
dose of study medication will be included in the mITT 
Population. The mITT Population is the primary analysis 
population for efficacy. Patients will be analyzed according 
to the treatment they were allocated to at randomization; 
not necessarily the treatment they actually received. Results 
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12.13.6 
Clinical Study Protocol Version 4 (29 August 2019)  
This was a global amendment to protocol Version 3 and was regarded as a substantial amendment. 
Overall Rationale for the Amendment  
The primary reasons for this amendment to Protocol PRN1008-012, Version 4 are: 
• 
To align number of PV/PF patients with the analysis plan, 
• 
To remove interim analysis, 
• 
To clarify to reduce unnecessary FSH/pregnancy testing for women with confirmed 
menopause, 
• 
To clarify CDA, ECP, and CR timing and requirements, 
• 
To clarify CS dosing and adjustment, and that CS tapering occurs after ECP confirmation, 
• 
To add provision to extend screening window, 
• 
To add the allowed dose interval of 8 hours for consecutive PRN1008/placebo doses, 
• 
To add washout period for warfarin and intralesional steroid use,  
• 
To remove Warfarin statement due to the potential of CYP3A inhibition, 
• 
To update clinical data in alignment with IB V10 dated 17May2019, 
• 
To add a Week 39 visit in open-label extension, 
• 
To remove the inclusion criterion #4 linked to BMI restriction, 
• 
To update exclusion criteria #17, #18 and #20, 
• 
To clarify biopsy requirements to ensure pemphigus diagnosis for eligibility, 
• 
To clarify that rituximab may be allowed if disease control is never achieved,  
• 
To clarify qualifying relapse and rituximab management in OLE, 
• 
To add flow chart to assist Investigator with Efficacy Outcome Assessment. 
 
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Protocol Amendment summary of changes Table 
PRN1008-012 Protocol V4.0 (29 August 2019) 
The protocol Version 4.0, 29 August 2019 has been updated throughout to correct errors and to clarify or adjust study procedures and assessments. 
Deleted text has strikethrough and new text is bolded. 
Section(s) 
Amended or New Wording 
Justification of Change 
Throughout the protocol 
9 Oct 201829 Aug 2019, Version 34 
Administrative change. 
Protocol Signature Page 
Updated Chief Medical 
Officer information. 
2.6 Study Population, 
3.13. Other Statistical 
Considerations,  
8.2 Data Safety Monitoring 
Board (DSMB) and Interim 
Analysis  
And 
 9.1 Determination of Sample 
Size 
 
2.6:  Initially, approximatelyApproximately 120 male or female patients with newly 
diagnosed or relapsing moderate to severe pemphigus (pemphigus vulgaris [PV] or 
pemphigus foliaceus [PF]) will be enrolled with a targeted minimum of 40 45 patients with 
PV per group, and a targeted minimum maximum of 10 patients with PF per group. 
Twenty four additional patients 
may be added after an interim analysis that will assess the observed complete remission 
(CR) rate in the control group. 
Updated to ensure that the 
number of PV patients is 
consistent with the analysis 
plan in Section 3.13. The 
interim analysis was removed 
to avoid any potential issues 
in controlling the Type I error 
rate.   
3.1. Pemphigus Clinical 
Definitions (Consensus 
Guideline, Murrell 2018) 
Control of Disease Activity (CDA): 
Control of disease activity (disease control) is defined as the timevisit at which new lesions 
cease to form and established lesions begin to heal. This is also considered the beginning of 
the consolidation phase. The expected interval of time to reach the control of disease 
activity is 
on the order of weeks, although it may be shorter. 
Clarification that “time” 
when referenced with CDA 
refers to the visit the CDA 
was assessed at and achieved. 
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3.1. Pemphigus Clinical 
Definitions (Consensus 
Guideline, Murrell 2018) 
 
End of Consolidation Phase (ECP): 
The end of the consolidation phase is defined as the timevisit at which no new lesions have 
developed for a minimum of 2 weeks and the majority (approximately 80%) of established 
lesions have healed. It is at this point that most clinicians begin to taper corticosteroid 
doses.Therefore, in order to achieve ECP, CDA must be confirmed at a visit ≥ 2 weeks 
later and 80% of the lesions seen previously must have healed. 
Clarification that “time” 
when referenced with ECP 
refers to the visit a minimum 
of 2 weeks after CDA was 
documented. Language 
regarding the ECP milestone. 
clarified for ease of 
understanding, as consistent 
with guidelines. 
3.3.1 Study Design  
(Blinded Treatment Period - 
Weeks 1 to 37) 
After informed consent is obtained, patients with moderate to severe pemphigus (PV and 
PF) 
at Screeningwill be screened and if eligible will be randomized in a 1:1 allocation ratio to 
receive either PRN1008 400 mg twice daily (bid) (n ~ 60) or placebo bid (n ~ 60) during the 
Blinded Treatment Period (Week 1 to Week 37). 
 
At Screening, patients will begin to take Sponsor-provided CS according to the minimum 
dose requirements, shown in Table 1 above, and as required to adequately treat the disease. 
CS 
doses may be adjusted per Investigator discretion during the Screening period in the 
mandated range (CS and Rituximab Management, Appendix 1) but the dose should not be 
reduced below the required minimum initial dose levels (Table 1).  CS taper should 
not being until ECP has been achieved. 
 
PRN1008 (400 mg tablet) or placebo will be taken twice daily by mouth starting on Day 1. 
Tablets may be taken with or without food. 
 
If a patient achieves CDA (no new lesions and established lesions begin to heal), a 
follow-up visit ≥ 2 weeks later must confirm the finding of no new lesions prior to 
declaring ECP and tapering CS. ECP is achieved with the confirmation of CDA (no 
new lesions for ≥ 2 weeks) with approximately 80% of the established lesions 
epithelialized (healed). If needed, confirmation of CDA and achievement of ECP may 
be documented at an Unscheduled Visit, prior to the next scheduled study visit. See 
Clarified “at screening” 
means the patients will be 
screened and that 
randomization would occur 
only if eligible. 
 
Updated text for consistency 
with Appendix 1, which 
specifies that only up-titration 
is allowed for CS during 
Screening.  
 
Added clarifying text 
regarding the use of 
Unscheduled Visits as 
allowed per protocol to 
document CDA and/or ECP.  
Minor changes were made to 
language throughout Sec 
3.3.1 to ensure clarity and for 
consistency with these 
clarifications. 
 
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Table 2 for all required assessments for an Unscheduled Visit, which also includes 
Efficacy Outcome Assessment and PDAI. 
 
While continuing on PRN1008 or placebo, commencing duringfollowing the period of 
achievement of CDA to approximately the ECP (CDA ECP), patients will undergo a 
moderately rapid CS taper regimen as recommended by recently published consensus 
guidelines (Consensus Guidelines, Murrell 2018) with the goal to reduce the CS dose to 
5 mg/day by no later than Study Week 29, with CS dose-adjustment as clinically indicated 
to 
control disease (CS and Rituximab Management protocol, Appendix 1). 
 
CS taper should not begin until ECP has been achieved. 
 
If the first documentation of CDA coincides with no disease activity (PDAI=0), a 
follow-up visit ≥ 2 weeks later must still confirm that no new lesions are seen and 
PDAI=0. At this time the patient is deemed to have confirmed CDA, ECP, and CR and 
therefore CS tapering can begin. If new lesion(s) are seen, the patient is no longer in 
CDA and therefore CS tapering should not begin. If a patient has not achieved CDA 
or new lesions emerge or existing lesions worsen but do not meet definition of relapse, 
refer to Appendix 1 regarding increasing steroid dosage. 
 
Once patients achieve CR on a dose of 5 mg/day of CS, that dose should be maintained (not 
tapered further) until Study Week 37 (time of primary endpoint). 
 
Throughout the Blinded Treatment Period, patients who fail to respond to treatment or 
experience a worsening of disease should have their CS dose increased per CS Management 
Guidelines (Appendix 1) until CDA-ECP is obtained and tapering of CS can (re)commence. 
If ECP is not achieved in a timely manner, it is encouraged that CS dose be further 
increased unless clinically contraindicated. The PI should consult with the Medical 
Monitor in such cases. 
 
Efficacy Outcome Assessment should be performed per the Efficacy Outcome 
Assessment 
 
Updated to clarify CS 
tapering occurs after ECP 
confirmation. 
 
 
 
 
 
 
 
 
Added context for CDA, ECP 
and CR. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Flowchart, Appendix 9. 
 
Once patients achieve CR on a dose of 5 mg/day of CS, that dose should be maintained 
(not tapered further) until Study Week 37 (time of primary endpoint). 
 
Rituximab treatment may be administered during the Blinded Treatment Period at or after 
the 
Week 5 visit, unless contraindicated,only after a second or subsequent, clinically significant 
“qualifying relapse” occurs, unless contraindicated (Appendix 1). 
 
If rituximab is administered, patients should remain on trial and blinded to treatment 
assignment, but will be considered treatment failures for all efficacy endpoints except for 
cumulative CS and composite Glucocorticoid Toxicity Index (GTI) score. After completing 
the Blinded Treatment Period, patients will enter the Open-Label Extension Period to 
receive 
active treatment with PRN1008 described below. A patient in the Blinded Treatment Period 
requiring an additional “top up” dose of rituximab after their initial rituximab dose 
shouldcourse of treatment must be discontinued from the trial. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.3.1 Study Design  
(Open Label Extension 
Period - Weeks 37 to 61) 
From Week 37, all patients will receive active drug in the Open-Label Extension Period. 
Patients who received placebo will thus receive active treatment with PRN1008 400 mg bid. 
Patients requiring treatment by rituximab or other immunosuppressants (other than CS) for 
relapse during this period, willmust be discontinued from the study. 
 
From Week 37 (time of primary endpoint), further tapering to 0 mg CS should be attempted 
in patients with CR unless medically contraindicated. Patients who fail to respond to 
treatment or experience worsening of disease should have their CS dose increased per CS 
management guidelines (Appendix 1) until control of disease is obtained and tapering of CS 
can (re)commence. CDA is obtained. If ECP is not achieved in a timely manner, it is 
encouraged that CS dose be further increased unless clinically contraindicated. The PI 
should consult with the Medical Monitor is such cases.  
 
Updated to clarify CS dosing 
and adjustment. 
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3.4.1 Corticosteroid Starting 
Doses and Management 
during Screening and at Day 
1, and   
Appendix 1 
3.4.1: 
 Corticosteroid Starting Doses and Management during Screening and at Day 1 
Required, initial doses of CS for the duration of Screening are ≥ 0.2 mg/kg/day of CS for 
patients with relapsing disease (diagnosed > 6 months prior to Screening) and ≥ 0.5 
mg/kg/day for patients with newly diagnosed disease (diagnosed ≤ 6 months prior to 
Screening). At Screening, patients will begin to take Sponsor-provided CS according to the 
minimum dose requirements, and as required to adequately treat the disease during the 
Screening period. CS doses may be adjusted upward per Investigator discretion during the 
Screening period (Appendix 1) but the dose should not be reduced below the initial 
required minimum initial dose levels (Table 1). CS taper should not begin until ECP 
has been achieved.  
Clarified that tapering can 
begin during Screening if 
ECP is achieved. 
3.4.2. Corticosteroid 
Management during 
Treatment Period and Open-
Label Extension Period, 
Appendix 1 
CORTICOSTEROID AND 
RITUXIMAB 
MANAGEMENT, 
Figure 1 Study Design Flow 
Chart, 
and 
5.5 Trial Design Rationale 
3.4.2: 
Corticosteroid-Tapering (Consensus Guideline, Murrell 2018) 
CS will be tapered from CDA ECP towards a goal of 5 mg/day by ≤ Week 29. Once the 5 
mg 
level is achieved it will be kept at 5 mg/day until the time of the primary endpoint at Week 
37 
is reached. After that, taper towards 0 mg should commence as clinically indicated.From 
Week 
37, further tapering to 0 mg CS should be attempted in patients with CR unless 
medically 
contraindicated. 
 
CS tapering should follow the modified dosing guidelines below (Murrell 2018). 
Adjustment 
of the taperingdosing guideline protocol by investigators is permitted for safety reasons, 
based 
on assessment and documentation of clinical need. 
 
• Start tapering CS as soon as CDA is reached or up to the ECP is confirmed. 
• Decrease CS by ~25% every two weeks, until ~20 mg per day 
• Once at ~20 mg per day, decrease CS by ~2.5 mg per week 
Clarified tapering to zero 
after Week 37 should occur 
unless medically 
contraindicated. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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• Once at ~10 mg/day, decrease CS by 1 mg per week 
 
Note, because 1 mg will be the smallest CS dosage provided and tablet splitting is not 
allowed, 
the Investigator must round up or down to the nearest whole milligram for CS dose after 
calculation of the new dose level. 
 
Corticosteroid-Up-Titration (Harman 2017) 
CS up titration is allowed if disease significantly worsens prior to initial CDA ECP or after 
CDA ECP, during CS taper. Up titration should be a temporary increase until CDA ECP is 
achieved (again), after which tapering can recommence. 
 
Patients who fail to respond to treatment or experience a worsening of disease should 
have their CS dose increased per CS Management Guidelines (Appendix 1) until CDA 
is obtained. If ECP is not achieved in a timely manner, it is encouraged that CS dose 
be further increased unless clinically contraindicated. The PI should consult with the 
Medical Monitor in such cases. 
 
For full details of up-titration see Appendix 1. 
 
 
Text replaced with updated 
language to clarify CS up-
titration should occur if 
patients fail to respond or 
experience worsening of 
disease.   
 
3.5. Concomitant 
Medications and 5.9.2 
Particular Permissible 
Medications 
3.5:  
 Strong to Moderate Inducers or Inhibitors of cytochrome P450 (CYP)3A, and “Sensitive” 
CYP3A Substrate Drugs with a narrow therapeutic index are not permitted (Appendix 8). 
Other “Sensitive” CYP3A drugs should be used cautiously by administering them only if 
the 
benefit-risk is favorable, using staggered administration at least 2 hours after PRN1008 or 
placebo. 
 
Patients on proton pump inhibitor drugs should have their medication changed to histamine 
2 
(H2) blockers during Screening and at least 3 days before Day 1. H2 blockers should be 
administered at least 2 hours after PRN1008 or placebo. 
 
 
Warfarin statement removed 
due to the potential of 
CYP3A inhibition (see 
Section 5.9.1 and Appendix 
8).  
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Warfarin should be monitored carefully as there is limited experience of co administration 
with PRN1008. To date, two patients on chronic anticoagulation (rivaroxaban) have been 
treated without bleeding complications. 
3.6 Inclusion Criteria #1, 
and Section 7.7.3 
7.7.3.  Biopsies 
A new biopsy (cutaneous and/or mucosal) is not required if there is a prior and available 
biopsy report documenting histopathologic findings diagnostic for PV or PF. A new biopsy 
should be performed if an archival biopsy report is not available. 
New biopsies should include local hematoxylin and eosin (H&E) histopathological review 
and direct immunofluorescence (DIF) for the characteristic pattern diagnostic of pemphigus 
(Note: anti desmoglein antibodies may be used as an alternative confirmation if DIF is 
negative and histopathology is characteristic of pemphigus).   
Histopathology on biopsies is evaluated for consistency with a diagnosis of PV or PF: 
• 
If DIF is positive, the patient is eligible in the presence of positive anti-
desmoglein antibodies. 
• 
If DIF is negative, the patient is not eligible. In these cases, where the H&E 
histopathology is characteristic of pemphigus and anti-desmoglein antibodies 
are positive, the biopsy may be repeated at the discretion of the investigator. 
• 
If DIF is not available, the patient is eligible in the presence of positive anti-
desmoglein antibodies and H&E histopathology characteristic of pemphigus.  
Biopsy requirements to 
ensure pemphigus diagnosis 
for eligibility were clarified.  
3.6. Inclusion Criteria #4 
 
Body mass index (BMI) > 17.5 (only applicable through Protocol v3.0) 
The setting of BMI > 17.5 
was based on early pre-
clinical findings of weight 
loss in the 4-13-week repeat 
dose GLP toxicity study in 
dogs (see IB Version 10 
dated 17May2019, Sections 
4.2.3.1 and 4.5.2.2). In the 
absence of human data at the 
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time of the first clinical study 
in pemphigus patients 
(PRN1008-005), BMI 
restriction was used to 
exclude patients with low 
body weight. As there were 
no changes in weight or 
appetite in the Phase 2 study, 
PRN1008-005, the BMI 
criteria has now been 
removed in this protocol. 
3.7. Exclusion Criteria #17 
Positive interferon-gamma release assay (IGRA) (eg, T-spot TB Test, 
QuantiFERON®-TB Gold, or T spot TB® Test)QuantiFERON®-TB Gold Plus (QFT 
Plus), at Screening. Unless, the patient has latent TB and all of the following 3 
conditions are true: 
a) Chest X-ray does not show evidence suggestive of active tuberculosis (TB) disease 
b) There are no clinical signs and symptoms of pulmonary and/or extra-pulmonary TB 
disease 
c) Documented receipt of a courseone of the following prophylactic TB treatment of 
at least regimens: 
 
i. Oral daily Isoniazid for 6 months 
 
 
 
or 
 
ii. Oral daily Rifampin (RIF) for 4 months 
 
 
 
or 
 
iii. Isoniazid and Rifapentine weekly for 3 months (3HP) 
On a case by case basis, after discussion and approval by the Sponsor, a local TB test 
that is negative and is considered equivalent to 1 of the above tests may be used for 
eligibility. For example, if a QuantiFERON®-TB Gold, or QuantiFERON-TB Gold 
Plus (QFT Plus) is positive and a local blood test or T-Spot TB test is negative, the 
patient may be enrolled using the local result upon approval of the Sponsor. 
Clarification of the options 
for TB testing and conditions 
to reduce the number of false 
positive and indeterminate 
test results, and to enable 
accurate results in patients 
who have received the BCG 
vaccine. 
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3.7. Exclusion Criteria #18 
History of serious infections requiring intravenous therapy with the potential for 
recurrence or currently active moderate to severe infection at Screening (Grade 2 or 
higher). 
Clarification to ensure that 
patients with moderate to 
severe active infection are not 
enrolled.  
3.7. Exclusion Criteria #20 
Any other clinically significant disease, condition [including contraindication to CS 
and/or inability to follow CS dosing as outlined in the protocol (see Table 1 for more 
details)], or medical history that, in the opinion of the Investigator, would interfere with 
patient safety, trial evaluations, and/or trial procedures. In areas endemic for Chagas 
disease, screening is recommended prior to enrollment. 
Provided recommendation for 
areas where Chagas may be 
endemic to screen and rule 
out the disease prior to 
enrolling.  
Table 2 Schedule of 
Assessments 
Footnote f: To confirm postmenopausal status for women who are not surgically sterile 
only. 
Any woman of age ≥ 55 years with amenorrhea for >1 year, will be considered as 
having confirmed menopause and will not need FSH or pregnancy testing. 
Postmenopausal females < 55 years of age (defined as amenorrhea > 1 year) should 
have menopause confirmed by follicle-stimulating hormone (FSH) and serum 
pregnancy testing at screening. Surgically sterile females do not require any further 
confirmation of menopause and will not be considered to have reproductive potential. 
Clarified to reduce 
unnecessary FSH/pregnancy 
testing for women with 
confirmed menopause. 
Table 3 Schedule of 
Assessments 
Week 39 ± 3 days / Weight: X 
Week 39 ± 3 days / Abbreviated physical exam: X 
Week 39 ± 3 days / Vital Signs: X 
Week 39 ± 3 days / Hematology, coagulation, and serum chemistryc: X 
Week 39 ± 3 days / PK Samplee: X 
Week 39 ± 3 days / PDAI: X 
Week 39 ± 3 days / ABQOL: X 
Week 39 ± 3 days / TABQOL: X 
Week 39 ± 3 days / EQ-5D-5L: X 
Week 39 ± 3 days / Efficacy Outcome Assessmentf: X 
Week 39 ± 3 days / Adverse events: X 
Week 39 ± 3 days / Photographyh: X 
Week 39 ± 3 days / Concomitant medications: X 
A Week 39 visit in open-label 
was added for consistency, to 
match the Week 3 double-
blind Visit, so that patients 
starting active PRN1008 for 
the first time in the Open 
Label Extension have a visit 
two weeks after starting 
PRN1008 dosing in this 
protocol.   
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5.4 Clinical Experience 
In clinical studies to date, PRN1008 has been administered to 140more than 200 people, 
including healthy volunteers, 27 and patients with pemphigus (mainly pemphigus vulgaris 
variant, i.e. PV) and 4and Idiopathic thrombocytopenia. Twenty-seven patients with 
immune 
thrombocytopenic purpura (ITP). Patients with PV in a Phase 2 study (NCT02704429) used 
a starting dose of 400 mg BID which was shown to produce adequate BTK occupancies in 
all but one patient. One patient dose escalated to 500 mg BID and onetwo to 600mg BID, 
with all other patients using the 400mg BID dose. An interim analysis of the first 27 
patients in this study found evidence of clinically significant activity in 80% of patients, 
with onset of disease control in the first 2 weeks of therapy, and an acceptable safety profile 
(DSUR 2018 and IB Section 5). The primary endpoint of the study, “control of disease 
activity by the Week 5 visit on ≤ 0.5mg/kg/day of prednisone (or equivalent CS)” was met 
by 54% (14/26) of patients. Complete remission on ≤ 0.5mg/kg/day of CS was achieved by 
25% (5/20) of patients completing 12 weeks treatment. 
 
Additional clinical data 
provided in alignment with 
current IB V10 dated 
17May2019. 
5.9.1 Prohibited Medications 
The following medications are prohibited for use during the trial: 
• 
Concomitant use of any immunosuppressant medication, other than CS and 
rituximab as described in this protocol. Patients who need other immunosuppressant 
therapy during the trial should be withdrawn. See Exclusion # 6 Section 3.7 for 
washout periods. 
• 
Concomitant use of known strong to moderate inducers or inhibitors of 
cytochrome P450 (CYP) 3A (Appendix 8) within 3 days or 5 half-lives (whichever 
is longer) of Day 
• 
Use of CYP3A-sensitive substrate drugs with a narrow therapeutic index (within 3 
days or 5 half-lives (whichever is longer) of Day 1 including, but not limited to, 
alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, sirolimus, tacrolimus, (topical and oral), or 
terfenadine. 
• 
Proton pump inhibitors are not permitted. Esomeprazole was shown to reduce the 
exposure of PRN1008 by approximately 50%, presumably due to the effects of a 
lack of an acidic environment on tablet dissolution. Subjects who are on proton 
Washout period for warfarin 
use and intralesional steroid 
use were added.  
 
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pump inhibitors should be changed to histamine (H2) receptor blocking drugs if 
possible or not enroll in the trial. Details of H2 receptor blocker administration is 
provided in Section 5.9.2. 
• 
Intralesional steroids are not permitted within 3 months of Screening, during 
Screening and for the duration of the study. 
• 
Warfarin use is not permitted within 1 week or 5 half-lives (whichever is 
longer) of Day 1 and for the duration of the study. 
 
6.1.2 Preparation and 
Administration 
 
Treatment medication will be taken twice daily by mouth starting on Day 1. PRN1008 or 
placebo may be taken with or without food. Consecutive PRN1008/placebo doses should 
not be taken within 8 hours of each other. Tablets should not be broken or crushed. 
Further details for dispensation and administration of blinded treatment are provided in the 
Pharmacy Manual. 
Added the allowed dose 
interval. 
7.6.1 Screening (Day -29 to 
Day -1) 
And 
Table 2 
7.6.1. Screening (Day -29 to Day -1) 
Informed consent will be obtained at Screening before performing any trial procedures. 
Patients will undergo Screening assessments, including, but not limited to; blood sampling, 
ECG, clinical assessment and various quality of life assessments. Please refer to Table 2. 
In cases where laboratory assessments are delayed due to logistic considerations, the 
Sponsor may permit an extension of the Screening Period for laboratory assessments 
up to 7 days in order to determine eligibility. Week 1 Day 1 should occur as soon as 
possible upon evaluation of the delayed assessments and no later than 35 days after the 
initial Screening visit. 
Added a provision for 
Screening window extension 
by ≤7 days in the case where 
laboratory assessments are 
delayed for a logistical 
reason, after discussion with 
Sponsor. 
7.6.3 Blinded Treatment 
Period (Weeks 1 to 37) 
and 
Appendix 9 EFFICACY 
OUTCOME ASSESSMENT 
FLOWCHART  
Please refer to Table 2 for specific assessments at each visit. CS dosing, and use of 
rituximab for a second qualifying relapse, are detailed in Appendix 1. The Efficacy 
Outcome Assessment Flowchart is detailed in Appendix 9. 
Added Appendix 9 flow chart 
to assist Investigator with 
Efficacy Outcome 
Assessment.  
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Appendix 1 
CORTICOSTEROID AND 
RITUXIMAB 
MANAGEMENT 
2. Non life-theatening worsening of disease during taper of CS prior to initial CDA 
confirmation of ECP 
During Screening or the treatment periods of the trial, where an initial induction of CDA 
has not been achieved and blistering continues without improvement, CS should be 
increased by 50 to 100% every 5 to 7 days until CDA-confirmation of ECP.  After ECP is 
achieved, and confirmed CS taper can should commence. Rituximab therapy may not be 
used in this situation.  Patients who have been treated with a minimum of 1.5mg/kg/day 
of corticosteroids for 2 weeks and have not achieved control of disease activity may be 
eligible after discussion with Principia to receive rituximab.   
Added to clarify that Sponsor 
may provide rituximab (if 
approved as rescue 
medication, by the relevant 
Competent Authority and 
Ethics Committees) in cases 
where disease control is 
never reached, despite 
adequate treatment with CS, 
upon discussion with 
Sponsor. 
Appendix 1 
CORTICOSTEROID AND 
RITUXIMAB 
MANAGEMENT 
Rituximab Management during Blinded Treatment Period 
 
Rituximab for second “qualifying relapse”: 
• 
“Qualifying relapse” for this purpose is defined as a relapse occurring after CDA
ECP is achieved, ECP has been confirmed and CS taper has begun, that is not life-
threatening (when a patient should be withdrawn) but is severe enough such that the 
PDAI total activity score is equal to or greater than the Screening or Day 1 baseline 
PDAI score (whichever is higher) for that patient. For example, if the Screening 
PDAI was 25, the Day 1 baseline was 21, and the relapse PDAI 23, the relapse 
would not be severe enough to be “qualifying”. Whereas if the relapse PDAI was ≥ 
25 it would be “qualifying”. 
• 
Where a second qualifying relapse occurs meeting the above definition, and it is at 
or after the Week 5 visit, then one course of rituximab, which consists of two 
intravenous doses of 1 gram two weeks apart, may be administered, unless 
contraindicated. 
• 
Oral CS doses should be managed as indicated for the patient at the time of the 2nd 
qualifying relapse 
• 
Rituximab should be administered as recommended in the Pharmacy Manual. 
• 
Patients should not be unblinded to treatment assignment and should continue in the 
trial. 
Updated to match the same 
discontinuation instruction 
from Section 3.3.1. 
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• 
The need for rituximab rescue will be considered “treatment failure” for the 
analysis of all efficacy endpoints except cumulative CS and composite GTI score. 
Rituximab Management during Open-Label Extension Period 
• 
Patients requiring treatment by rituximab or other immunosuppressants 
(other than CS) for relapse during this period, will be discontinued from the 
study. 
 
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12.13.7 
Clinical Study Protocol Version 4.1 for Germany (30 September 2019)  
This was a local amendment to protocol Version 4 and was regarded as a substantial amendment. 
Overall Rationale for the Amendment  
The primary reasons for this amendment to Protocol PRN1008-012, Version 4.1 are: 
• 
To revise Week 39 window to 3 days for consistency and to match the Week 3 double-
blind Visit, 
• 
To update the number of PV patients in accordance with the analysis plan, and to remove 
the interim analysis, 
• 
To clarify text regarding the use of Unscheduled Visits as allowed per protocol to 
document CDA and/or ECP, 
• 
To clarify CS dosing and adjustment, 
• 
To remove Warfarin statement due to the potential of CYP3A inhibition. 
 
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Protocol Amendment summary of changes Table 
PRN1008-012 Protocol V4.1 (30 September 2019) 
The protocol Version 4.1, 30 September 2019 has been updated throughout to correct errors and to clarify or adjust study procedures and 
assessments.  Deleted text has strikethrough and new text is bolded. 
Section(s) 
Amended or New Wording 
Justification of Change 
Throughout the protocol 
22 May 2019 30 Sep 2019, Version 3.2 4.1 
Administrative change. 
1. Synopsis (Study 
Population and Other 
Statistical Considerations),  
4.5 Study Population,  
9.2 Data Safety Monitoring 
Board (DSMB) and Interim 
Analysis  
and 
10.1 Determination of 
Sample Size 
2.6:  Initially, approximatelyApproximately 120 male or female patients with newly 
diagnosed or relapsing moderate to severe pemphigus (pemphigus vulgaris [PV] or 
pemphigus foliaceus [PF]) will be enrolled with a targeted minimum of 40 45 patients with 
PV per group, and a targeted minimum maximum of 10 patients with PF per group. 
Twenty four additional patients 
may be added after an interim analysis that will assess the observed complete remission 
(CR) rate in the control group. 
Updated to ensure that the 
number of PV patients is 
consistent with the analysis 
plan in Section 3.  The 
interim analysis was removed 
to avoid any potential issues 
in controlling the Type I error 
rate.   
1. Synopsis (Outcome 
Assessment Definitions),  
and 
3.2.1. Pemphigus Clinical 
Definitions (Consensus 
Guideline, Murrell 2018) 
Control of Disease Activity (CDA): 
Control of disease activity (disease control) is defined as the timevisit at which new lesions 
cease to form and established lesions begin to heal. This is also considered the beginning of 
the consolidation phase. The expected interval of time to reach the control of disease 
activity is on the order of weeks, although it may be shorter. 
Clarification that “time” 
when referenced with CDA 
refers to the visit the CDA 
was assessed at and achieved. 
1. Synopsis (Outcome 
Assessment Definitions),  
and 
3.2.1. Pemphigus Clinical 
Definitions (Consensus 
Guideline, Murrell 2018) 
End of Consolidation Phase (ECP): 
The end of the consolidation phase is defined as the timevisit at which no new lesions have 
developed for a minimum of 2 weeks and the majority (approximately 80%) of established 
lesions have healed. It is at this point that most clinicians begin to taper corticosteroid 
doses.Therefore, in order to achieve ECP, CDA must be confirmed at a visit ≥ 2 weeks 
later and 80% of the lesions seen previously must have healed. 
Clarification that “time” 
when referenced with ECP 
refers to the visit a minimum 
of 2 weeks after CDA was 
documented. Language 
regarding the ECP milestone. 
clarified for ease of 
understanding, as consistent 
with guidelines. 
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1. Synopsis (Study Design), 
and 
4.2 Study Design  
(Blinded Treatment Period - 
Weeks 1 to 37) 
After informed consent is obtained, patients with moderate to severe pemphigus (PV and 
PF) 
at Screeningwill be screened and if eligible will be randomized in a 1:1 allocation ratio to 
receive either PRN1008 400 mg twice daily (bid) (n ~ 60) or placebo bid (n ~ 60) during the 
Blinded Treatment Period (Week 1 to Week 37). 
 
At Screening, patients will begin to take Sponsor-provided CS according to the minimum 
dose requirements, shown in Table 1 above, and as required to adequately treat the disease. 
CS 
doses may be adjusted per Investigator discretion during the Screening period in the 
mandated range (CS and Rituximab Management, Appendix 1) but the dose should not be 
reduced below the required minimum initial dose levels (Table 1).  CS taper should 
not begin until ECP has been achieved. 
 
PRN1008 (400 mg tablet) or placebo will be taken twice daily by mouth starting on Day 1. 
Tablets may be taken with or without food. 
 
If a patient achieves CDA (no new lesions and established lesions begin to heal), a 
follow-up visit ≥ 2 weeks later must confirm the finding of no new lesions prior to 
declaring ECP and tapering CS. ECP is achieved with the confirmation of CDA (no 
new lesions for ≥ 2 weeks) with approximately 80% of the established lesions 
epithelialized (healed). If needed, confirmation of CDA and achievement of ECP may 
be documented at an Unscheduled Visit, prior to the next scheduled study visit. See 
Table 2 for all required assessments for an Unscheduled Visit, which also includes 
Efficacy Outcome Assessment and PDAI. 
 
While continuing on PRN1008 or placebo, commencing duringfollowing the period of 
achievement of CDA to approximately the ECP (CDA ECP), patients will undergo a 
moderately rapid CS taper regimen as recommended by recently published consensus 
guidelines (Consensus Guidelines, Murrell 2018) with the goal to reduce the CS dose to 
5 mg/day by no later than Study Week 29, with CS dose-adjustment as clinically indicated 
to control disease (CS and Rituximab Management protocol, Appendix 1). 
 
Clarified “at Screening” 
means the patients will be 
screened and that 
randomization would occur 
only if eligible. 
 
Updated text for consistency 
with Appendix 1, which 
specifies that only up-titration 
is allowed for CS during 
Screening.  
 
Added clarifying text 
regarding the use of 
Unscheduled Visits as 
allowed per protocol to 
document CDA and/or ECP.  
Minor changes were made to 
language throughout Sec 
3.3.1 to ensure clarity and for 
consistency with these 
clarifications. 
 
 
Updated to clarify CS 
tapering occurs after ECP 
confirmation. 
 
 
 
 
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CS taper should not begin until ECP has been achieved. 
 
If the first documentation of CDA coincides with no disease activity (PDAI=0), a 
follow-up visit ≥ 2 weeks later must still confirm that no new lesions are seen and 
PDAI=0. At this time the patient is deemed to have confirmed CDA, ECP, and CR and 
therefore CS tapering can begin. If new lesion(s) are seen, the patient is no longer in 
CDA and therefore CS tapering should not begin. If a patient has not achieved CDA 
or new lesions emerge or existing lesions worsen but do not meet definition of relapse, 
refer to Appendix 1 regarding increasing steroid dosage. 
 
Once patients achieve CR on a dose of 5 mg/day of CS, that dose should be maintained (not 
tapered further) until Study Week 37 (time of primary endpoint). 
 
Throughout the Blinded Treatment Period, patients who fail to respond to treatment or 
experience a worsening of disease should have their CS dose increased per CS Management 
Guidelines (Appendix 1) until CDA-ECP is obtained and tapering of CS can (re)commence. 
If ECP is not achieved in a timely manner, it is encouraged that CS dose be further 
increased unless clinically contraindicated. The PI should consult with the Medical 
Monitor in such cases. 
 
Efficacy Outcome Assessment should be performed per the Efficacy Outcome 
Assessment 
Flowchart, Appendix 9. 
 
Once patients achieve CR on a dose of 5 mg/day of CS, that dose should be maintained 
(not tapered further) until Study Week 37 (time of primary endpoint). 
 
Rituximab treatment may be administered during the Blinded Treatment Period at or after 
the 
Week 5 visit, unless contraindicated,only after a second or subsequent, clinically significant 
“qualifying relapse” occurs, unless contraindicated (Appendix 1). 
 
If rituximab is administered, patients should remain on trial and blinded to treatment 
 
Added context for CDA, ECP 
and CR. 
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assignment, but will be considered treatment failures for all efficacy endpoints except for 
cumulative CS and composite Glucocorticoid Toxicity Index (GTI) score. After completing 
the Blinded Treatment Period, patients will enter the Open-Label Extension Period to 
receive active treatment with PRN1008 described below. A patient in the Blinded 
Treatment Period requiring an additional “top up” dose of rituximab after their initial 
rituximab dose shouldcourse of treatment must be discontinued from the trial. 
1. Synopsis (Study Design),  
and 
4.3 Study Design  
(Open Label Extension 
Period - Weeks 37 to 61) 
From Week 37, all patients will receive active drug in the Open-Label Extension Period. 
Patients who received placebo will thus receive active treatment with PRN1008 400 mg bid. 
Patients requiring treatment by rituximab or other immunosuppressants (other than CS) for 
relapse during this period, willmust be discontinued from the study. 
 
From Week 37 (time of primary endpoint), further tapering to 0 mg CS should be attempted 
in patients with CR unless medically contraindicated. Patients who fail to respond to 
treatment or experience worsening of disease should have their CS dose increased per CS 
management guidelines (Appendix 1) until control of disease is obtained and tapering of CS 
can (re)commence. CDA is obtained. If ECP is not achieved in a timely manner, it is 
encouraged that CS dose be further increased unless clinically contraindicated. The PI 
should consult with the Medical Monitor is such cases.  
Updated to clarify CS dosing 
and adjustment. 
1. Synopsis (Corticosteroid 
Management),  
6.1.2.1 Corticosteroid 
Starting Doses and 
Management during 
Screening and at Day 1,  
and   
Appendix 1 
CORTICOSTEROID AND 
RITUXIMAB 
MANAGEMENT 
Corticosteroid Starting Doses and Management during Screening and at Day 1 
Required, initial doses of CS for the duration of Screening are ≥ 0.2 mg/kg/day of CS for 
patients with relapsing disease (diagnosed > 6 months prior to Screening) and 
≥ 0.5 mg/kg/day for patients with newly diagnosed disease (diagnosed ≤ 6 months prior to 
Screening). At Screening, patients will begin to take Sponsor-provided CS according to the 
minimum dose requirements, and as required to adequately treat the disease during the 
Screening period. CS doses may be adjusted upward per Investigator discretion during the 
Screening period (Appendix 1) but the dose should not be reduced below the initial 
required minimum initial dose levels (Table 1). CS taper should not begin until ECP 
has been achieved.  
Clarified that tapering can 
begin during Screening if 
ECP is achieved. 
1. Synopsis (Corticosteroid 
Management),  
Corticosteroid-Tapering (Consensus Guideline, Murrell 2018) 
Clarified tapering to zero 
after Week 37 should occur 
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6.1.2.2 Corticosteroid 
Management during 
Treatment Period and Open-
Label Extension Period, 
Appendix 1 
CORTICOSTEROID AND 
RITUXIMAB 
MANAGEMENT, 
Figure 1 Study Design Flow 
Chart, 
and 
2.6 Trial Design Rationale 
CS will be tapered from CDA ECP towards a goal of 5 mg/day by ≤ Week 29. Once the 5 
mg level is achieved it will be kept at 5 mg/day until the time of the primary endpoint at 
Week 37 is reached. After that, taper towards 0 mg should commence as clinically 
indicated.From Week 37, further tapering to 0 mg CS should be attempted in patients 
with CR unless medically 
contraindicated. 
 
CS tapering should follow the modified dosing guidelines below (Murrell 2018). 
Adjustment 
of the taperingdosing guideline protocol by investigators is permitted for safety reasons, 
based 
on assessment and documentation of clinical need. 
 
• Start tapering CS as soon as CDA is reached or up to the ECP is confirmed. 
• Decrease CS by 25% every two weeks, until ~20 mg per day 
• Once at ~20 mg per day, decrease CS by ~2.5 mg per week 
• Once at ~10 mg/day, decrease CS by 1 mg per week 
 
Note, because 1 mg will be the smallest CS dosage provided and tablet splitting is not 
allowed, 
the Investigator must round up or down to the nearest whole milligram for CS dose after 
calculation of the new dose level. 
 
Corticosteroid-Up-Titration (Harman 2017) 
CS up titration is allowed if disease significantly worsens prior to initial CDA ECP or after 
CDA ECP, during CS taper. Up titration should be a temporary increase until CDA ECP is 
achieved (again), after which tapering can recommence. 
 
Patients who fail to respond to treatment or experience a worsening of disease should 
have their CS dose increased per CS Management Guidelines (Appendix 1) until CDA 
is obtained. If ECP is not achieved in a timely manner, it is encouraged that CS dose 
be further increased unless clinically contraindicated. The PI should consult with the 
Medical Monitor in such cases. 
unless medically 
contraindicated. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Text replaced with updated 
language to clarify CS up-
titration should occur if 
patients fail to respond or 
experience worsening of 
disease.   
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For full details of up-titration see Appendix 1. 
1. Synopsis (Concomitant 
Medications), 
and  
6.5.2 Particular Permissible 
Medications 
Strong to Moderate Inducers or Inhibitors of cytochrome P450 (CYP)3A, and “Sensitive” 
CYP3A Substrate Drugs with a narrow therapeutic index are not permitted (Appendix 8). 
Other “Sensitive” CYP3A drugs should be used cautiously by administering them only if 
the benefit-risk is favorable, using staggered administration at least 2 hours after PRN1008 
or placebo. 
 
Patients on proton pump inhibitor drugs should have their medication changed to histamine 
2 (H2) blockers during Screening and at least 3 days before Day 1. H2 blockers should be 
administered at least 2 hours after PRN1008 or placebo. 
 
Warfarin should be monitored carefully as there is limited experience of co administration 
with PRN1008. To date, two patients on chronic anticoagulation (rivaroxaban) have been 
treated without bleeding complications. 
Warfarin statement removed 
due to the potential of 
CYP3A inhibition (see 
Section 6.5.1 and Appendix 
8).  
1, Synopsis (Inclusion 
Criteria #1),  
5.1 Inclusion Criteria #1, 
and  
7.7.3 Biopsies 
7.7.3.  Biopsies 
A new biopsy (cutaneous and/or mucosal) is not required if there is a prior and available 
biopsy report documenting histopathologic findings diagnostic for PV or PF. A new biopsy 
should be performed if an archival biopsy report is not available. 
New biopsies should include local hematoxylin and eosin (H&E) histopathological review 
and direct immunofluorescence (DIF) for the characteristic pattern diagnostic of pemphigus 
(Note: anti desmoglein antibodies may be used as an alternative confirmation if DIF is 
negative and histopathology is characteristic of pemphigus).   
Histopathology on biopsies is evaluated for consistency with a diagnosis of PV or PF: 
• 
If DIF is positive, the patient is eligible in the presence of positive anti-
desmoglein antibodies. 
• 
If DIF is negative, the patient is not eligible. In these cases, where the H&E 
histopathology is characteristic of pemphigus and anti-desmoglein antibodies 
are positive, the biopsy may be repeated at the discretion of the investigator. 
Biopsy requirements to 
ensure pemphigus diagnosis 
for eligibility were clarified.  
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• 
If DIF is not available, the patient is eligible in the presence of positive anti-
desmoglein antibodies and H&E histopathology characteristic of pemphigus.  
1. Synopsis (Inclusion 
Criteria #4),  
and 
5.1 Inclusion Criteria #4 
 
Body mass index (BMI) > 17.5 (only applicable through Protocol v3.2) 
The setting of BMI > 17.5 
was based on early pre-
clinical findings of weight 
loss in the 4-13-week repeat 
dose GLP toxicity study in 
dogs (see IB Version 10 
dated 17May2019, Sections 
4.2.3.1 and 4.5.2.2). In the 
absence of human data at the 
time of the first clinical study 
in pemphigus patients 
(PRN1008-005), BMI 
restriction was used to 
exclude patients with low 
body weight. As there were 
no changes in weight or 
appetite in the Phase 2 study, 
PRN1008-005, the BMI 
criteria has now been 
removed in this protocol. 
1. Synopsis (Exclusion 
Criteria #17), 
and 
5.2. Exclusion Criteria #17 
Positive interferon-gamma release assay (IGRA) (eg, T-spot TB Test, 
QuantiFERON®-TB Gold, or T spot TB® Test)QuantiFERON®-TB Gold Plus (QFT 
Plus), at Screening. Unless, the patient has latent TB and all of the following 3 
conditions are true: 
a) Chest X-ray does not show evidence suggestive of active tuberculosis (TB) disease 
b) There are no clinical signs and symptoms of pulmonary and/or extra-pulmonary TB 
disease 
c) Documented receipt of a courseone of the following prophylactic TB treatment of 
at least regimens: 
Clarification of the options 
for TB testing and conditions 
to reduce the number of false 
positive and indeterminate 
test results, and to enable 
accurate results in patients 
who have received the BCG 
vaccine. 
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i. Oral daily Isoniazid for 6 months 
 
 
 
or 
 
ii. Oral daily Rifampin (RIF) for 4 months 
 
 
 
or 
 
iii. Isoniazid and Rifapentine weekly for 3 months (3HP) 
On a case by case basis, after discussion and approval by the Sponsor, a local TB test 
that is negative and is considered equivalent to 1 of the above tests may be used for 
eligibility. For example, if a QuantiFERON®-TB Gold, or QuantiFERON-TB Gold 
Plus (QFT Plus) is positive and a local blood test or T-Spot TB test is negative, the 
patient may be enrolled using the local result upon approval of the Sponsor. 
1. Synopsis (Exclusion 
Criteria #18), 
and 
5.2. Exclusion Criteria #18 
History of serious infections requiring intravenous therapy with the potential for recurrence 
or currently active moderate to severe infection at Screening (Grade 2 or higher). 
Clarification to ensure that 
patients with moderate to 
severe active infection are not 
enrolled.  
1. Synopsis (Exclusion 
Criteria #20 & 21),  
and  
5.2 Exclusion Criteria #20  
Any other clinically significant disease, condition, or medical history that, in the opinion of 
the Investigator, would interfere with patient safety, trial evaluations, and/or trial 
procedures. In areas endemic for Chagas disease, screening is recommended prior to 
enrollment. 
 
Provided recommendation for 
areas where Chagas may be 
endemic to screen and rule 
out the disease prior to 
enrolling.  
5.2 Exclusion Criteria #21 
Patients who have a known contraindication to Sponsor-provided corticosteroid and/or 
inability to follow corticosteroid dosing as outlined in the protocol (see Table 1 for 
more details) or with a known sensitivity to PRN1008 or its excipients 
Clarification to ensure that 
patients that are unable (for 
reasons other than 
contraindication) to take the 
required corticosteroid doses 
are not enrolled. 
Table 2 Schedule of 
Assessments 
Footnote f: To confirm postmenopausal status for women who are not surgically sterile 
only. 
To be drawn only in women with amenorrhea > 12 months who require confirmation 
of menopause (refer to protocol Section 5).  
Clarified to reduce 
unnecessary FSH/pregnancy 
testing for women with 
confirmed menopause. 
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Table 3 Schedule of 
Assessments 
Week 39 ± 3 5 days  
 
The Week 39 visit window 
was revised for consistency, 
to match the Week 3 double-
blind Visit.   
2.4 Clinical Experience 
In clinical studies to date, PRN1008 has been administered to 140more than 200 people, 
including healthy volunteers, 27 and patients with pemphigus (mainly pemphigus vulgaris 
variant, i.e. PV) and 4and Idiopathic thrombocytopenia. Twenty-seven patients with 
immune 
thrombocytopenic purpura (ITP). Patients with PV in a Phase 2 study (NCT02704429) used 
a starting dose of 400 mg BID which was shown to produce adequate BTK occupancies in 
all but one patient. One patient dose escalated to 500 mg BID and onetwo to 600mg BID, 
with all other patients using the 400mg BID dose. An interim analysis of the first 27 
patients in this study found evidence of clinically significant activity in 80% of patients, 
with onset of disease control in the first 2 weeks of therapy, and an acceptable safety profile 
(DSUR 2018 and IB Section 5). The primary endpoint of the study, “control of disease 
activity by the Week 5 visit on ≤ 0.5mg/kg/day of prednisone (or equivalent CS)” was met 
by 54% (14/26) of patients. Complete remission on ≤ 0.5mg/kg/day of CS was achieved by 
25% (5/20) of patients completing 12 weeks treatment. 
Additional clinical data 
provided in alignment with 
current IB V10 dated 
17May2019. 
6.5.1 Prohibited Medications 
The following medications are prohibited for use during the trial: 
• 
Concomitant use of any immunosuppressant medication, other than CS and 
rituximab as described in this protocol. Patients who need other immunosuppressant 
therapy during the trial should be withdrawn. See Exclusion # 6 Section 3.7 for 
washout periods. 
• 
Concomitant use of known strong to moderate inducers or inhibitors of cytochrome 
P450 (CYP) 3A (Appendix 8) within 3 days or 5 half-lives (whichever is longer) of 
Day 
• 
Use of CYP3A-sensitive substrate drugs with a narrow therapeutic index (within 3 
days or 5 half-lives (whichever is longer) of Day 1 including, but not limited to, 
alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, sirolimus, tacrolimus, (topical and oral), or 
terfenadine. 
Washout period for warfarin 
use and intralesional steroid 
use were added.  
 
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• 
Proton pump inhibitors are not permitted. Esomeprazole was shown to reduce the 
exposure of PRN1008 by approximately 50%, presumably due to the effects of a 
lack of an acidic environment on tablet dissolution. Subjects who are on proton 
pump inhibitors should be changed to histamine (H2) receptor blocking drugs if 
possible or not enroll in the trial. Details of H2 receptor blocker administration is 
provided in Section 5.9.2. 
• 
Intralesional steroids are not permitted within 3 months of Screening, during 
Screening and for the duration of the study. 
• 
Warfarin use is not permitted within 1 week or 5 half-lives (whichever is 
longer) of Day 1 and for the duration of the study. 
6.2.1 Preparation and 
Administration 
 
Treatment medication will be taken twice daily by mouth starting on Day 1. PRN1008 or 
placebo may be taken with or without food. Consecutive PRN1008/placebo doses should 
not be taken within 8 hours of each other. Tablets should not be broken or crushed. 
Further details for dispensation and administration of blinded treatment are provided in the 
Pharmacy Manual. 
Added the allowed dose 
interval. 
7.6.1 Screening  
(Day -29 to Day -1), 
and 
Table 2 Schedule of 
Assessments 
7.6.1. Screening (Day -29 to Day -1) 
Informed consent will be obtained at Screening before performing any trial procedures. 
Patients will undergo Screening assessments, including, but not limited to; blood sampling, 
ECG, clinical assessment and various quality of life assessments. Please refer to Table 2. 
In cases where laboratory assessments are delayed due to logistic considerations, the 
Sponsor may permit an extension of the Screening Period for laboratory assessments 
up to 7 days in order to determine eligibility. Week 1 Day 1 should occur as soon as 
possible upon evaluation of the delayed assessments and no later than 35 days after the 
initial Screening visit. 
Added a provision for 
Screening window extension 
by ≤7 days in the case where 
laboratory assessments are 
delayed for a logistical 
reason, after discussion with 
Sponsor. 
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7.6.3 Blinded Period  
(Weeks 1 to 37), 
and 
Appendix 9 EFFICACY 
OUTCOME ASSESSMENT 
FLOWCHART  
Please refer to Table 2 for specific assessments at each visit. CS dosing, and use of 
rituximab for a second qualifying relapse, are detailed in Appendix 1. The Efficacy 
Outcome Assessment Flowchart is detailed in Appendix 9. 
Added Appendix 9 flow chart 
to assist Investigator with 
Efficacy Outcome 
Assessment.  
Appendix 1 
CORTICOSTEROID AND 
RITUXIMAB 
MANAGEMENT 
2. Non life-theatening worsening of disease during taper of CS prior to initial CDA 
confirmation of ECP 
During Screening or the treatment periods of the trial, where an initial induction of CDA 
has not been achieved and blistering continues without improvement, CS should be 
increased by 50 to 100% every 5 to 7 days until CDA-confirmation of ECP.  After ECP is 
achieved, and confirmed CS taper can should commence. Rituximab therapy may not be 
used in this situation.  Patients who have been treated with a minimum of 1.5mg/kg/day 
of corticosteroids for 2 weeks and have not achieved control of disease activity may be 
eligible after discussion with Principia to receive rituximab.   
Added to clarify that Sponsor 
may provide rituximab (if 
approved as rescue 
medication, by the relevant 
Competent Authority and 
Ethics Committees) in cases 
where disease control is 
never reached, despite 
adequate treatment with CS, 
upon discussion with 
Sponsor. 
Appendix 1 
CORTICOSTEROID AND 
RITUXIMAB 
MANAGEMENT 
Rituximab Management during Blinded Treatment Period 
 
Rituximab for second “qualifying relapse”: 
• 
“Qualifying relapse” for this purpose is defined as a relapse occurring after CDA
ECP is achieved, ECP has been confirmed and CS taper has begun, that is not life-
threatening (when a patient should be withdrawn) but is severe enough such that the 
PDAI total activity score is equal to or greater than the Screening or Day 1 baseline 
PDAI score (whichever is higher) for that patient. For example, if the Screening 
PDAI was 25, the Day 1 baseline was 21, and the relapse PDAI 23, the relapse 
would not be severe enough to be “qualifying”. Whereas if the relapse PDAI was ≥ 
25 it would be “qualifying”. 
• 
Where a second qualifying relapse occurs meeting the above definition, and it is at 
or after the Week 5 visit, then one course of rituximab, which consists of two 
Updated to match the same 
discontinuation instruction 
from Section 4.2. 
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intravenous doses of 1 gram two weeks apart, may be administered, unless 
contraindicated. 
• 
Oral CS doses should be managed as indicated for the patient at the time of the 2nd 
qualifying relapse 
• 
Rituximab should be administered as recommended in the Pharmacy Manual. 
• 
Patients should not be unblinded to treatment assignment and should continue in the 
trial. 
• 
The need for rituximab rescue will be considered “treatment failure” for the 
analysis of all efficacy endpoints except cumulative CS and composite GTI score. 
 
Rituximab Management during Open-Label Extension Period 
• 
Patients requiring treatment by rituximab or other immunosuppressants 
(other than CS) for relapse during this period, will be discontinued from the 
study. 
 
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12.13.8 
Clinical Study Protocol Version 4.1 for US (04 December 2019)  
This was a local amendment to protocol Version 4 and was regarded as a nonsubstantial 
amendment. 
Overall Rationale for the Amendment  
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Protocol Amendment summary of changes Table 
PRN1008-012 Protocol V4.1 (4 December 2019) 
The protocol Version 4.1, 4 December 2019 has been updated throughout as shown in the following Table. Deleted text has strikethrough and new 
text is bolded. 
Section(s) 
Amended or New Wording 
Justification of Change 
Throughout the protocol 
29 Aug 2019, 4 Dec 2019, Version 4.0 4.1  
Administrative change. 
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12.13.9 
Clinical Study Protocol Version 5 (22 January 2020)  
This was a global amendment to protocol Version 4 and was regarded as a substantial amendment. 
Overall Rationale for the Amendment  
The primary reasons for this amendment to Protocol PRN1008-012, Version 5 are: 
• 
To update molecule name to rilzabrutinib, 
• 
To add LTE Period and eligibility criteria, 
• 
To add study design flow chart, 
• 
To clarify dosing requirements for patients on rituximab, 
• 
To clarify text related to a second infusion of rituximab during OLE period that would not 
lead to discontinuation, 
• 
To add TBNK at Week 37, 
• 
To allow hydrocortisone for tapering at 5 mg, 
• 
To clarify that patients intolerant to CS dose can receive rituximab, 
• 
To remove the inclusion criterion #4 and renumber inclusion/exclusion criteria, 
• 
To allow patients previously vaccinated against hepatitis B, 
• 
 
• 
To update SoA visit windows and footnotes, 
• 
To clarify that LTE patient will not receive sponsor provided CS, 
• 
To add assessments to Week 61, 
• 
To clarify an extended screening window of 7 business days, 
• 
To clarify that previous labs are allowed for rescreen patients, 
• 
To update allowed concomitant medications, 
• 
To clarify ITT and mITT, 
• 
To update efficacy outcome flowchart. 
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Protocol Amendment summary of changes Table 
PRN1008-012 Protocol V5.0 (22 January 2020) 
The protocol Version 5.0, 22 January 2020 has been updated throughout to correct errors and to clarify or adjust study procedures and 
assessments. Deleted text has strikethrough and new text is bolded. 
Section(s) 
Amended or New Wording 
Justification of Change 
Throughout the protocol 
29 Aug 2019 22 Jan 2020, Version 45.0 
Administrative change. 
Throughout the protocol 
PRN1008 (Rilzabrutinib) 
Recommended name by the 
World Health Organization 
(WHO) International 
Nonproprietary Names (INN) 
Committee. 
2.6 Study Population, 
And 
9.1 Determination of 
Sample Size 
Section 2.6: Approximately 120 male or female patients with newly diagnosed or relapsing 
moderate to severe pemphigus (pemphigus vulgaris [PV] or pemphigus foliaceus [PF]) will be 
enrolled with a targeted minimum of 4590 patients with PV per group and a target maximum 
of 1022 patients with PF per group. 
 
Section 9.1: …Assuming a response is achieved in 50% of ITT patients treated with PRN1008 
versus 15% in placebo treated patients, then, a sample size of ≥ 55 patients (there is a targeted 
minimum of 45 PV patients and a maximum of 10 PF patients in each treatment group) results 
in > 90% power at a 0.05 significance level using a 2-sided Pearson chi-square test for the 
analysis of PV disease type alone and PV and PF combined. Up to a total of approximately 
120 patients may be enrolled, with a targeted cap of 3022 PF patients. 
 
The targeted minimum number 
of enrolled PV patients was 
updated from a per group total 
(45) to a per study total (90) to 
ensure the number of PV 
patients in each group are 
reasonably balanced (placebo 
and active) using the block 
randomization schedule in this 
study, without requiring 
Sponsor unblinding. 
The text, “maximum of 10 PF 
patients in each treatment 
group” changed to “maximum 
of 22 PF patients” to ensure the 
number of PF patients in each 
group are reasonably balanced 
(placebo and active) using the 
block randomization schedule 
in this study, without requiring 
Sponsor unblinding. 
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2.7 Duration of Trial 
Participation 
Long Term Extension Period 
Study duration for the patients who enter the Long Term Extension Period will be 
determined by the criteria described in the Study Design Section 3.3.1 of the Study 
Synopsis.  
After completing the Open-Label Extension Period, eligible patients may continue in the 
Long Term Extension Period of 48 weeks. Patients will continue to have a 4 week follow-
up visit after the patient’s last dose of PRN1008 as detailed in the Follow-Up Period and a 
Follow up Period of 4 weeks. section below.  
Long Term Extension (LTE) Period (Week 61 to Week 109):  
After completing the Open-Label Extension Period, patients who are responding to 
PRN1008 treatment will be eligible to enter the Long Term Extension Period and will 
continue to receive open-label PRN1008 400 mg bid for 48 weeks per Table 4: Schedule of 
Assessments Long Term Extension Period.  
Patients are eligible to participate in the LTE if:  
a) they have achieved and/or maintained an ECP with ≤ 10 mg/day CS at any time 
between 37 and 61 weeks in the study.  
Patients are not eligible to participate in the LTE if:  
a) they have more than one relapse following ECP requiring treatment with > 10 mg/day 
CS (excluding CS taken short-term for dental work or surgery) or  
b) have failed to adequately recover after a relapse despite maximal tolerated CS dose.  
Failure to adequately recover is defined as: <25% decrease from peak PDAI despite 
treatment with maximal steroid doses (minimum of 1.5mg/kg/d unless there is a specific 
documented medical contraindication) for at least 2 weeks.  
CS doses above refer to doses of prednisone or its equivalent.  
Patients may continue in the LTE until:  
13.9.1.1 they have had more than one relapse following ECP that requires > 10 mg/day CS 
(excluding CS taken short-term for dental work or surgery) or have failed to adequately 
recover after a relapse despite maximal tolerated CS dose (per definition of failure to 
adequately recover above);  
The primary purpose of the 48-
week, Long Term Extension 
Period (LTE) is to provide 
extended access to PRN1008 for 
patients who are receiving 
clinical benefit and to accrue 
additional long term data on the 
safety of PRN1008. 
 
Patients will be eligible for the 
LTE if they show adequate 
response to PRN1008 during the 
Open Label Period ie, achieve 
or maintain ECP (at least 
80% healing of lesions and no 
new lesions for at least 2 weeks) 
while on a low CS dose 
(≤ 10 mg/day prednisone or 
equivalent) as defined in the 
pemphigus treatment guidelines. 
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b) the drug is no longer being developed by the Sponsor for this indication;  
c) the program is stopped for safety reasons.  
Patients who have previously completed the Open-Label Extension Period prior to this  
amendment and were responders per the LTE requirement may enroll into the LTE.  
Beginning at Week 61, patients entering the LTE will no longer receive Sponsor-provided 
CS, but can receive site-provided CS per required standard of care. From Week 61, 
following CS Management Guidelines (Appendix 1) is recommended.  
Patients requiring rituximab during the Long Term Extension Period will be 
discontinued from the trial.  
Follow-up Period (4 Weeks 61 to 65after last Trial Visit):  
End of Trial for the overall clinical trial is defined as the point at which the last patient has  
completed the last visit of the study.  
End of Trial for each patientFor patients eligible for the Long Term Extension, the End of 
Trial is defined as the point at which the patient has completed their Week 113 visit (4 
weeks after the patient’s last dose of PRN1008).  
For patients that are not eligible for the Long Term Extension, the End of Trial is defined 
as the point at which the patient has completed their Week 65 visit (4 weeks after the patient’s 
last dose of PRN1008).  
Patients who are not able to complete the Open-Label Extension Period or Long Term  
Extension Period (for patients who qualify) as planned Week 65 visit and discontinue the 
study early should be encouraged to come back for their last visit, and this will be recorded as 
the End of Trial (EOT) visit. Patients that discontinue early will have the ETEarly 
Termination (ET) assessments completed as outlined in the Schedule of Assessments based 
upon from which phase treatment they are terminating, Table 2 (Blinded Treatment Period) 
and), Table 3 (Open-Label Extension Period), or Table 4 (Long Term Extension Period). 
 
 
Study PRN1008-012 is a randomized, parallel-group, double-blind, placebo-controlled trial 
over 36 weeks (Blinded Treatment Period) followed by an Open-Label Extension Period of 24 
weeks, Long Term Extension Period of 48 weeks, and a follow-up period of 4 weeks, which 
 
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Table 3 Schedule of 
Assessments - Open Label 
Extension Period 
is intended to evaluate the efficacy and safety of oral PRN1008 (Rilzabrutinib) in moderate to 
severe pemphigus.  
…The primary purpose of the 24-week, Open-Label Extension Period is(OLE) is to allow 
access to study drug who were on placebo medication as well as to evaluate durability of 
clinical response and accrue additional long term data on the safety of PRN1008.  
The primary purpose of the 48-week, Long Term Extension Period (LTE) is to provide 
extended access to PRN1008 for patients who are receiving clinical benefit and to accrue 
additional long term data on the safety of PRN1008.  
Footnote l: If patient is eligible for the Long Term Extension Period at Week 61 they will 
continue to receive PRN1008 per Table 4: Schedule of Assessments Long Term Extension 
Period. If the patient is not eligible for the Long Term Extension Period at Week 61 they 
will discontinue PRN1008 and complete the EOT visit at Week 65. 
Table 4 Schedule of 
Assessments - Long Term 
Extension Period 
 
 
 
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Figure 1: Study Design 
Flow Chart 
 
3.3.1 Study Design 
If rituximab is administered, patients should continue to take 
PRN1008/placebo, remain on trial and blinded to treatment 
assignment, but will be considered treatment failures for all efficacy 
endpoints except for cumulative CS dosing and composite 
Glucocorticoid Toxicity Index (GTI) score. After completing the 
Blinded Treatment Period, patients will enter the Open-Label 
Updated to clarify that patients 
who receive rituximab should 
continue to take 
PRN1008/placebo and remain 
on trial unless they meet a 
discontinuation criterion. 
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Extension Period to receive active treatment with PRN1008 described 
below. A patient in the Blinded Treatment Period requiring an 
additional “top up” dose of rituximab after their initial rituximab 
course of treatment must be discontinued from the trial.  
3.3.1 Study Design, And 
 
 
 
 
 
 
Table 3 Schedule of 
Assessments 
Open-Label Extension Period (Weeks 37 to 61): 
From Week 37, all patients will receive active drug in the Open-Label Extension Period for 24 
weeks per Table 3: Schedule of Assessments Open-Label Extension Period. Patients who 
received placebo will thus receive active treatment with PRN1008 400 mg bid. Patients 
requiring treatment by rituximab or other immunosuppressants (other than CS) for relapse 
during this period, must be discontinued from the study. If a patient has a qualifying relapse 
during the Blinded Treatment Period and the second infusion from the rituximab course 
of treatment occurs during the Open-Label Extension period, the patient may continue in 
the trial. Patients that received rituximab during the Blinded Treatment Period and are 
continuing in the study, will complete TBNK testing (T and B and Natural Killer 
Lymphocyte Panel) at their Week 37 visit. 
 
Footnote m: Patients that received rituximab during the Blinded Treatment Period and 
are continuing in the study, TBNK panel will be drawn at their Week 37 visit. 
Updated to clarify that if a 
patient has a qualifying relapse 
during the Blinded Treatment 
Period and the second infusion 
from the rituximab course of 
treatment occurs during the 
Open-Label Extension period, 
the patient may continue in the 
trial. 
 
 
 
 
TBNK Pantel is an assessment 
of T, B, and Natural Killer cell 
counts in patients who received 
rituximab rescue. This will 
establish a baseline prior to 
open-label PRN1008 treatment 
to assist in better understanding 
the action of PRN1008 in 
patients already treated with 
rituximab. 
Appendix 1 Corticosteroid 
and Rituximab 
Management 
Corticosteroid Management during Blinded Treatment Period and, Open- Label Extension 
Period, and Long Term Extension Period 
CS will be tapered from ECP towards a goal of 5 mg/day by ≤ Week 29. Once the 5 mg level is 
achieved it will be kept at 5 mg/day until the time of the primary endpoint at Week 37 is 
reached. From Week 37, further tapering to 0 mg CS should be attempted in patients with CR 
unless medically contraindicated. At Investigator discretion, the CS may be switched to 
Hydrocortisone, a short acting 
steroid, is often used as the 
preparation of choice for 
graduated tapering off of 
steroids in patients with a 
history of chronic use and 
potential dependence. Since 
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equivalent doses of oral hydrocortisone instead of prednisone or prednisolone when 
tapering from 5 mg to 0 mg CS. 
During Screening or the treatment periods of the trial, where an initial induction of CDA has not 
been achieved and blistering continues without improvement, CS should be increased by 50 to 
100% every 5 to 7 days until confirmation of ECP. After ECP is confirmed CS taper should 
commence. Rituximab therapy may not be used in this situation. Patients who have been treated 
with a minimum of 1.5 mg/kg/day of corticosteroids for 2 weeks and have not achieved control 
of disease activity may be eligible after discussion with Principia to receive rituximab. For 
patients that have a documented and specific medical contraindication, the maximally 
tolerated dose of corticosteroid may be considered for this purpose following consultation 
with the medical monitor. 
It is recommended to follow the CS Guidelines during the Long Term Extension. 
this may be standard of care in 
some places, replacement of 
prednisone/prednisolone with 
equivalent doses of oral 
hydrocortisone will be 
permitted to taper off from 5mg 
of prednisone. 
 
 
Updated to clarify that patients 
who are intolerant to high doses 
of corticosteroid may be eligible 
for rescue medication 
3.6 Inclusion Criteria 
4. Body mass index (BMI) > 17.5 (only applicable through Protocol v3.0) 
Removed as this criterion was 
only applicable through 
Protocol v3.0. 
3.7 Exclusion Criteria 
Positive at Screening for human immunodeficiency virus (HIV), hepatitis B (surface antigen 
and core antibodies unrelated to vaccination, surface antigen), or hepatitis C (anti-HCV 
antibody confirmed with Hep C RNA) 
Clarified language on Hepatitis 
B positive patients to ensure 
that vaccinated patients can be 
included and patients with prior 
exposure to Hepatitis B are 
excluded from the study. 
3.7 Exclusion Criteria #16 
On a case by case basis, after discussion and approval by the Sponsor, a local TB test hat is 
negative and is considered equivalent to 1 of the above tests may be used for eligibility. For 
example, if a QuantiFERON®-TB Gold, or QuantiFERON-TB Gold Plus (QFT Plus) is 
positiveindeterminate for any reason and a local blood test or TSpot TB test is negative, the 
patient may be enrolled using the local result upon approval of the Sponsor. 
Clarified that a positive central 
lab test for TB will satisfy the 
exclusion criteria. Local lab 
results may be used when 
central lab is indeterminate for 
any reason. 
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Table 2 Schedule of 
Assessments 
Footnote e: PT/INR, thrombin time, aPTT, and fibrinogen level and will be collected at 
Screening, Day 1 Week 1 Pre-dose, and Weeks 3, 5, 9, 1713, 25, & 37. 
Footnote correction to match 
assessments listed in Table 2. 
Table 3 Schedule of 
Assessments 
Week 37 Visit Window: ± 53 days 
Clarified for consistency 
through protocol. 
Table 3 Schedule of 
Assessments 
Week 39 ± 3 days / Drug reconciliation (PRN1008 /CS Dosing Documentation): X 
Clarified to match Week 3 and 
the other follow-up study visits. 
Table 3 Schedule of 
Assessments 
Footnote c: PT/INR, thrombin time, aPTT, and fibrinogen level and will be collected at Weeks 
39, 49, 61, ET, and EOT (if applicable)... 
Footnote correction to match 
assessments listed in Table 3. 
Table 3 Schedule of 
Assessments 
Footnote i: Beginning at Week 61, 
patients entering the LTE will no longer 
receive Sponsor-provided CS, but can 
receive site-provided CS per required 
standard of care. From Week 61, 
following CS Management Guidelines 
(Appendix 1) is recommended.  
Clarified that during the LTE 
patients will no longer receive 
Sponsor-provided CS, but can 
receive site-provided CS per 
standard of care. 
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Oral corticosteroids (prednisone or 
prednisolone) will be provided during the 
Blinded Treatment Period and Open-
Label Extension Period. Beginning at 
Week 61, patients entering the LTE will 
no longer receive Sponsor-provided CS, 
but can receive site-provided CS per 
required standard of care.  
Table 3 Schedule of 
Assessments 
Week 61 ± 5 days / 12-lead ECG: X  
Week 61 ± 5 days / Urinalysis: X  
Week 61 ± 5 days / HbA1c and LDL (fasting): X  
Week 61 ± 5 days / GTI Index: X  
Week 61 ± 5 days / PRN1008 dispensed: X  
 
Week 61 is the end of the 
primary study and the last visit 
for patients not rolling over to 
the LTE. These tests are 
performed to document end of 
study safety. 
Table 3 Schedule of 
Assessments 
 
 
 
 
 
 
7.6.1 Screening (Day -29 to 
Day -1) 
    Footnote n: As described in Section 7.6.1, 
laboratory assessments delayed due to 
logistic considerations may be performed 
with an extended Screening window (up 
to 7 additional business days), upon 
Sponsor review and approval. Patients 
may be re-screened once. Any labs 
completed in prior Screening, within 2 
weeks of re-screening will remain valid 
and should not be repeated. Labs 
performed for a previous screening 
within 6 weeks, may be considered for 
determination of eligibility on approval 
of the medical monitor. In the specific 
cases of QuantiFERON-TB, anti 
desmoglein antibodies and 
hepatitis/HIV testing, tests may be 
considered for determination of 
eligibility if performed in a previous 
Clarified that 7 days is 7 
business days to allow for 
adequate processing. 
 
Labs done for safety screening 
are likely to remain stable over 
short periods. The medical 
monitor will review for any 
change in the patient’s status 
that requires a repeat. 
Anti-dsg antibodies once 
confirmed during screening, 
should not need to be repeated 
in most cases. This will reduce 
burden on patient’s and avoid 
repeat assessments when not 
necessary. 
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screen within the last 12 weeks, with the 
approval of the medical monitor. 
However, pregnancy tests should be 
repeated at re-screening.  
 
In cases where laboratory assessments are 
delayed due to logistic considerations, the 
Sponsor may permit an extension of the 
Screening Period for laboratory 
assessments up to 7 business days in 
order to determine eligibility. Week 1 Day 
1 should occur as soon as possible upon 
evaluation of the delayed assessments and 
no later than 35 days after the initial 
Screening visit.  
Medical history and demographic data, 
including sex, age, race, body weight (kg), 
height (cm), and body mass index (BMI), 
will be recorded.  
Patients not already on the mandated CS 
doses for the commencement of the 
Screening Period will commence the 
protocol-mandated CS doses. 
Patients may be re-screened once following 
a Screen failure. Any labs performed in 
prior screening, within 2 weeks of re-
screening will remain valid and should 
not be repeated. Labs performed for a 
previous screening within 6 weeks, may 
be considered for determination of 
eligibility on approval of the medical 
monitor. In the specific cases of 
QuantiFERON-TB, anti desmoglein 
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antibodies and hepatitis/HIV testing, 
tests may be considered for 
determination of eligibility if performed 
in a previous screen within the last 12 
weeks, with the approval of the medical 
monitor. However, pregnancy tests 
should be repeated at re-screening. 
Please see Schedule of Assessments Table 
2. 
 
5.9.2 Particular Permissible 
Medications 
Histamine 2 (H2) receptor blocking drugs (ranitidine or famotidine) and antacids are 
permitted provided they can be given 2 hours or more after dosesadministration of PRN1008 
or placebo. 
Clarified that ranitidine and 
famotidine are preferred H2 
antagonists. When administered 
2 hours or more after 
PRN1008, their effects on PK 
of the study drug are minimal. 
6.3 Rituximab 
 
 
 
 
 
7.4.1 Patient 
Discontinuation and 
Stopping Rules 
Rituximab (or biosimilar) will be provided for patients having a second qualifying relapse 
(Appendix 1) during the Blinded Treatment Period. However, in the event a patient in the 
Blinded Treatment Period requires an additional “top up” dose of rituximab after their initial 
rituximab course of treatment, this will not be provided because the patient must be 
discontinued. Similarly, if a patient in the Open-Label Extension Period or Long Term 
Extension Period requires rituximab, the patient must be discontinued and rituximab will not 
be provided. If a patient has a qualifying relapse during the Blinded Treatment Period 
and the second infusion from the rituximab course of treatment occurs during the open 
label period, the patient may continue in the trial. 
 
Reasons for discontinuing a patient may include, but are not necessarily limited to, the 
following: 
• 
A patient in the Blinded Treatment Period requiring an additional “top up” dose of 
rituximab after their initial rituximab course of treatment or a patient in the Open-Label 
Extension Period or Long Term Extension Period requiring rituximab 
Updated to clarify that if a 
patient has a qualifying relapse 
during the Blinded Treatment 
Period and the second infusion 
from the rituximab course of 
treatment occurs during the 
Open-Label Extension period, 
the patient may continue in the 
trial. 
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7.6.5 Long Term Extension 
Period 
Appendix 1 
Please refer to Table 4 for specific assessments at each visit. CS dosing is detailed in 
Appendix 1. Rituximab therapy is not allowed during this period unless the patient is 
withdrawn from the trial. 
Rituximab Management during Open-Label Extension Period and Long Term Extension 
Period: Patients requiring treatment by rituximab or other immunosuppressants (other than 
CS) for relapse during this period, must be discontinued from the studythese study periods, 
must be discontinued from the study. If a patient has a qualifying relapse during the 
Blinded Treatment Period and the second infusion from the rituximab course of 
treatment occurs during the Open-Label Extension period the patient may continue in 
the trial. 
 
7.7.6 Electrocardiogram 
Monitoring 
Single 12-lead ECGs will be performed at Screening, Week 37, Week 61, and Week 37.109 
(for patients in the Long Term Extension). All ECGs will be performed with the patient in a 
supine position. 
Updated to match Schedule of 
Assessments and addition of 
LTE. 
9.4 Analysis Populations 
ThreeFour populations will be defined for 
data analysis: the Safety Population, the 
Intent-to- Treat Population, Modified 
Intent-to-Treat (mITT) (efficacy) 
Population, and the Pharmacokinetic 
Population. 
 
Safety Population:  
All patients who receive at least one dose 
of study medication will be included in the 
Safety Population. The Safety 
Population is the primary analysis 
population for safety. Patients will be 
analysed according to the treatment 
they actually received, not necessarily 
the treatment they were allocated to at 
randomization. Results will be presented 
“as treated.” 
Clarified distinction between 
Intent-to-Treat Population and 
Modified Intent-to-Treat 
population for statistical 
analysis. 
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Intent-to-Treat (ITT) Population:  
All patients who are randomized will be 
included in the ITT Population. The 
ITT Population will be used for 
sensitivity analyses. Patients will be 
analyzed according to the treatment 
they were allocated to at 
randomization; not necessarily the 
treatment they actually received. 
Results will be presented “as 
randomized.” 
 
Modified Intent-to-Treat (mITT) 
Population:  
All patients who are randomized and 
receive at least one dose of study 
medication will be  
included in the ITTmITT Population. The 
ITT populationmITT Population is the 
primary analysis population for 
efficacy. Patients will be analyzed 
according to the treatment they were 
allocated to at randomization; not 
necessarily the treatment they actually 
received. Results will be presented “as 
randomized.”  
Appendix 8, Efficacy 
Outcome Assessment 
Flowchart 
ECP - End of Consolidation Phase 
Is CDA confirmed (ie, no new lesions for ≥ 2 weeks)? 
Clarified in ECP, CDA 
confirmed is defined as no new 
lesions for ≥2 weeks, per 
protocol. 
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12.13.10 
Clinical Study Protocol Version 5.1 for Germany (19 May 2020)  
This was a local amendment to protocol Version 5 and was regarded as a substantial amendment. 
Overall Rationale for the Amendment  
The primary reason for this amendment to Protocol PRN1008-012, Version 5.1 is: 
• 
To align the content of the protocol for Germany to the global one and incorporating the 
same changes as the global version V5.0. 
 
 
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Protocol Amendment summary of changes Table 
PRN1008-012 Protocol V4.1 to 5.1 (19 May 2020) 
The protocol Version 5.0, 22 January 2020 has been updated throughout to correct errors and to clarify or adjust study procedures and 
assessments.  Deleted text has strikethrough and new text is bolded. 
Section(s) 
Amended or New Wording 
Justification of Change 
Throughout the protocol 
19 May 2020, Version 5.1 
Administrative change. 
Throughout the protocol 
PRN1008 (Rilzabrutinib) 
Recommended name by the 
World Health Organization 
(WHO) International 
Nonproprietary Names (INN) 
Committee. 
List of Abbreviations 
 
New entries added for clarity 
1.0 Synopsis 
 
 
 
 
 
 
 
 
 
2.6 Background Trial Design 
Rational  
 
 
 
Urgent Safety Measures Initiated Due to COVID-19 Pandemic 
Each participating site, ethics committees, and the Federal Institute for Drugs and 
Medical Devices the (BfArM) were informed (22 April 2020) of urgent safety 
measures implemented to ensure continued supply of study medication and safety 
monitoring for patients. These measures are described in the “Updated Guidelines to 
Sites for Delayed Patient Visits or Missed Visits due to travel restrictions and any 
foreseeable impacts of COVID-19” (Appendix 9). When the COVID-19 pandemic 
resolves, the measures will be repealed back to the previous state as government rules 
and benefit/risk assessment allow. 
 
During the COVID-19 pandemic, measures to ensure continued drug supply and 
safety monitoring for patients are described in the “Updated Guidelines to Sites for 
Delayed Patient Visits or Missed Visits due to travel restrictions and any foreseeable 
impacts of COVID-19” (Appendix 9). These measures include remote study visits, 
enrollment procedures, direct to patient delivery of study medication and urine 
pregnancy tests, as well as handling of protocol deviations and remote site 
monitoring. 
COVID-19 pandemic  
procedures to aid sites for 
managing study subjects and 
study processes as outlined in 
the “Updated Guidelines to Sites 
for Delayed Patient Visits or 
Missed Visits due to travel 
restrictions and any foreseeable 
impacts of COVID-19” 
Appendix 9. 
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6.4 Drug Management 
 
 
 
 
 
 
7.2 Trial Enrollment Procedures 
 
 
 
 
7.6 Visit Overview 
 
 
 
 
 
9.3.1 Adverse Events 
 
During the COVID-19 pandemic, drug supply can be sent to patients when the patient 
may is not able to travel to the site or the site cannot host a patient visit. Site 
instructions for shipment of supplies directly to patients and procedures for 
conducting remote site visits inclusive of ensuring drug supply maintenance are 
described in Appendix 9 (“Updated Guidelines to Sites for Delayed Patient Visits or 
Missed Visits due to travel restrictions and any foreseeable impacts of COVID-19”). 
 
During the COVID-19 pandemic, we need to assess the feasibility of implementing a 
plan for patient access to study drug and any additional measures required to monitor 
patient safety on an ongoing basis. Please notify Principia and your CRO study 
monitor if your site suspends patient enrollment. (Appendix 9) 
 
During the COVID-19 pandemic, remote (eg, telephone call, video call) study visits 
may be performed when a patient is not able to travel to the site or the site cannot host 
a patient visit. Procedures to be performed during remote site visits are described in 
Appendix 1 of “Updated Guidelines to Sites for Delayed Patient Visits or Missed 
Visits due to travel restrictions and any foreseeable impacts of COVID-19” 
(Appendix 9). 
 
During the COVID-19 pandemic, we need to assess the feasibility of implementing a 
plan for patient access to study drug and any additional measures required to monitor 
patient safety on an ongoing basis. Please notify Principia and your CRO study 
monitor if your site suspends patient enrollment. (Appendix 9) 
1.0 Synopsis, Study Population 
and 
4.6 Study Population, 
and 
 
Approximately 120 male or female patients with newly diagnosed or relapsing 
moderate to severe pemphigus (pemphigus vulgaris [PV] or pemphigus foliaceus 
[PF]) will be enrolled with a targeted minimum of 4590 patients with PV per group, 
and a target maximum of 1022 patients with PF per group. 
 
The targeted minimum number 
of enrolled PV patients was 
updated from a per group total 
(45) to a per study total (90) to 
ensure the number of PV 
patients in each group are 
reasonably balanced (placebo 
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10.1 Determination of Sample 
Size 
Section 10.1: … Assuming a response is achieved in 50% of ITT patients treated with 
PRN1008 versus 15% in placebo treated patients, then, a sample size of ≥ 55 patients 
(there is a targeted minimum of 90 PV patients and a maximum of 22 PF patients in 
each treatment group) results in > 90% power at a 0.05 significance level using a 
2-sided Pearson chi-square test for the analysis of PV disease type alone and PV and 
PF combined. Up to a total of approximately 120 patients may be enrolled, with a 
targeted cap of 2022 PF patients. 
and active) using the block 
randomization schedule in this 
study, without requiring Sponsor 
unblinding. 
The text, “with a cap of 20 PF 
patients” changed to “targeted 
cap of 22 patients” to ensure the 
number of PF patients in each 
group are reasonably balanced 
(placebo and active) using the 
block randomization schedule in 
this study, without requiring 
Sponsor unblinding. 
1.0 Synopsis, Duration of Trial 
Participation 
and 
4.1. Duration of Trial 
Participation 
 
Long Term Extension Period 
Study duration for the patients who enter the Long-Term Extension Period will 
be determined by the criteria described in Section 4.4 
 
The primary purpose of the 
48-week, Long Term Extension 
Period (LTE) is to provide 
extended access to PRN1008 for 
patients who are receiving 
clinical benefit and to accrue 
additional long term data on the 
safety of PRN1008. 
1. Synopsis, Study Design 
and 
 
 
 
 
4. Study Design 
 
This is a randomized, parallel-group, double-blind, placebo-controlled trial with 36 
weeks of treatment during a Blinded Treatment Period followed by an Open-Label 
Extension Period of 24 weeks and a follow up period of 4 weeks. After completing 
the Open-Label Extension Period, eligible patients may continue in the Long 
Term Extension Period of 48 weeks. Patients will continue to have a 4 week 
follow-up visit after the patient’s last dose of PRN1008 as detailed in the Follow-
Up Period section below. 
This is a randomized, parallel-group, double-blind, placebo-controlled trial with 
36 weeks of treatment during a Blinded Treatment Period followed by an Open-Label 
Extension Period of 24 weeks After completing the Open-Label Extension Period, 
eligible patients may continue in the Long Term Extension Period of 48 weeks. 
Patients will be eligible for the 
LTE if they show adequate 
response to PRN1008 during the 
Open Label Period ie, achieve or 
maintain ECP (at least 
80% healing of lesions and no 
new lesions for at least 2 weeks) 
while on a low CS dose 
(≤ 10 mg/day prednisone or 
equivalent) as defined in the 
pemphigus treatment guidelines. 
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Patients will continue to have a 4 week follow-up visit after the patient’s last dose 
of PRN1008 as detailed in the and a Follow-up Period (Section 4.5) below. of 4 
weeks (Figure 1). 
1. Synopsis, Study Design 
and 
4.2  Blinded Treatment Period 
(Weeks 1 to 37) 
and 
 
 
7.4.1. Patient Discontinuation 
and Stopping Rules 
If rituximab is administered, patients should continue to take PRN1008/placebo, 
remain on trial and blinded to treatment assignment, but will be considered treatment 
failures for all efficacy endpoints except cumulative for CS dosing and composite 
Glucocorticoid Toxicity Index (GTI) score. After completing the Blinded Treatment 
Period, patients will enter the Open-Label Extension Period to receive active 
treatment with PRN1008 described below. A patient in the Blinded Treatment Period 
requiring an additional “top up” dose of rituximab after their initial rituximab course 
of treatment must be discontinued from the trial. 
Mandatory termination criteria for a patient in this study include: 
• 
Severe and life-threatening pemphigus disease activity 
• 
Grade 4 PRN1008 -related TEAE 
• 
Serious allergic reaction to PRN1008 or placebo including anaphylactic reaction 
• 
A patient in the Blinded Treatment Period requiring an additional “top up” dose of 
rituximab after their initial rituximab course of treatment or a patient in the Open-
Label Extension Period or Long Term Extension Period requiring rituximab 
Updated to clarify that patients 
who receive rituximab should 
continue to take 
PRN1008/placebo and remain 
on trial unless they meet a 
discontinuation criterion 
1. Synopsis, Open-Label 
Extension Period (Weeks 37 to 
61) 
and 
4.3. Open-Label Extension 
Period (Weeks 37 to 61) 
and 
 
 
 
From Week 37, all patients will receive active drug in the Open-Label Extension 
Period for 24 weeks per Table 3: Schedule of Assessments Open-Label Extension 
Period. Patients who received placebo will thus receive active treatment with 
PRN1008 400 mg bid. Patients requiring treatment by rituximab or other 
immunosuppressants (other than CS) for relapse during this period, must be 
discontinued from the study. If a patient has a qualifying relapse during the 
Blinded Treatment Period and the second infusion from the rituximab course of 
treatment occurs during the Open-Label Extension period, the patient may 
continue in the trial. Patients that received rituximab during the Blinded 
Treatment Period and are continuing in the study, will complete TBNK testing 
(T and B and Natural Killer Lymphocyte Panel) at their Week 37 visit. 
Updated to clarify that if a 
patient has a qualifying relapse 
during the Blinded Treatment 
Period and the second infusion 
from the rituximab course of 
treatment occurs during the 
Open-Label Extension period, 
the patient may continue in the 
trial. 
TBNK Panel is an assessment of 
T, B, and Natural Killer cell 
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Table 3 Schedule of 
Assessments 
and 
 
 
Appendix 1 
 
 
Footnote m: Patients that received rituximab during the Blinded Treatment 
Period and are continuing in the study, TBNK panel will be drawn at their Week 
37 visit. 
 
 
Management during Open-Label Extension Period and Long Term Extension 
Period 
• 
Patients requiring treatment by rituximab or other immunosuppressants (other 
than CS) for relapse during these study periods, must be discontinued from 
the study. If a patient has a qualifying relapse during the Blinded Treatment 
Period and the second infusion from the rituximab course of treatment 
occurs during the Open-Label Extension period the patient may continue in 
the trial.this period, must be discontinued from the study. 
counts in patients who received 
rituximab rescue. This will 
establish a baseline prior to 
open-label PRN1008 treatment 
to assist in better understanding 
the action of PRN1008 in 
patients already treated with 
rituximab. 
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1. Synopsis, Long Term 
Extension (LTE) Period (Week 
61 to Week 109) 
and 
4.4. Long Term Extension 
(LTE) Period (Week 61 to Week 
109) 
Long Term Extension (LTE) Period (Week 61 to Week 109)  
After completing the Open-Label Extension Period, patients who are responding 
to PRN1008 treatment will be eligible to enter the Long Term Extension Period 
and will continue to receive open-label PRN1008 400 mg bid for 48 weeks per 
Table 4: Schedule of Assessments Long Term Extension Period. 
Patients are eligible to participate in the LTE if: 
a. they have achieved and/or maintained an ECP with ≤ 10 mg/day CS 
at any time between 37 and 61 weeks in the study. 
Patients are not eligible to participate in the LTE if: 
a. they have more than one relapse following ECP requiring treatment 
with> 10 mg/day CS (excluding CS taken short-term for dental work 
or surgery) or 
b. have failed to adequately recover after a relapse despite maximal 
tolerated CS dose. 
Failure to adequately recover is defined as: <25% decrease from peak PDAI 
despite treatment with maximal steroid doses (minimum of 1.5mg/kg/d unless 
there is a specific documented medical contraindication) for at least 2 weeks. 
CS doses above refer to doses of prednisone or its equivalent. 
Patients may continue in the LTE until: 
a. they have had more than one relapse following ECP that requires 
> 10 mg/day CS (excluding CS taken short-term for dental work or 
surgery) or have failed to adequately recover after a relapse despite 
maximal tolerated CS dose (per definition of failure to adequately 
recover above);  
b. the drug is no longer being developed by the Sponsor for this 
indication; 
c. the program is stopped for safety reasons 
Patients will be eligible for the 
LTE if they show adequate 
response to PRN1008 during the 
Open Label Period ie, achieve or 
maintain ECP (at least 
80% healing of lesions and no 
new lesions for at least 2 weeks) 
while on a low CS dose (≤10 
mg/day prednisone or 
equivalent) as defined in the 
pemphigus treatment guidelines. 
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Patients who have previously completed the Open-Label Extension Period prior 
to this amendment and were responders per the LTE requirement may enroll 
into the LTE. 
Beginning at Week 61, patients entering the LTE will no longer receive Sponsor-
provided CS, but can receive site-provided CS per required standard of care. 
From Week 61, following CS Management Guidelines (Appendix 1) is 
recommended. 
Patients requiring rituximab during the Long Term Extension Period will be 
discontinued from the trial. 
Synopsis, Follow-up Period 
(4 Weeks after last Trial Visit 
and 
4.5. (Follow-up Period (4 Weeks 
after last Trial Visit) 
 
 
Follow-up Period (4 Weeks 61 to 65after last Trial Visit): 
End of Trial for the overall clinical trial is defined as the point at which the last 
patient has completed the last visit of the study. 
End of Trial for each patientFor patients eligible for the Long Term Extension, the 
End of Trial is defined as the point at which the patient has completed their 
Week 113 visit (4 weeks after the patient’s last dose of PRN1008). 
For patients that are not eligible for the Long Term Extension, the End of Trial 
is defined as the point at which the patient has completed their Week 65 visit (4 
weeks after the patient’s last dose of PRN1008). 
Patients who are not able to complete the Open-Label Extension Period or Long 
Term Extension Period (for patients who qualify) as planned Week 65 visit and 
discontinue the study early should be encouraged to come back for their last visit, and 
this will be recorded as the End of Trial (EOT) visit. Patients that discontinue early 
will have the ETEarly Termination (ET) assessments completed as outlined in the 
Schedule of Assessments based upon from which phase treatment they are 
terminating, Table 2 (Blinded Treatment Period) and), Table 3 (Open-Label 
Extension Period), or Table 4 (Long Term Extension Period). 
Patients will be eligible for the 
LTE if they show adequate 
response to PRN1008 during the 
Open Label Period ie, achieve or 
maintain ECP (at least 
80% healing of lesions and no 
new lesions for at least 2 weeks) 
while on a low CS dose 
(≤ 10 mg/day prednisone or 
equivalent) as defined in the 
pemphigus treatment guidelines. 
1. Synopsis, Corticosteroid 
Management (Consensus 
Guideline, Murrell 2018) 
Corticosteroid Management during Blinded Treatment Period and, Open-Label 
Extension Period, and Long Term Extension Period 
1 
Hydrocortisone, a short 
acting steroid, is often used as 
the preparation of choice for 
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and  
6.1.2.2.1.Corticosteroid-
Tapering (Consensus Guideline, 
Murrell 2018) 
and 
6.1.2. Corticosteroids 
and    
Appendix 1 Corticosteroid and 
Rituximab Management 
CS will be tapered from ECP towards a goal of 5 mg/day by ≤ Week 29. Once the 
5 mg level is achieved it will be kept at 5 mg/day until the time of the primary 
endpoint at Week 37 is reached. From Week 37, further tapering to 0 mg CS should 
be attempted in patients with CR unless medically contraindicated. At Investigator 
discretion, the CS may be switched to equivalent doses of oral hydrocortisone 
instead of prednisone or prednisolone when tapering from 5 mg to 0 mg CS. 
Oral corticosteroids (prednisone or prednisolone) will be provided during the 
Blinded Treatment Period and Open-Label Extension Period. Beginning at 
Week 61, patients entering the LTE will no longer receive Sponsor-provided CS 
but can receive site-provided CS per required standard of care. 
During Screening or the treatment periods of the trial, where an initial induction of 
CDA has not been achieved and blistering continues without improvement, CS should 
be increased by 50 to 100% every 5 to 7 days until confirmation of ECP. After ECP is 
confirmed CS taper should commence. Rituximab therapy may not be used in this 
situation. Patients who have been treated with a minimum of 1.5 mg/kg/day of 
corticosteroids for 2 weeks and have not achieved control of disease activity may be 
eligible after discussion with Principia to receive rituximab. For patients who are 
unable to escalate CS up to 1.5 mg/kg/day due to documented adverse events 
related to CS and cannot achieve CDA following 2 weeks of treatment with their 
maximally tolerated CS dose, rescue with rituximab therapy may be offered. 
Please consult with the medical monitor. 
graduated tapering of steroids in 
patients with a history of chronic 
use and potential dependence. 
Since this may be standard of 
care in some places, replacement 
of prednisone/ prednisolone with 
equivalent doses of oral 
hydrocortisone will be permitted 
to taper off from 5mg of 
prednisone.  
Updated to clarify that patients 
who are intolerant to high doses 
of corticosteroid may be eligible 
for rescue medication  
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1. Synopsis, Inclusion Criteria 
and 
5.1. Inclusion Criteria 
4. Body mass index (BMI) > 17.5 (only applicable through Protocol v3.0) 
2 
Removed as this criterion 
was only applicable through 
Protocol v3.0. 
1. Synopsis, Exclusion Criteria 
and 
5.2.  Exclusion Criteria 
5. A history of malignancy of any type within 5 years before Day 1, other than 
surgically excised non-melanoma skin cancers or in situ cervical cancer within 5 
years before Day 1 
3 
Rephrased 
1. Synopsis, Exclusion Criteria 
and 
5.2.  Exclusion Criteria 
7. Use of proton pump inhibitor drugs such as omeprazole and esomeprazole within 
3 days of Day 1 (It is acceptable to change patient to H2 receptor blocking drugs prior 
to Day 1.) 
4 
Clarified that the 3 days 
period required for stopping of 
proton pump inhibitors is prior 
to Day 1 
1. Synopsis, Exclusion Criteria 
and 
5.2.  Exclusion Criteria 
16. Positive at Screening for human immunodeficiency virus (HIV), hepatitis B 
(surface antigen and core antibodies unrelated to vaccination, surface antigen), or 
hepatitis C (anti-HCV antibody confirmed with Hep C RNA) 
5 
Clarified language on 
Hepatitis B positive patients to 
ensure that vaccinated patients 
can be included and patients 
with prior exposure to Hepatitis 
B are excluded from the study. 
1. Synopsis, Exclusion Criteria 
and 
5.2.  Exclusion Criteria 
17. On a case by case basis, after discussion and approval by the Sponsor, a local TB 
test that is negative and is considered equivalent to 1 of the above tests may be used 
for eligibility. For example, if a QuantiFERON®-TB Gold, or QuantiFERON-TB 
Gold Plus (QFT Plus) is positiveindeterminate for any reason and a local blood test 
or TSpot TB test is negative, the patient may be enrolled using the local result upon 
approval of the Sponsor. 
6 
Clarified that a positive 
central lab test for TB will 
satisfy the exclusion criteria. 
Local lab results may be used 
when central lab is 
indeterminate for any reason. 
2.6. Trial Design Rationale 
Study PRN1008-012 is a randomized, parallel-group, double-blind, placebo-
controlled trial over 36 weeks (Blinded Treatment Period) followed by an Open-Label 
Extension Period of 24 weeks, Long Term Extension Period of 48 weeks, and a 
follow-up period of 4 weeks, which is intended to evaluate the efficacy and safety of 
oral PRN1008 (Rilzabrutinib) in moderate to severe pemphigus. 
…The primary purpose of the 24-week, Open-Label Extension Period is(OLE) is to 
allow access to study drug who were on placebo medication as well as to evaluate 
Clarified the purpose of the long 
term extension study 
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durability of clinical response and accrue additional long term data on the safety of 
PRN1008. 
The primary purpose of the 48-week, Long Term Extension Period (LTE) is to 
provide extended access to PRN1008 for patients who are receiving clinical 
benefit and to accrue additional long term data on the safety of PRN1008. 
Table 2 Schedule of 
Assessments, Footnote e 
PT/INR, thrombin time, aPTT, and fibrinogen level and will be collected at 
Screening, Day 1 Week 1 Pre-dose, and Weeks 3, 5, 9, 1713, 25, & 37. 
Footnote correction to match 
assessments listed in Table 2. 
Table 2 Schedule of 
Assessments- Open Label 
Extension Period Footnote n 
and 
 
 
 
 
 
 
 
7.6.1. Screening  
(Day -29 to Day -1) 
Footnote n: As described in Section 7.6.1, laboratory assessments delayed due to 
logistic considerations may be performed with an extended Screening window (up to 
7 additional business days), upon Sponsor review and approval. Patients may be re-
screened once. Any labs completed in prior Screening, within 2 weeks of re-screening 
will remain valid and should not be repeated. Labs performed for a previous 
screening within 6 weeks, may be considered for determination of eligibility on 
approval of the medical monitor. In the specific cases of QuantiFERON-TB, anti 
desmoglein antibodies and hepatitis/HIV testing, tests may be considered for 
determination of eligibility if performed in a previous screen within the last 12 
weeks, with the approval of the medical monitor.  However, pregnancy tests should 
be repeated at re-screening. 
 
In cases where laboratory assessments are delayed due to logistic considerations, the 
Sponsor may permit an extension of the Screening Period for laboratory assessments 
up to 7 business days in order to determine eligibility. Week 1 Day 1 should occur as 
soon as possible upon evaluation of the delayed assessments and no later than 35 days 
after the initial Screening visit. 
Medical history and demographic data, including sex, age, race, body weight (kg), 
height (cm), and body mass index (BMI), will be recorded. 
Patients not already on the mandated CS doses for the commencement of the 
Screening Period will commence the protocol-mandated CS doses. 
Patients may be re-screened once following a Screen failure. Any labs performed in 
prior screening, within 2 weeks of re-screening will remain valid and should not 
be repeated. Labs performed for a previous screening within 6 weeks, may be 
7 
Clarified that 7 days is 
7 business days to allow for 
adequate processing. 
Labs done for safety screening 
are likely to remain stable over 
short periods. The medical 
monitor will review for any 
change in the patient’s status 
that requires a repeat. 
Anti-dsg antibodies once 
confirmed during screening, 
should not need to be repeated 
in most cases. This will reduce 
burden on patient’s and avoid 
repeat assessments when not 
necessary. 
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considered for determination of eligibility on approval of the medical monitor. In 
the specific cases of QuantiFERON-TB, anti desmoglein antibodies and 
hepatitis/HIV testing, tests may be considered for determination of eligibility if 
performed in a previous screen within the last 12 weeks, with the approval of the 
medical monitor.  However, pregnancy tests should be repeated at re-screening. 
Please see Schedule of Assessments Table 2. 
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Table 3 Schedule of 
Assessments 
Week 37 Visit Window: ± 53 days 
Clarified for consistency 
through protocol. 
Table 3 Schedule of 
Assessments 
OLE EOT Week 65/EOT 4 wk visit 
Clarification in heading for 
Follow-up Period. 
Table 3 Schedule of 
Assessments 
Week 39 ± 3 days / TBNK Panel Week 37: X 
Added TBNK Panel to week 37 
assessments. 
Table 3 Schedule of 
Assessments 
Week 61 ± 5 days / 12-lead ECG: X 
Week 61 ± 5 days / Urinalysis: X 
Week 61 ± 5 days / HbA1c and LDL (fasting): X 
Week 61 ± 5 days / GTI Index: X 
Week 61 ± 5 days / PRN1008 dispensed: X 
Week 61 is the end of the 
primary study and the last visit 
for patients not rolling over to 
the LTE. These tests are 
performed to document end of 
study safety. 
Table 3 Schedule of 
Assessments, Footnote g deleted 
Online cognitive testing will be performed at designated sites. 
 
Table 3 Schedule of 
Assessments, Footnote i 
and 
6.1.2. Corticosteroids 
Beginning at Week 61, patients entering the LTE will no longer receive Sponsor-
provided CS but can receive site-provided CS per required standard of care. 
From Week 61, following CS Management Guidelines (Appendix 1) is 
recommended. 
Oral corticosteroids (prednisone or prednisolone) will be provided during the 
Blinded Treatment Period and Open-Label Extension Period. Beginning at 
Week 61, patients entering the LTE will no longer receive Sponsor-provided CS 
but can receive site-provided CS per required standard of care. 
Clarified that during the LTE 
patients will no longer receive 
Sponsor-provided CS but can 
receive site-provided CS per 
standard of care. 
Table 3 Schedule of 
Assessments - Open Label 
Extension Period Footnote l 
Footnote l: If patient is eligible for the Long Term Extension Period at Week 61 
they will continue to receive PRN1008 per Table 4: Schedule of Assessments 
Long Term Extension Period. If the patient is not eligible for the Long Term 
Extension Period at Week 61 they will discontinue PRN1008 and complete the 
EOT visit at Week 65. 
8 
Edited for consistency  
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Table 3 Schedule of 
Assessments - Open Label 
Extension Period Footnote m 
Footnote m: Patients that received rituximab during the Blinded Treatment 
Period and are continuing in the study, TBNK panel will be drawn at their Week 
37 visit. 
9 
Updated to clarify that if a 
patient has a qualifying 
relapse during the Blinded 
Treatment Period and the second 
infusion from the rituximab 
course of treatment occurs 
during the Open-Label 
Extension period, the patient 
may continue in the 
trial. TBNK Pantel is an 
assessment of T, B, and Natural 
Killer cell counts in patients 
who received rituximab rescue. 
This will establish a baseline 
prior to open-label PRN1008 
treatment to assist in better 
understanding the action of 
PRN1008 in patients already 
treated with rituximab. 
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Table 4 Schedule of 
Assessments - Long Term 
Extension Period 
 
 
New table added to describe 
scheduled assessments to be 
conducted in the Long-Term 
Extension Period.  Also contains 
additional pregnancy testing 
(once/month) 
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Section(s) 
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2.6. Trial Design Rationale 
Study PRN1008-012 is a randomized, parallel-group, double-blind, placebo-
controlled trial over 36 weeks (Blinded Treatment Period) followed by an Open-Label 
Extension Period of 24 weeks, Long Term Extension Period of 48 weeks, and a 
follow-up period of 4 weeks, which is intended to evaluate the efficacy and safety of 
oral PRN1008 (Rilzabrutinib) in moderate to severe pemphigus. 
…The primary purpose of the 24-week, Open-Label Extension Period is(OLE) is to 
allow access to study drug who were on placebo medication as well as to evaluate 
durability of clinical response and accrue additional long term data on the safety of 
PRN1008. 
The primary purpose of the 48-week, Long Term Extension Period (LTE) is to 
provide extended access to PRN1008 for patients who are receiving clinical 
benefit and to accrue additional long term data on the safety of PRN1008. 
Patients will be eligible for the 
LTE if they show adequate 
response to PRN1008 during the 
Open Label Period ie, achieve or 
maintain ECP (at least 
80% healing of lesions and no 
new lesions for at least 2 weeks) 
while on a low CS dose 
(≤ 10 mg/day prednisone or 
equivalent) as defined in the 
pemphigus treatment guidelines. 
4. Figure 1: Study Design Flow 
Chart 
 
The flow chart was replaced to 
include the long term extension 
period. 
6.5.2. Particular Permissible 
Medications 
Histamine 2 (H2) receptor blocking drugs (ranitidine or famotidine) and antacids 
are permitted provided they can be given 2 hours or more after dosesadministration 
of PRN1008 or placebo. 
Clarified that ranitidine and 
famotidine are preferred H2 
antagonists. When administered 
2 hours or more after PRN1008, 
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their effects on PK of the study 
drug are minimal. 
7.2. Trial Enrollment Procedures 
Under no circumstances will participants who enroll in this trial and complete 
treatment as specified be permitted to re-enroll in the trial unless in the rare case 
where Sponsor approval is granted (eg, for a subject who completed and exited 
the OLE that is eligible to participate in the LTE). 
Edited for consistency 
7.6.5. Long Term Extension 
Period 
Please refer to Table 4 for specific assessments at each visit. CS dosing is detailed 
in Appendix 1. Rituximab therapy is not allowed during this period unless the 
patient is withdrawn from the trial. 
Edited for Consistency 
7.7.6. Electrocardiogram 
Monitoring 
Single 12-lead ECGs will be performed at Screening, Week 37, Week 61, and 
Week 37.109 (for patients in the Long Term Extension). All ECGs will be 
performed with the patient in a supine position. 
Updated to match Schedule of 
Assessments and addition of 
LTE. 
9.3.1. Adverse Event Collection 
Period 
The AE Collection Period begins at the time of the first Screening/eligibility 
assessment and ends at the end End of the studyTrial for each patient. 
Rephrased 
10.2.1. Analysis Populations 
Four populations will be defined for data analysis: the Safety Population, the Intent-
to-Treat (efficacy)Population, the Modified Intent-to-Treat (mITT) (efficacy) 
Population, and the Pharmacokinetic Population. 
Clarified distinction between 
Intent-to-Treat Population and 
Modified Intent-to-Treat 
population for statistical 
analysis. 
11. Investigator Responsibilities 
and 
 
 
 
 
 
 
 
By signing this protocol and the Investigator Statement (eg, national equivalent of 
Form FDA1572), the Investigator agrees to do the following: 
1. Conduct the trial in accordance with the relevant current protocol and make 
changes only after notifying the Sponsor, except when immediate changes are 
necessary to protect the safety, rights, or welfare of the patients 
2. Comply with the currently endorsed E6 International Conference on Council for 
Harmonisation Tripartite Guideline on Good Clinical Practice and applicable Food 
and Drug Administration (FDA) Codes of Federal Regulations (CFRs) 
3. Personally conduct or supervise the described investigation 
To reflect a change in 
terminology for the ICH. 
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13.1 Patient Confidentiality and 
Disclosure of Data 
4. Inform any patients, or any persons used as controls, that the drugs are being used 
for investigational purposes 
5. Ensure that the requirements relating to obtaining informed consent and IRB/IEC 
review and approval have been met 
6. Report to the Sponsor adverse experiences that occur in the course of the 
investigation as speciﬁed in 21 CFR 312.64 and the E6 International Conference 
onCouncil for Harmonisation Tripartite Guideline on Good Clinical Practice and 
any local regulations 
7. Have read and understood the Investigator Brochure, including potential risks and 
side effects of the drug 
8. Ensure that all associates, colleagues, and employees assisting in the conduct of the 
trial are informed about their obligations in meeting the above commitments 
9. Maintain adequate and accurate records and make these available for inspection by 
the Sponsor, its designee, the FDA, the IRB/IEC, and other applicable national or 
local health authorities or agency authorized by law, as deﬁned in 21 CFR 312.68 
and currently endorsed E6 International Conference onCouncil for 
Harmonisation Tripartite Guideline on Good Clinical Practice. 
Documents that are not for submission to the Sponsor and/or its designee (eg, signed 
ICFs and Patient Information Sheets) should be kept in strict conﬁdence by the 
Investigator in compliance with Federal regulations or other applicable laws or 
International Conference onCouncil for Harmonization (ICH) and Good Clinical 
Practice (GCP) Guidelines. 
15. References 
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. 
New reference for PDAI. 
Appendix 2 Pemphigus Disease 
Activity: PDAI 
Pemphigus Disease Area Index (PDAI) (Rosenbach 2009, Murrell 2018) 
The PDAI form was replaced 
and a reference was added  
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Appendix 6, Appendix 7, 
Appendix 8, Appendix 9 
Appendix 6 Description of Online Cognitive Testing  
Appendix 7 Appendix 6 Glucocorticoid Toxicity Index (GTI) 
Appendix 8 Appendix 7 Strong to Moderate CYP3A Inhibitors and Inducers and 
Sensitive CYP3A Substrates 
Appendix 9 Appendix 8 Efficacy Outcome Assessment Flowchart 
Renumbered appendices 
because of deletion of 
Appendix 6 
Table 4, Table 5, Table 6 
Table 4 Schedule of Assessments - Long Term Extension Period 
Table 4 Table 5 Definitions of Moderate to Severe Population and starting CS doses* 
Table 5  Table 6 Example Taper for a 60 mg Dose of CS  
Renumbered Tables because of 
addition of new Table 4 
 
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12.13.11. 
Clinical Study Protocol Version 5.2 for Germany (30 November 2020)  
This was a local amendment to protocol Version 5.1 and was regarded as a substantial 
amendment. 
Overall Rationale for the Amendment  
The primary reasons for this amendment to Protocol PRN1008-012, Version 5.2 are: 
• 
To add Long Term Extension (LTE) objective and endpoints in alignment with German 
Central Ethics Committee request to provide LTE endpoints., 
• 
To add a new exclusion criterion #24 per German Central Ethics Committee requirement, 
• 
To add COVID testing at every visit per German Central Ethics Committee requirement, 
• 
To address measures taken due to the COVID-19 pandemic, 
• 
To update trial stopping and discontinuation rules per German Central Ethics Committee 
requirement. 
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Protocol Amendment summary of changes Table 
PRN1008-012 Protocol Version 5.1 (19 May 2020) to Version 5.2 (30 November 2020) 
Protocol Version 5.1 dated 19 May 2020 has been updated throughout to correct for administrative errors as well as for consistency. Deleted text 
has strikethrough and new text is bolded. Minor editorial changes are not included in this summary document. 
Section(s) 
Amended or New Wording 
Justification of Change 
Throughout the protocol 
19 May 2020 30 November 2020 
Administrative change to reflect 
new protocol date 
Throughout the protocol 
Version 5.1 Version 5.2 
Administrative change to reflect 
new protocol date 
Synopsis: Long Term Extension 
Objective 
Section 3.1.5 Long Term 
Extension Objective 
Long Term Extension Objective 
• 
To evaluate the long-term safety of PRN1008 
Addition of Long Term 
Extension Objective in 
alignment with German Central 
Ethics Committee request to 
provide LTE endpoints. 
Synopsis: Investigational Plan - 
Long Term Extension (LTE) 
Period (Week 61 to Week 109) 
Section 4.4 Long Term 
Extension (LTE) Period 
(Week 61 to Week 109) 
 
Beginning at Week 61, pPatients entering the LTE will no longer receive Sponsor-
provided CS, but can receive site provided CS per required standard of care. From 
Week 61, following CS Management Guidelines (Appendix 1) is recommended. 
Updated to reflect that the 
Sponsor will be the source of 
corticosteroids to patients in the 
LTE 
Table 3 Schedule of 
Assessments - Open Label 
Extension Period 
Table 4 Schedule of 
Assessments - Long Term 
Extension Period 
[footnote i] 
i. …Beginning at Week 61, patientsPatients entering the LTE will no longer receive 
Sponsor-provided CS, but can receive site provided CS per required standard of care. 
From Week 61, following CS Management Guidelines (Appendix 1) is 
recommended. 
 
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6.1.2 Corticosteroids 
1) 
Oral corticosteroids (prednisone or prednisolone) will be provided during the 
Blinded Treatment Period and Open-Label Extension Period. Beginning at Week 61, 
patientsPatients entering the LTE will no longer receive Sponsor-provided CS, but 
can receive site provided CS per required standard of care. 
 
Synopsis: Exclusion Criterion 
#24 
Section 5.2 Exclusion Criteria - 
Exclusion Criterion #24 
[new exclusion criterion] 
Patients who have a positive test result for severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) infection per local testing standards. 
Per German Central Ethics 
Committee requirement 
2) 
Synopsis: Outcome 
Measures 
3) 
Section 3.2.9 Long 
Term Extension Endpoints 
4) 
Long Term Extension Endpoints 
• 
Nature, frequency, and severity of adverse events, including serious adverse 
events, adverse events leading to discontinuation and possible corticosteroid-
related adverse effects during the LTE from Week 61 to Week 113 
• 
Average daily dose of CS from Week 61 to Week 113 
• 
Time to relapse during the LTE 
Per German Central Ethics 
Committee request to provide 
LTE Endpoints. 
Table 2 Schedule of 
Assessments - Blinded 
Treatment Period 
[row title] 
SARS-CoV-2r 
“X” added at each visit. 
[new footnote r] 
• 
r. Subjects must be tested for SARS-CoV-2 infection within one week 
prior to each visit or up to 2 days after each visit. Every effort should be made to 
comply with local or institutional testing procedures. If the time required for 
obtaining results exceeds this testing window, an extension may be granted by 
the Medical Monitor. The requirement for the test may be waived by the 
Medical Monitor (with approval from the Ethics Committee) if the local 
regulations change with control of the pandemic. 
Per German Central Ethics 
Committee requirement 
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Table 3 Schedule of 
Assessments - Open Label 
Extension Period 
“X” added for the Drug reconciliation (PRN1008/CS Dosing Documentation) at the 
OLE EOT Week 65 4 wk FU Visit 
Updated to correct error to 
reflect that drug reconciliation 
occurs at this visit. 
 
[footnote c, final sentence] 
c. … At Week 37, the HbA1c and LDL level (fasting) will be collected with GTI 
assessment. 
 
Updated to provide clarity 
regarding laboratory samples. 
 
[row title] 
SARS-CoV-2n 
“X” added at each visit. 
[new footnote n] 
n. Subjects must be tested for SARS-CoV-2 infection within one week prior to 
each visit or up to 2 days after each visit. Every effort should be made to comply 
with local or institutional testing procedures. If the time required for obtaining 
results exceeds this testing window, an extension may be granted by the Medical 
Monitor. The requirement for the test may be waived by the Medical Monitor 
(with approval from the Ethics Committee) if the local regulations change with 
control of the pandemic. 
 
Per German Central Ethics 
Committee requirement 
Table 4 Schedule of 
Assessments - Long Term 
Extension Period 
[rows for “HbA1c and LDL (fasting)” and “GTI Index” removed] 
[footnote c, final sentence] 
c. …HbA1c and LDL level (fasting) will be collected with GTI assessment. 
Updated to reflect that these 
procedures are not performed 
during the LTE, in line with the 
new LTE endpoints.   
 
“X” removed in the rows for PDAI, ABQOL and TABQOL, EQ-5D-5L, 
and Photography from visits at Weeks 65, 69, 73, 85, 97, 109, 113; at ET; and at the 
Unscheduled visit 
[footnote g] 
g. Any photos should be taken and stored in accordance with local regulations (Week 
61 only). 
Updated to reflect that these 
procedures are not performed 
during the LTE, in line with the 
new LTE endpoints. 
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Section(s) 
Amended or New Wording 
Justification of Change 
 
[row title] 
SARS-CoV-2k 
“X” added at each visit. 
[new footnote k] 
k. Subjects must be tested for SARS-CoV-2 infection within one week prior to 
each visit or up to 2 days after each visit. Every effort should be made to comply 
with local or institutional testing procedures. If the time required for obtaining 
results exceeds this testing window, an extension may be granted by the Medical 
Monitor. The requirement for the test may be waived by the Medical Monitor 
(with approval from the Ethics Committee) if the local regulations change with 
control of the pandemic. 
Per German Central Ethics 
Committee requirement 
Section 4.6 Urgent Safety 
Measures Initiated Due to 
COVID-19 Pandemic 
Urgent Safety Measures Initiated Due to COVID-19 Pandemic 
Each participating site, ethics committees, and the Federal Institute for Drugs 
and Medical Devices (BfArM) were informed (22 April 2020) of urgent safety 
measures implemented to ensure continued supply of study medication and 
safety monitoring for patients. These measures are described in the “Updated 
Guidelines to Sites for Delayed Patient Visits or Missed Visits due to travel 
restrictions and any foreseeable impacts of COVID-19” (Appendix 9). When the 
COVID-19 pandemic resolves, the measures will be repealed back to the 
previous state as government rules and benefit/risk assessment allow. 
New section added to address 
measures taken due to the 
COVID-19 pandemic that were 
earlier submitted as an Urgent 
Safety Measures letter. 
7.3 Trial Stopping Rules 
The trial will be terminated if major safety concerns related to PRN1008 
(Rilzabrutinib) or placebo emerge. Trial safety stopping criteria in Germany are: 
5.  If the insurance cover cannot be adjusted to the maximum sum necessary in 
the event that the risk profile worsens. 
6.  If the approval or the positive assessment has been revoked by the State 
Office for Health and Social Affairs; Ethics Commission of the State of 
Berlin.   
Per German Central Ethics 
Committee requirement 
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7.4.1 Patient Discontinuation 
and Stopping Rules 
 
Mandatory termination criteria for a patient in this study in Germany include: 
[new 6th bullet] 
• 
Positive SARS-CoV-2 test at any time during the study 
Per German Central Ethics 
Committee requirement 
7.6 Visit Overview 
During the trial, patients will return at specified times on an outpatient basis for 
assessment of vital signs, physical examination, assessment of AEs and concomitant 
medication use, assessment of clinical benefit and for provision of blood samples for 
clinical safety, PK, and PD assessment. Subjects must be tested for SARS-CoV-2 
infection within one week prior to each visit or up to 2 days after each visit. 
… 
Per German Central Ethics 
Committee requirement 
7.7.15 SARS-CoV-2 Testing 
Requirement 
7.7.15 SARS-CoV-2 Testing Requirement 
Testing for infection with SARS-CoV-2 will be required and collected during 
screening and for all regular study visits. The testing for SARS-CoV-2 infection 
must be performed within one-week (7 days) prior to each visit or up to two (2) 
days after. SARS-CoV-2 tests can be performed following local or institutional 
guidelines in order to fulfil protocol requirements. Documentation of test results 
must be provided to the Investigator. If the time required for obtaining results 
exceeds this testing window, an extension may be granted by the Medical 
Monitor. The requirement for the test may be waived by the Medical Monitor 
(with approval from the Ethics Committee) if the local regulations change with 
control of the pandemic. 
Per German Central Ethics 
Committee requirement 
10.2.14 Long Term Extension 
Analysis 
The Long Term Extension endpoints will be summarized descriptively. 
Summaries of patient disposition, demographics, and baseline characteristics 
will be provided. The number of received doses and treatment duration will be 
described. Safety data including adverse events, laboratory evaluations and vital 
signs assessments will also be summarized. 
New analysis section added to 
reflect addition of LTE 
endpoints 
 
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12.13.12. 
Clinical Study Protocol Version 5.1 for UK (22 June 2020)  
This was a local amendment to protocol Version 5 and was regarded as a substantial amendment. 
Overall Rationale for the Amendment  
The primary reason for this amendment to Protocol PRN1008-012, Version 5.1 is: 
• 
To remove the Long Term Extension Period and all associated procedures and language. 
 
 
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Protocol Amendment summary of changes Table 
PRN1008-012 Protocol V 5.0 (22 January 2020) to 5.1 United Kingdom (24 June 2020) 
 
Protocol Version 5.0 dated 22 January 2020 has been updated throughout to correct for administrative errors as well as for consistency. Deleted 
text has strikethrough and new text is bolded. Minor editorial changes are not included in this summary document. 
Section #/Name 
Amended or New Wording 
Justification of Change 
Throughout the protocol 
22 Jan 2020 24 Jun 2020  
Administrative change to 
reflect new protocol date 
Throughout the protocol 
Version 5.0 Version 5.1 
Administrative change to 
reflect new protocol date 
Synopsis - Duration of Trial Participation 
Synopsis - Study Design 
Synopsis - Corticosteroid Management during 
Blinded 
Treatment Period and Open-Label Extension Period 
Figure 1 
Table 4 (original) et seq. 
5.6 Trial Design Rationale 
6.2 Corticosteroids 
7.2 Trial Enrollment Procedures 
7.4.1 Patient Discontinuation and Stopping Rules 
7.6.5 Long Term Extension Period (Beginning 
Week 61) 
(original) et seq. 
7.6.6 Early Termination Visit 
7.7.6 Electrocardiogram Monitoring 
Appendix 1 Corticosteroid and Rituximab 
Management 
Removal of text related to the Long Term Extension (LTE) Period 
throughout. 
Renumbering of subsequent table after Table 4 Schedule of 
Assessments  Long Term Extension Period removed. 
Renumbering of subsequent sections after original Section 7.6.5 Long 
Term Extension Period (Beginning Week 61) removed. 
Removal of the Long Term 
Extension Period pending 
adjustments of analysis plan 
and statistical assessments 
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12.13.13. 
Clinical Study Protocol Version 5.2 for UK (21 December 2020)  
This was a local amendment to protocol Version 5.1 and was regarded as a substantial 
amendment. 
Overall Rationale for the Amendment  
The primary reasons for this amendment to Protocol PRN1008-012, Version 5.2 are: 
• 
To add Long Term Extension (LTE) objective in alignment with UK MHRA request to 
provide study endpoints including the LTE Period, 
• 
To update eligibility criteria to enroll in the LTE, 
• 
To add consent required before entering LTE, 
• 
To reflect that the Sponsor will be the source of corticosteroids in the LTE, 
• 
To reflect that patients requiring rituximab during the LTE must be discontinued. 
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Protocol Amendment summary of changes Table 
PRN1008-012 Protocol Version 5.1 (22 Jun 2020) to Version 5.2 (21 December 2020) 
Protocol Version 5.1 dated 22 Jun 2020 has been updated throughout to correct for administrative errors as well as for consistency. Deleted text 
has strikethrough and new text is bolded. Minor editorial changes are not included in this summary document. 
Section(s) 
Amended or New Wording 
Justification of Change 
Throughout the protocol 
22 June 2020 21 December 2020 
Administrative change to 
reflect new protocol date 
Throughout the protocol 
Version 5.1 Version 5.2 
Administrative change to 
reflect new protocol date 
Protocol Signature Page 
Administrative change to 
reflect new protocol signatory 
Synopsis:  
2.7. Duration of Trial 
Participation 
Long Term Extension Period 
Study duration for the patients who enter the Long Term Extension Period will be 
determined by the criteria described in the Study Design Section 3.3.1 of the Study 
Synopsis. 
Updated to reflect study 
duration including Long Term 
Extension. 
Synopsis:  
3.2.5 Long Term Extension 
Objective 
Long Term Extension Objective 
• 
To evaluate the long-term safety of PRN1008 
Addition of Long Term 
Extension (LTE) Objective in 
alignment with UK MHRA 
request to provide study 
endpoints including the LTE 
Period. 
Synopsis:  
3.3.1 Study Design 
Long Term Extension (LTE) 
Period (Week 61 to Week 109) 
After completing the Open-Label Extension Period, patients who are responding to 
PRN1008 treatment will be eligible to enter the Long Term Extension Period and 
will continue to receive open-label PRN1008 400 mg bid for 48 weeks per Table 4.  
Patients are eligible to participate in the LTE if: 
Addition of requirements for 
eligibility to enroll in the 
LTE. 
 
 
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a) 
they have achieved and/or maintained an ECP with ≤10 mg/day CS at 
any time between 37 and 61 weeks in the study. 
Patients are not eligible to participate in the LTE if: 
a) 
they have more than one relapse following ECP requiring treatment 
with >10 mg/day CS (excluding CS taken short-term for dental work or 
surgery), or  
b) 
have failed to adequately recover after a relapse despite maximal 
tolerated CS dose. 
Failure to adequately recover is defined as: <25% decrease from peak PDAI 
despite treatment with maximal steroid doses (minimum of 1.5 mg/kg/day unless 
there is a specific documented medical contraindication) for at least 2 weeks.  
CS doses above refer to doses of prednisone or its equivalent. 
The maximum acceptable maximum acceptable duration between completing the 
OLE Period and entering the LTE Period is 14 days.  In addition to meeting the 
disease response criteria defined above, eligibility to enter the LTE requires the 
following: 
• 
Based on the PI’s clinical assessment, the patient is able to continue the 
study and undertake all protocol requirements, does not have any 
conditions that would preclude participation and the benefit risk 
assessment for participation remains favorable for the patient.  
• 
Lab evaluations (hematology, coagulation and serum chemistry) at the 
Week 61 visit should be within normal limits or not considered clinically 
significant for the purpose of the patient’s participation in the study, by the 
Investigator. 
• 
No currently active moderate to severe infection at Week 61 (Grade 2 
or higher). 
Patients may continue in the LTE until: 
a) 
they have had more than one relapse following ECP that requires >10 
mg/day CS (excluding CS taken short-term for dental work or surgery) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Detail provided for maximum 
gap between OLE and LTE. 
 
 
 
 
 
 
 
 
 
 
 
Detail provided for patients to 
discontinue when no longer 
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or have failed to adequately recover after a relapse despite maximal 
tolerated CS dose (per definition of failure to adequately recover 
above);  
b) 
the drug is no longer being developed by the Sponsor for this 
indication;  
c) 
the program is stopped for safety reasons. 
Patients who have previously completed the Open-Label Extension Period prior to 
this amendment and were responders per the LTE requirement may enroll into the 
LTE.   
Patients entering the LTE will receive Sponsor-provided CS, following CS 
Management Guidelines (Appendix 1). 
Patients requiring rituximab during the Long Term Extension Period will be 
discontinued from the trial. 
responding to PRN1008 
within the LTE. 
 
 
 
 
 
 
Reflects that the Sponsor will 
be the source of 
corticosteroids in the LTE and 
that patients who require 
rescue rituximab must be 
discontinued. 
 
Synopsis: Outcome Measures 
Section 3.8.8 Long Term 
Extension Endpoints 
Long Term Extension Endpoints 
• 
Nature, frequency, and severity of adverse events, including serious adverse 
events, adverse events leading to discontinuation and possible corticosteroid-
related adverse effects during the LTE from Week 61 to Week 113 
• 
Average daily dose of CS from Week 61 to Week 113 
• 
Time to relapse during the LTE 
Per UK MHRA request to 
include LTE Endpoints. 
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Amended or New Wording 
Justification of Change 
Figure 1: Study Design Flow 
Chart 
 
Updated to include LTE. 
Table 3. Schedule of 
Assessments - Open Label 
Extension Period  
 
  n. Patients will be asked to consent to participating in the LTE Period, prior to 
continuing in the LTE. 
 
Updated to indicate that 
patients must be asked to 
provide consent prior to 
continuing in the LTE, per 
MHRA request and to be 
consistent with Table 4. 
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Amended or New Wording 
Justification of Change 
Table 4. Schedule of 
Assessments - Long Term 
Extension Period 
 
a. The early termination (ET) visit should also be performed for patients who are 
not able to complete the Long-Term Extension period including Week 113 visit 
and discontinue from the trial early.  
b. Only if clinically indicated.  
c. Hematology will include the following: hemoglobin, hematocrit, erythrocyte 
count (red blood cell [RBC] count), thrombocyte count (platelets), leukocyte 
count (white blood cell [WBC] count) with differential in absolute counts 
(including neutrophils, eosinophils, basophils, lymphocytes, and monocytes). 
Serum chemistry will include the following: aspartate aminotransferase (AST); 
alanine aminotransferase (ALT); total, direct, and indirect bilirubin levels; 
alkaline phosphatase (ALP); albumin; creatinine; urea; total protein; sodium; 
chloride; calcium; phosphate; potassium; and glucose (random). Coagulation 
will include: PT/INR, thrombin time, aPTT, and fibrinogen level and will be 
collected at Weeks 61, 85, 97, 109, ET, and EOT. Urinalysis will include: pH, 
specific gravity, protein, glucose, ketones, bilirubin, blood, nitrites, 
urobilinogen, leukocytes and reflex microscopy.  
Added assessments for LTE. 
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Section(s) 
Amended or New Wording 
Justification of Change 
d. For women of childbearing potential only. May be performed monthly between 
Week 73 and Week 113 if required by local regulations. 
e. PK sample required at Week 61; and after Week 61 only if the patient 
experiences relapse. Time of draw will be captured as well as time of the last 
two PRN1008 doses, and time since the patient’s last meal. 
f. Pemphigus Clinical Response Definitions for CDA, CR, ECP, Relapse (refer to 
protocol Section 3.1).  
g. Any photos should be taken and stored in accordance with local regulations 
(Week 61 only). 
h. Subjects are required to bring all used and unused PRN1008 study drug 
supplies with them to every clinic visit. 
i. 
For CS management, refer to Appendix 1. Patients entering the LTE will 
receive Sponsor-provided CS. At any point if CS needs to be adjusted between 
required visits, the patient may return for an unscheduled visit and additional 
CS may be dispensed.  
j. Assessments performed at the Week 61 Visit of the Open-Label Period should 
not be repeated at this visit.  
k. Patients will be asked to consent to participating in the LTE Period, prior to 
continuing in the LTE. 
5.6 Trial Design Rationale 
The primary purpose of the 48-week, Long Term Extension Period (LTE) is to 
provide extended access to PRN1008 for patients who are receiving clinical benefit 
and to accrue additional long-term data on the safety of PRN1008. 
Added primary purpose of the 
LTE in line with endpoints. 
6.2. Corticosteroids 
Oral corticosteroids (prednisone or prednisolone) will be provided during the Blinded 
Treatment Period and Open-Label Extension Period. Patients entering the LTE will 
receive Sponsor-provided CS. 
 
Reflects that the Sponsor will 
be the source of 
corticosteroids in the LTE 
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Section(s) 
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Justification of Change 
7.4.1 Patient Discontinuation 
and Stopping Rules 
• 
A patient in the Blinded Treatment Period requiring an additional “top up” 
dose of rituximab after their initial rituximab course of treatment or a patient in the 
Open-Label Extension Period or Long Term Extension Period requiring rituximab 
Reflects that patients requiring 
rituximab during the LTE 
must be discontinued.   
7.6.7. Early Termination Visit 
Please refer to Table 2 (if terminating during double-blind treatment), Table 3 (if 
terminating during Open-Label Extension), or Table 4 (if terminating during Long 
Term Extension) for specific early termination assessments. An attempt should be 
made to have the patient return for a follow-up visit approximately 4 weeks after the last 
dose of PRN1008 or placebo. 
Patients in the OLE or LTE who are required to discontinue the study early per 
the rituximab receipt rules (Section 6.3) should have their Early Termination visit 
completed prior to rituximab infusion. 
 
Updated for consistency. 
9.4.9 Long Term Extension 
Analysis 
The Long Term Extension endpoints will be summarized descriptively. Summaries 
of patient disposition, demographics, and baseline characteristics will be provided. 
The number of received doses and treatment duration will be described. Safety 
data including adverse events, laboratory evaluations and vital signs assessments 
will also be summarized. 
New analysis section added to 
reflect addition of LTE 
endpoints 
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12.13.14. 
 Amended Clinical Trial Prototocol 06 (06 May 2021)   
This was a global amendment to protocol Version 5 and was considered to be substantial. 
OVERALL RATIONALE FOR THE AMENDMENT 
The primary reasons for this amendment to Protocol PRN1008-012 were: 
• 
To add an exploratory objective in order to evaluate the impact of the Investigational 
Medicinal Product (IMP) on vaccine responses,  
• 
To revise the key secondary efficacy, other secondary endpoints, and exploratory 
endpoints and associated statistical analyses, in particular to provide additional clinically 
meaningful endpoints assessing  reduction of corticosteroid (CS) use, duration of complete 
remission (CR) achieved with the use of minimal CS treatment, speed of action in 
achieving CR with minimal CS treatment, and proportion of relapses/flares as defined in 
consensus guidelines. 
• 
To clarify Long Term Extension (LTE) objectives and assessments, definitions of early 
termination (ET)/end of trial (EOT) visits, adaptations in response to Coronavirus disease 
2019 (COVID-19) pandemic, and  allowing pharmacokinetic (PK) assessment of 
rilzabrutinib metabolites and IV CS. 
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Protocol amendment summary of changes table 
PRN1008-012 Amended Clinical Trial Protocol 06 (06 May 2021) 
Section # and name 
Description of change 
Brief rationale 
Title Page, Approval of the 
Protocol, Sponsor Signatory name, 
Protocol Amendment Summary of 
Changes, and Section 1.1 Synopsis 
Document formatting revisions were made. Signatures pages were 
removed. A new section including protocol amendment summary of 
changes and document history was added. The International 
Nonproprietary Name (INN) (rilzabrutinib) was added on title page and in 
the header. The Sanofi compound number SAR444671 and study number 
EFC17092 were added to the header. The brief title “PEGASUS pivotal 
study”, NCT03762265 number, and “not applicable” for WHO, 
EUDAMED, and other regulatory agency identifier numbers were added 
on title page.  
Changes made to reflect the updated 
amended protocol 06 and to comply with 
parent company Sanofi standards and 
processes. Protocol approval is conducted 
via electronic signature. 
Section 1.1 Synopsis 
The numbering of subsections was removed. 
Changes made to comply with parent 
company Sanofi standards. 
Section 1.1 Synopsis: Duration of 
Trial Participation, and Blinded 
Treatment Period, and Section 4.1 
Overall Design, Duration of Trial 
Participation and Blinded 
Treatment Period 
The duration of trial participation was changed to: “For each patient, the 
trial will last approximately 68 weeks including Screening Period (up to 4 
weeks), the Blinded Treatment Period (Week 1 through Week 37), the 
Open-Label Extension Period (Week 37 to Week 61), and a 4-week end 
of treatment follow-up (up to Week 65).” 
Changes made for clarification. 
Section 1.1 Synopsis: Pemphigus 
Clinical Definitions and Section 3 
Objectives and Endpoints 
The definition of Relapse/Flare was revised in bold as follows: “They are 
defined by the appearance of 3 or more new lesions after CDA and within 
a month that do not heal spontaneously within 1 week, or by the extension 
of established lesions, in a patient who has achieved CDA”. 
Changes made for clarification. 
Section 1.1 Synopsis: Exploratory 
Objectives, Exploratory Endpoints, 
Pharmacokinetic and 
Pharmacodynamic, and Section 3 
Objectives and Endpoints 
The following exploratory objective “To evaluate the PK of rilzabrutinib 
metabolites” was added with the new following endpoint “Plasma 
concentrations of rilzabrutinib metabolites”. 
Changes related to study procedures 
made for consistency with the added 
exploratory objective and to allow PK 
assessment of rilzabrutinib metabolites. 
The text was updated to "Individual and group PK (rilzabrutinib and 
metabolites as applicable) and PD (antidesmoglein-1 and -3) data will be 
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Section # and name 
Description of change 
Brief rationale 
summarized, displayed graphically, and by descriptive statistics for each 
visit, where measured. Please refer to the Statistical Section 9”. 
Section 1.1 Synopsis: Exploratory 
Objectives, Exploratory endpoints, 
and Section 3 Objectives and 
Endpoints 
The following exploratory objective “To explore association of vaccine 
response with rilzabrutinib” and following exploratory endpoint: 
“(Optional) Blood samples for exploratory analysis of vaccine IgG 
response during treatment” was added. 
Changes made to address the purpose of 
this amendment, and for consistency with 
the added exploratory objective. 
Section 1.3 Schedule of activities 
(SoA) (Table 2, Table 3, and Table 
4) 
Vaccine IgG and SARS-CoV-2 (for participants in Germany only, see 
specific instructions in Appendix 10) were added to Table 2, Table 3, and 
Table 4. 
Footnotes “r” and “s” of Table 2, footnotes “n” and “o” of Table 3 and 
footnotes “k” and “l” of Table 4 regarding passive collection and optional 
collections of blood pre-and post-vaccine dose regimen were added.  
Section 8.2 Trial Enrollment 
Procedures, Section 8.3.1 
Screening (Day -29 to Day -1), 
Section 8.3.5 Long Term Extension 
Period (Beginning Week 61), 
Section 8.4.8.1 Vaccine IgG, 
Section 10.3 Informed Consent and 
Section 12.11 Appendix 11 
Vaccine Response 
Wording specifying that consent for collection of 2 blood samples for 
assay of vaccine IgG in serum for each vaccination was required by those 
patients who make mid-study decisions about vaccinations was added. 
A reference to Appendix 11 for additional details was added. Section 
8.4.8.1 and Appendix 11 were added to emphasize that this exploratory 
vaccination testing could be conducted in participants treated with 
rilzabrutinib for at least 6 weeks and expected to continue in the study for 
at least 12 weeks in either the Open-Label Period or Long-Term 
Extension Period. 
Section 9.3.7 Pharmacokinetic and 
Pharmacodynamic Analysis 
Concerning statistics from exploratory analyses, “will" was changed to 
"may" to align with the exploratory objectives. 
Section 9.3.8 Exploratory Analysis 
The following text was added: “If collected, vaccine response parameters 
may be summarized by treatment group and, by disease and antigenic 
strain of the vaccine dose regimen”. 
Section 1.1 Synopsis:  Blinded 
Treatment Period (Weeks 1 to 37), 
Section 9.3.5 Efficacy Analysis 
(mITT Population), and Section 
The following text was removed from Synopsis and Appendix 1: “but will 
be considered treatment failures for all efficacy endpoints except for CS 
dosing and composite Glucocorticoid Toxicity Index (GTI) score.”, and 
relocated in Section 9.3.5. 
Changes made for clarification by 
separating instructions to investigators on 
use of rituximab during the trial from 
treatment of rituximab use in the 
statistical analysis. 
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Section # and name 
Description of change 
Brief rationale 
12.1 Appendix 1 Corticosteroid and 
Rituximab Management  
Section 1.1 Synopsis, Long Term 
Extension Objective, Long Term 
Extension Endpoints, Long Term 
Extension Analysis, Section 2.1 
Study Rationale, Section 3 
Objectives and Endpoints, Section 
4.2 Scientific Rationale for Study 
Design, and Section 9.3.9 Long 
Term Extension Analysis 
The following objective “To evaluate the long-term safety and efficacy of 
rilzabrutinib” was added with the new following endpoints:  
• 
“Nature, frequency, and severity of adverse events, including serious 
adverse events, adverse events leading to discontinuation and possible 
corticosteroid-related adverse effects during the LTE from Week 61 to 
Week 113 
• 
Average daily dose of CS from Week 61 to Week 113 
• 
Time to initial relapse/flare from initial CDA to Week 109”. 
The section describing the analysis of LTE endpoints was added. 
Changes related to study procedures to 
clarify objectives and endpoints to be 
assessed during the LTE period. 
 
Section 1.1 Synopsis: 
Investigational Plan: Blinded 
treatment period (week 1 to 37), 
Corticosteroid Management, 
Section 4.1 Overall Design: 
Blinded treatment period (Week 1 
to 37), Section 6.1.2.1 
Corticosteroid Starting Doses and 
Management During Screening and 
at Day 1, and Section 12.1 
Appendix 1 Corticosteroid and 
Rituximab management  
The following wording “below the required minimum dose level” was 
added next to “CS taper”. 
Changes related to study procedures made 
for clarification. 
Section 1.1 Synopsis: End of Trial 
(Follow-up Period, 4 Weeks after 
last Trial Dose), Section 4.4 End of 
Study Definition 
“End of trial” was added next to the subtitle “(Follow-up Period, 4 Weeks 
after last Trial Dose)“. The following text was revised as follows: 
“Patients who are not able to complete the Blinded Treatment Period, 
Open-Label Extension Period or Long Term Extension Period as planned 
and discontinue the study early should be encouraged to come back for an 
Early Termination (ET) visit as soon as possible.” 
The following text was added: 
Changes related to study procedures made 
for clarity between ET and EOT visits. 
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Section # and name 
Description of change 
Brief rationale 
“In addition to the ET Visit, patients should return for the EOT Visit 4 
weeks following their last dose of rilzabrutinib/placebo or rilzabrutinib.   
In the event the ET Visit occurs ≥4 weeks after their last dose of 
rilzabrutinib/placebo or rilzabrutinib, this will be recorded as the ET Visit 
and there is no need for the 4-week safety follow-up (EOT) visit”. 
Section 1.1 Synopsis: Urgent 
Safety Measures Initiated Due to 
Coronavirus disease 2019 
(COVID-19) Pandemic, Section 4.2 
Scientific Rationale for Study 
Design, Section 6.2.2 Drug 
Management, Section 8.2 Trial 
Enrollment Procedures, Section 8.3 
Visit Overview, Section 8.6.3.1 
Adverse Event Collection Period, 
Section 12.9 Appendix 9 Updated 
Guidelines to Sites for Delayed 
Patient Visits or Missed Visits due 
to travel restrictions and any 
foreseeable impacts of COVID-19 
Urgent Safety Measures Initiated Due to Coronavirus disease 2019 
(COVID-19) Pandemic were added. These measures include at least 
remote study visits, enrollment procedures, direct to patient delivery of 
study medication for flexibility to continue the trial during regional or 
national emergency such as COVID-19 pandemic. 
Include flexibility and ease of 
continuation of study during regional or 
national emergency such as COVID-19. 
Section 1.1 Synopsis: Inclusion 
Criteria and Section 5.1 Inclusion 
Criteria 
The inclusion criterion I04 was revised as follows: “Adequate 
hematologic, hepatic, and renal function (including but not limited to 
absolute neutrophil count ≥1.5 × 109/L, hemoglobin [Hgb] >9 g/dL, 
platelet count ≥100 × 109/L, aspartate aminotransferase [AST] and/or 
alanine aminotransferase [ALT] ≤1.5 × upper limit of normal [ULN], 
albumin ≥3 g/dL, creatinine ≤1.5 × ULN).” 
Changes related to study procedures made 
for clarification. 
Section 1.1 Synopsis: Outcome 
Measures: Primary efficacy 
endpoint, Section 3 Objectives and 
Endpoints, Section 9.1 Sample size 
determination, and Section 9.3.5 
Week ≤ 29” was replaced by “Week 29”. 
Changes related to study procedures made 
for clarification. 
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Section # and name 
Description of change 
Brief rationale 
Efficacy Analysis (mITT 
Population) 
Section 1.1 Synopsis: Key 
Secondary Efficacy Endpoints, 
Section 3 Objectives and 
Endpoints, Section 9.3.5 Efficacy 
Analysis (mITT Population), and 
Section 9.3.6 Key Secondary 
Efficacy Sequential Testing  
Key secondary endpoints were changed to: 
• 
“Cumulative CS dose from Baseline to Week 37 
• 
Cumulative duration of CR with a CS dose ≤10 mg/day, from Baseline 
to Week 37 
• 
Time to first CR with a CS dose ≤10 mg/day, from Baseline to Week 
37 
• 
Proportion of patients with at least one disease relapse/flare from 
initial control of disease activity (CDA) to Week 37 
• 
Cumulative duration of CR with a CS dose ≤10 mg/day, from Week 
37 to Week 61 
• 
Cumulative duration of CR with a CS dose = 0 mg/day, from Week 37 
to Week 61”. 
Changes to clarify secondary endpoints 
and evaluate CR during the Open Label 
Extension (OLE) Period. 
Section 1.1 Synopsis: Other 
Secondary Endpoints, Section 3 
Objectives and Endpoints, and 
Section 9.3.6 Key Secondary 
Efficacy Sequential Testing 
New other secondary endpoints were added or revised as follows: 
• 
“The proportion of patients who are in CR from Week 29 to Week 37 
with a CS dose of ≤10 mg/day 
• 
The proportion of patients who have a PDAI score <3 from Week 29 
to Week 37 with a CS dose ≤10 mg/day 
• 
Cumulative duration of CR with a CS dose ≤10 mg/day from 
Baseline to Weeks 61 and 109 
• 
Cumulative duration of CR with a CS dose = 0 mg/day from Baseline 
to Weeks 61 and 109 
• 
Change in PDAI score from Baseline to Weeks 5, 13, 25, 37, 61, and 
109 
• 
Change in Autoimmune Bullous Disease Quality of Life (ABQOL) 
score from Baseline to Weeks 5, 13, 25, 37, 61, and 109 
• 
Proportion of patients with ABQOL Score of zero at Weeks 5, 13, 25, 
37, 61, and 109 
Changes related to secondary endpoints 
were made to evaluate efficacy during the 
OLE and LTE Periods.  
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Section # and name 
Description of change 
Brief rationale 
• 
Change in EuroQOL-5 Dimension 5 Level (EQ-5D-5L) results 
(visual analog scale [VAS] results and individual dimension) scores 
from Baseline to Weeks 5, 13, 25, 37, 61, and 109 
• 
Time to first CR with a CS dose ≤10 mg/day, from Baseline to Weeks 
61 and 109 
• 
Total number of disease relapses/flares from initial CDA to Week 37 
• 
Time to initial relapse/flare from initial CDA to Week 37 
• 
Proportion of patients with 3 or more new lesions within 1 month that 
do not heal spontaneously within 1 week, or with extension of 
established lesions, from baseline to Week 37”. 
Section 1.1 Synopsis: 
Pharmacodynamic Endpoints, and 
Section 3 Objectives and Endpoints 
“Week 109” was added to the PD endpoint timepoints for PD 
assessments. 
Changes made for correction. 
Section 1.1 Synopsis: Exploratory 
Endpoints, Section 3 Objectives 
and Endpoints 
 
New exploratory endpoints were added or revised as follows: 
• 
“Proportion of patients with relapse/flare after achievement of CR 
between Baseline and Weeks 61 and 109 
• 
Proportion of patients initially randomized to rilzabrutinib that are in 
CR with a zero CS dose, from Week 53 to Week 61 (no randomized 
treatment comparison) 
• 
Proportion of patients initially randomized to placebo that are in CR 
with a zero CS dose, from Week 53 to Week 61 (no randomized 
treatment comparison) 
• 
Change in Treatment of Autoimmune Bullous Disease Quality of Life 
(TABQOL) score from Baseline to Weeks 5, 13, 25, 37, 61, and 109 
• 
Total number of disease relapses/flares from Week 37 to Weeks 61 
and 109”. 
Changes related to exploratory endpoints 
to evaluate efficacy during the OLE and 
LTE Periods. 
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Section # and name 
Description of change 
Brief rationale 
Section 1.3 Schedule of activities 
(SoA) (Table 3) 
• 
Removal of HbA1C, LDL level (fasting) and GTI Index from 
Week 61. 
• 
Footnote “i” was updated as follows: "Patients entering the LTE will 
receive Sponsor-provided CS, following CS Management Guidelines 
(Appendix 1)”. 
Changes related to study procedures made 
for clarification and alignment with the 
document. 
Section 1.3 Schedule of activities 
(SoA) (Table 4) 
• 
Removal of HbA1C, LDL level (fasting), and GTI Index. 
• 
Removal of PK sample and photography after Week 61. 
• 
PDAI, ABQOL/TABQOL, EQ-5D-5L assessments remained only at 
Week 61, Week 109, and Early termination (ET) visits. 
• 
The following text was added to the footnote “d” to clarify the urine 
pregnancy test:“May be performed monthly between Week 73 and 
Week 113 if required by local regulations”. 
• 
The footnote “e” was revised as follows:” PK sample required at 
Week 61; and after Week 61 only if the patient experiences 
relapse/flare”.  
• 
“ (Week 61 only)” was added to the footnote “g” related to the intake 
of photos. 
Section 4.1 Overall Design 
“Phase 3” was added in the design section. 
Changes made to comply with parent 
company Sanofi standards. 
Section 4.3 Justification for dose 
Text referring “Black box” warnings and “Warnings and Precautions” in 
the US Product Information for RITUXAN was replaced by: 
“For detailed safety information on rituximab or other biosimilar agents  
investigators should refer to the current, locally applicable, approved 
product information.” 
Section updated to account for national 
variations in labeling for rituximab. 
Section 5 Study Population 
“Prospective approval of protocol deviations to recruitment and 
enrollment criteria, also known as protocol waivers or exemptions, is not 
permitted” was added. 
Changes made as per Sanofi template. 
Section 6 Study Intervention(s) and 
concomitant therapy 
Updated text providing study intervention definition in first paragraph. 
Changes made as per Sanofi template. 
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Section # and name 
Description of change 
Brief rationale 
Section 6.5.1 Prohibited 
Medications 
“Live vaccines” was added to the list of prohibited medications. 
Changes made for consistency with the 
exclusion criterion E19. 
Section 6.5.2 Particular Permissible 
Medications and Section 6.1.2 
Corticosteroids 
The text was added to specify possible use of short, defined courses of 
intravenous corticosteroids, if deemed clinically necessary and at doses 
consistent with the oral regimen, after consultation with Medical Monitor, 
and possible use of Sponsor-provided oral prednisolone during the 
Blinded Treatment Period. The "patients entering the LTE will no longer 
receive sponsor-provided CS" text was updated to "patients entering the 
LTE will receive Sponsor-provided CS". 
Changes related to study procedures made 
for clarification. 
Section 8.3.6 OLE EOT/Week 65 
and LTE EOT/Week 113 Visits 
(Follow-up Period, 4 Weeks after 
last Trial Dose) 
The wording of the subtitle was revised. The following text was added 
“EOT Visit for safety follow-up procedures performed 4 weeks after the 
last dose of study drug.” 
Changes related to study procedures made 
for clarification. 
Section 8.3.7 Early Termination 
Visit 
A statement was added concerning patients in the open-label extension 
(OLE) or LTE who should have their Early Termination (ET) Visit 
completed prior to rituximab infusion. 
Changes related to study procedures made 
for clarification. 
Section 8.4.15 SARS-CoV-2 
Testing Requirement (for German 
participants only) 
The entire section was added. 
Changes related to study procedures made 
for clarification. 
Section 8.5 Assessment of efficacy 
The entire section was added. 
Changes made for clarification and as per 
Sanofi template. 
Section 8.5.1 Specification of the 
Efficacy Parameters, Section 9.3.6 
Key Secondary Efficacy Sequential 
Testing, and Section 9.3.8 
Exploratory Analysis 
“Change in TABQOL score from baseline to Weeks 5, 13, 25, 37, 61, and 
109” is an exploratory endpoint. Then, TABQOL analysis moved from 
other secondary efficacy parameters analysis section to the exploratory 
analysis section. 
Changes made for correction. 
Section 8.6.4 Pregnancy 
Three bullets with information regarding reporting pregnancy AEs/SAEs, 
including complication or elective termination, abnormal pregnancy 
outcomes. and post-study pregnancy-related SAEs considered reasonably 
related to the study intervention by the Investigator were added. 
Changes related to statistical methodology 
made for clarification and as per Sanofi 
template. 
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Section # and name 
Description of change 
Brief rationale 
Section 9.1 Sample Size 
Determination 
The targeted minimum of PV patients changed from “45” to “90” as well 
as the maximum number of PF patients from “10” to “22”. 
Changes made for correction. 
Section 9.3.9 Long term extension 
analysis 
The following text “in general” was added after “The long term extension 
endpoints will be summarized descriptively”. “More details will be 
provided in the SAP” was added at the end of the paragraph. 
Changes made for clarification. 
Section 9.3.5 Efficacy Analysis 
(mITT Population) 
Text was amended to “Patients who drop out of the trial, withdraw, or 
who receive a rituximab dose prior to Week 37 will count as non-
responders in the analysis”. 
Changes to separate investigator 
instruction from statistical analysis 
approach regarding use of rituximab. 
Section 10 Investigator 
Responsibilities 
 
Updated to specify that investigators will sign the separate protocol and 
amended protocol agreement form. 
Changes made to comply with Sanofi 
standards. 
Section 12.1 Appendix 1:  
Corticosteroid and rituximab 
management 
The following text: “For patients that have a documented and specific 
medical contraindication, the maximally tolerated dose of corticosteroid 
may be considered for this purpose following consultation with the 
Medical Monitor” was changed to  
“For patients who are unable to escalate CS up to 1.5 mg/kg/day due to 
documented adverse events related to CS and cannot achieve CDA 
following 2 weeks of treatment with their maximally tolerated CS dose, 
rescue with rituximab therapy may be offered. Please consult with the 
Medical Monitor.” 
Changes made for clarification.  
Section 12.10 Appendix 10: 
Country-specific requirements  
This entire section was added to outline country specific requirements for 
participants from Germany such as additional inclusion/exclusion criteria, 
different contraception requirements, SARS-CoV-2 testing requirements, 
additional trial stopping rules and patient discontinuation rules (positive 
COVID test). 
Changes made to comply with Sanofi 
standards. 
Section 12.12 Appendix 12: 
Abbreviations 
List of abbreviations was updated by adding or removing abbreviations 
and moved to Appendix 12. 
List of abbreviations updated for 
correction and clarity and to comply with 
Sanofi standards. 
Section 12.13 Appendix 13: 
Protocol Amendment History 
This entire section was added.  
Changes made to comply with Sanofi 
standards. 
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Section # and name 
Description of change 
Brief rationale 
Section 13 References 
List of references was updated and numbered. 
Changes made to comply with Sanofi 
standards. 
Throughout document 
Document formatting revisions and other minor editorial changes have 
been made. Titles of sections were added. Order of sections was revised, 
and new sections were created. "PRN1008" has been replaced with 
“PRN1008 (rilzabrutinib)” or “rilzabrutinib". The wording "relapse” was 
changed to “relapse/flare". 
Changes made for clarification and to 
comply with Sanofi standards. 
 
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13 
REFERENCES  
1. Murrell DF, Peña S, Joly P, Marinovic B, Hashimoto T, Diaz LA, et al. Diagnosis and 
management of pemphigus: Recommendations of an international panel of experts. J Am 
Acad Dermatol. 2020;82(3):575-85. 
2. Shimizu T, Takebayashi T, Sato Y, Niizeki H, Aoyama Y, Kitajima Y, et al. Grading criteria 
for disease severity by pemphigus disease area index. J Dermatol. 2014;41(11):969-73. 
3. Boulard C, Duvert Lehembre S, Picard-Dahan C, Kern JS, Zambruno G, Feliciani C, et al. 
Calculation of cut-off values based on the Autoimmune Bullous Skin Disorder Intensity Score 
(ABSIS) and Pemphigus Disease Area Index (PDAI) pemphigus scoring systems for defining 
moderate, significant and extensive types of pemphigus. Br J Dermatol. 2016;175(1):142-9. 
4. Harman KE, Brown D, Exton LS, Groves RW, Hampton PJ, Mohd Mustapa MF, et al. British 
Association of Dermatologists' guidelines for the management of pemphigus vulgaris 2017. Br 
J Dermatol. 2017;177(5):1170-201. 
5. Baican A, Chiorean R, Leucuta DC, Baican C, Danescu S, Ciuce D, et al. Prediction of 
survival for patients with pemphigus vulgaris and pemphigus foliaceus: a retrospective cohort 
study. Orphanet J Rare Dis. 2015;10:48. 
6. Frew JW, Martin LK, Murrell DF. Evidence-based treatments in pemphigus vulgaris and 
pemphigus foliaceus. Dermatol Clin. 2011;29(4):599-606. 
7. Sideras P, Smith CI. Molecular and cellular aspects of X-linked agammaglobulinemia. Adv 
Immunol. 1995;59:135-223. 
8. Burger JA, Sivina M, Jain N, Kim E, Kadia T, Estrov Z, et al. Randomized trial of ibrutinib vs 
ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood. 
2019;133(10):1011-9. 
9. Chams-Davatchi C, Mortazavizadeh A, Daneshpazhooh M, Davatchi F, Balighi K, Esmaili N, 
et al. Randomized double blind trial of prednisolone and azathioprine, vs. prednisolone and 
placebo, in the treatment of pemphigus vulgaris. J Eur Acad Dermatol Venereol. 
2013;27(10):1285-92. 
10. Strehl C, Bijlsma JW, de Wit M, Boers M, Caeyers N, Cutolo M, et al. Defining conditions 
where long-term glucocorticoid treatment has an acceptably low level of harm to facilitate 
implementation of existing recommendations: viewpoints from an EULAR task force. Ann 
Rheum Dis. 2016;75(6):952-7. 
11. Joly P, Maho-Vaillant M, Prost-Squarcioni C, Hebert V, Houivet E, Calbo S, et al. First-line 
rituximab combined with short-term prednisone versus prednisone alone for the treatment of 
pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial. 
Lancet. 2017;389(10083):2031-40. 
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267 
12. Murrell DF, Amagai M, Werth VP. Scoring systems for blistering diseases in practice: why 
bother, and which one should you use? JAMA Dermatol. 2014;150(3):245-7. 
13. Sebaratnam DF, Hanna AM, Chee SN, Frew JW, Venugopal SS, Daniel BS, et al. 
Development of a quality-of-life instrument for autoimmune bullous disease: the Autoimmune 
Bullous Disease Quality of Life questionnaire. JAMA Dermatol. 2013;149(10):1186-91. 
14. Wijayanti A, Zhao CY, Boettiger D, Chiang YZ, Ishii N, Hashimoto T, et al. The Reliability, 
Validity and Responsiveness of Two Disease Scores (BPDAI and ABSIS) for Bullous 
Pemphigoid: Which One to Use? Acta Derm Venereol. 2017;97(1):24-31. 
15. EuroQol Group. EuroQol--a new facility for the measurement of health-related quality of life. 
Health Policy. 1990;16(3):199-208. 
16. Miloslavsky EM, Naden RP, Bijlsma JW, Brogan PA, Brown ES, Brunetta P, et al. 
Development of a Glucocorticoid Toxicity Index (GTI) using multicriteria decision analysis. 
Ann Rheum Dis. 2017;76(3):543-6. 
17. Beissert S, Werfel T, Frieling U, Böhm M, Sticherling M, Stadler R, et al. A comparison of 
oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of 
pemphigus. Arch Dermatol. 2006;142(11):1447-54. 
18. Rosenbach M, Murrell DF, Bystryn JC, Dulay S, Dick S, Fakharzadeh S, et al. Reliability and 
convergent validity of two outcome instruments for pemphigus. J Invest Dermatol. 
2009;129(10):2404-10. 
19. Tjokrowidjaja A, Daniel BS, Frew JW, Sebaratnam DF, Hanna AM, Chee S, et al. The 
development and validation of the treatment of autoimmune bullous disease quality of life 
questionnaire, a tool to measure the quality of life impacts of treatments used in patients with 
autoimmune blistering disease. Br J Dermatol. 2013;169(5):1000-6. 
20. Feng Y, Devlin N, Herdman M. Assessing the health of the general population in England: 
how do the three- and five-level versions of EQ-5D compare? Health Qual Life Outcomes. 
2015;13:171. 
 
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SAP_001.pdf: 


 
Statistical Analysis Plan,  
 
Sponsor Principia Biopharma  
 
Protocol Number PRN1008-012  
 
 
Version 3.0,  29-Aug-2021 
 Page 2 of 52 
 
Document History  
 
SAP version 
Number 
Date 
Approved 
Rational 
Description of statistical 
changes 
1 
6-Apr-2020 
 
Original SAP 
2 
17-Jun-2021 
Please see Section 2.2 
for details. 
Please see Section 2.2 for 
details 
3 
29-Aug-2021 
Please see Section 2.2 
for details. 
Please see Section 2.2 for 
details 
 
 
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Statistical Analysis Plan,  
 
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Protocol Number PRN1008-012  
 
 
Version 3.0,  29-Aug-2021 
 Page 3 of 52 
 
Table of Contents  
Document History ........................................................................................................................... 2 
Table of Contents ............................................................................................................................ 3 
List of Tables .................................................................................................................................. 5 
1. 
Overview ............................................................................................................................. 6 
2. 
Study Objectives and Endpoints ......................................................................................... 6 
2.1. 
Study Objectives ........................................................................................................... 6 
2.1.1. Efficacy Objectives ....................................................................................................... 6 
2.1.2. Safety Objectives .......................................................................................................... 6 
2.1.3. PK/PD Objectives ......................................................................................................... 7 
2.1.4. Exploratory Objectives ................................................................................................. 7 
2.1.5. Long Term Extension Objective ................................................................................... 7 
2.2. 
Statistical Modifications made in the Statistical Analysis Plan .................................... 7 
2.3. 
Study Endpoints .......................................................................................................... 10 
2.3.1. Safety Endpoints ......................................................................................................... 10 
2.3.2. Efficacy Endpoints ...................................................................................................... 10 
2.3.3. Pharmacokinetic/Pharmacodynamic Endpoints .......................................................... 12 
2.3.4. Exploratory Endpoints ................................................................................................ 12 
2.3.5. Long Term Extension Endpoints ................................................................................ 12 
3. 
Overall Study Design and Plan ......................................................................................... 13 
3.1. 
Overall Design ............................................................................................................ 13 
3.2. 
Sample Size and Power ............................................................................................... 13 
3.3. 
Study Population ......................................................................................................... 14 
3.4. 
Treatments Administered ............................................................................................ 14 
3.5. 
Method of Assigning Subjects to Treatment Groups .................................................. 14 
3.6. 
Blinding and Unblinding............................................................................................. 15 
3.7. 
Schedule of Events ...................................................................................................... 15 
4. 
Statistical Analysis and Reporting .................................................................................... 16 
4.1. 
Introduction ................................................................................................................. 16 
4.2. 
Data Monitoring .......................................................................................................... 16 
4.3. 
Timing of Analyses ..................................................................................................... 17 
5. 
Analysis Populations ......................................................................................................... 17 
6. 
General Issues for Statistical Analysis .............................................................................. 18 
6.1. 
Statistical Definitions and Algorithms ........................................................................ 18 
6.1.1. Baseline Definitions .................................................................................................... 18 
6.1.2. Study Day.................................................................................................................... 18 
6.1.3. Adjustments for Covariates and Subgroup Analyses.................................................. 18 
6.1.4. Multiple Comparisons ................................................................................................. 18 
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6.1.5. Handling of Dropouts or Missing Data ....................................................................... 19 
6.1.6. Analysis Visit Windows ............................................................................................. 22 
6.1.7. Pooling of Sites ........................................................................................................... 23 
6.1.8. Derived Variables ....................................................................................................... 23 
6.1.9. Corticosteroid Dose Derivation for Efficacy Analyses .............................................. 28 
6.1.10. GTI Scores .................................................................................................................. 29 
6.1.11. Data Adjustments/Handling/Conventions .................................................................. 31 
7. 
Study Patients/Subjects and Demographics ...................................................................... 32 
7.1. 
Disposition of Patients/Subjects and Withdrawals ..................................................... 32 
7.2. 
Protocol Violations and Deviations ............................................................................ 32 
7.3. 
Demographics and Other Baseline Characteristics ..................................................... 32 
7.4. 
Exposure and Compliance .......................................................................................... 33 
8. 
Efficacy Analysis .............................................................................................................. 34 
8.1. 
Primary Efficacy Analysis .......................................................................................... 37 
8.2. 
Key Secondary Efficacy Analyses .............................................................................. 37 
8.3. 
Other Secondary Analyses .......................................................................................... 38 
8.4. 
Exploratory Analyses .................................................................................................. 40 
9. 
Safety and Tolerability Analysis ....................................................................................... 40 
9.1. 
Adverse Events ........................................................................................................... 41 
9.1.1. Adverse Events Related to Corticosteroid Use ........................................................... 42 
9.1.2. Adverse Events Leading to Withdrawal ..................................................................... 42 
9.1.3. Deaths and Serious Adverse Events ........................................................................... 42 
9.2. 
Clinical Laboratory Evaluations ................................................................................. 42 
9.3. 
Vital Signs ................................................................................................................... 43 
9.4. 
Physical Examinations ................................................................................................ 43 
9.5. 
Electrocardiograms ..................................................................................................... 43 
9.6. 
Prior and Concomitant Medication ............................................................................. 43 
9.7. 
Long Term Extension Analysis .................................................................................. 43 
10. 
Changes from Planned Analysis ....................................................................................... 44 
11. 
Other Planned Analysis..................................................................................................... 44 
11.1. Pharmacokinetic and Pharmacodynamic Analysis ..................................................... 44 
11.2. Questionnaires and health economic Analysis ........................................................... 44 
12. 
References ......................................................................................................................... 44 
Appendix 1: Abbreviations ........................................................................................................... 46 
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List of Tables  
Table 1: Statistical analysis plan statistical changes from Version 1 ............................................. 7 
Table 2:  Analysis Visit Windows – Blinded Treatment Period ................................................... 22 
Table 3:  Analysis Visit Windows – Open-Label and Long Term Period Extension Periods ...... 23 
Table 4: Event and Censoring Details for Time to First CR with a CS dose at or below 10 
mg/day................................................................................................................................... 24 
Table 5: Event and Censoring Details for Time to First flare/relapse after initial CDA .............. 26 
Table 6: Efficacy Endpoints and Analysis Methods ..................................................................... 34 
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Statistical Analysis Plan,  
 
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1. 
Overview  
This statistical analysis plan (SAP) describes the planned analysis and reporting for Principia 
Biopharma protocol number PRN1008-012 (A Randomized, Double-Blind, Placebo-Controlled, 
Multicenter Trial to Evaluate the Efficacy and Safety of Oral BTK Inhibitor PRN1008 in 
Moderate to Severe Pemphigus), amendment 6 version 2 dated 06-May-2021. Reference 
materials for this statistical plan include the protocol and the accompanying sample data 
collection documents. Operational aspects related to collection and timing of planned clinical 
assessments are not repeated in this SAP unless relevant to the planned analysis. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA), European Medicines Agency (EMA), 
and International Council for Harmonisation (ICH) of Technical Requirements for Registration 
of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical Trials1. All 
work planned and reported for this SAP will follow internationally accepted guidelines, 
published by the American Statistical Association2 and the Royal Statistical Society3 for 
statistical practice. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. Also, post-hoc exploratory analyses not 
necessarily identified in this SAP may be performed to further examine study data. Any post-hoc 
or unplanned, exploratory analysis performed will be clearly identified as such in the final CSR. 
The statistical plan described hereafter is an a priori plan. It will be submitted to file prior to any 
unblinded inferential or descriptive analysis of data pertaining to Principia Biopharma’s study 
PRN1008-012. 
2. 
Study Objectives and Endpoints  
2.1. 
Study Objectives  
2.1.1. Efficacy Objectives  
• To evaluate the efficacy of PRN1008 (Rilzabrutinib) in achieving durable complete 
remission (CR) on low to zero doses of oral corticosteroid (CS) and on the time course of 
quantitative disease activity scores 
o CR is defined as the absence of new and established lesions and is intended to 
mean “no disease activity,” as reported by study investigators. 
• To assess the ability of PRN1008 to reduce CS exposure and the adverse effects of CS 
• To evaluate the time to specified clinical endpoints 
• To assess the longer term durability of CR 
2.1.2. Safety Objectives  
• To evaluate the safety of PRN1008 
• To evaluate differences in potentially CS-related adverse events 
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2.1.3. PK/PD Objectives  
• To evaluate the population pharmacokinetics (PK) of PRN1008 
• To evaluate pharmacodynamics (PD) effects of PRN1008 on anti-desmoglein (anti-dsg) 
autoantibody titers (anti-dsg1 and anti-dsg3) 
2.1.4. Exploratory Objectives  
• To examine the effects of PRN1008, if any, of the baseline covariates on PK and/or PD, 
and the relationship between PK, PD and efficacy 
• To examine the effect of PRN1008 on the costs of hospitalizations, outpatient medical 
visits, adverse events, concomitant medication use and other relevant health economic 
outcomes 
• To examine the temporal relationship of change from baseline in Pemphigus Disease 
Area Index (PDAI) total activity score and quality of life and health economic measures 
2.1.5. Long Term Extension Objective  
• To evaluate the long-term safety and efficacy of PRN1008 
2.2. 
Statistical Modifications made in the Statistical Analysis Plan  
The statistical analysis plan history table below gives the timing, rationale, and key details for 
major changes to the statistical analysis features in the statistical analysis plan from Version 1 of 
the SAP. The table also incorporated changes made in protocol amendments since Version 1 of 
SAP that affect statistical analyses. 
 
Table 1: Statistical analysis plan statistical changes from Version 1  
SAP 
version  
number 
Date 
approved 
Rationale 
Description of statistical changes 
2 
17-June-2021 
Changes to key secondary endpoints 
following feedback from FDA dated  
 and protocol 
amendment. 
The following key secondary endpoint was 
exchanged with  ‘Proportion of patients with 3 or 
more lesions within 1 month that do not heal 
spontaneously within 1 week, or by the extension 
of established lesions, from Baseline to Week 37’ 
(moved to Other Secondary Endpoints): 
• 
Proportion of patients with at least one disease 
relapse/flare from initial control of disease 
activity (CDA) to Week 37 
The following key secondary endpoint was added: 
• 
Cumulative duration of CR with a CS dose = 
0 mg/day, from Week 37 to Week 61”. 
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SAP 
version  
number 
Date 
approved 
Rationale 
Description of statistical changes 
 
 
Changes related to secondary 
endpoints were made to evaluate 
efficacy during the LTE Periods. This 
change was made due to protocol 
amendment. 
The following other secondary endpoints were 
revised to include evaluation during the LTE 
periods : 
• 
Cumulative duration of CR with a CS dose 
≤10 mg/day from Baseline to Weeks 61 and 
109 
• 
Cumulative duration of CR with a CS dose 
= 0 mg/day from Baseline to Weeks 61 and 
109 
• 
Change in PDAI score from Baseline to 
Weeks 5, 13, 25, 37, 61, and 109 
• 
Change in Autoimmune Bullous Disease 
Quality of Life (ABQOL) score from Baseline 
to Weeks 5, 13, 25, 37, 61, and 109 
• 
Proportion of patients with ABQOL Score of 
zero at Weeks 5, 13, 25, 37, 61, and 109 
• 
Change in EuroQOL-5 Dimension 5 Level 
(EQ-5D-5L) results (visual analog scale [VAS] 
results and individual dimension) scores from 
Baseline to Weeks 5, 13, 25, 37, 61, and 109 
• 
Time to first CR with a CS dose ≤10 mg/day, 
from Baseline to Weeks 61 and from baseline 
to Week 109 
 
 
 
Changes made for correction. This 
change was made due to protocol 
amendment. 
“Week 109” was added to the PD endpoint 
timepoints for PD assessments. 
 
 
Changes related to exploratory 
endpoints to evaluate efficacy during 
the LTE Periods. This change was 
made due to protocol amendment. 
Exploratory endpoints were revised to include 
evaluation during the LTE periods as follows: 
• 
“Proportion of patients with relapse/flare after 
achievement of CR between Baseline and 
Weeks 61, and between Baseline and Week 
109 
• 
Change in Treatment of Autoimmune Bullous 
Disease Quality of Life (TABQOL) score from 
Baseline to Weeks 5, 13, 25, 37, 61, and 109 
• 
Total number of disease relapses/flares from 
Week 37 to Weeks 61, and from Week 61 to 
Week 109”. 
 
 
Changes made for correction. This 
change was made due to protocol 
amendment. 
“Change in TABQOL score from baseline to 
Weeks 5, 13, 25, 37, 61, and 109” is an 
exploratory endpoint. Thus, TABQOL analysis was 
moved from other secondary efficacy parameters 
analysis section to the exploratory analysis 
section. 
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SAP 
version  
number 
Date 
approved 
Rationale 
Description of statistical changes 
 
 
Changes related to statistical 
methodology made for clarification 
and as per Sanofi template. This 
change was made due to protocol 
amendment. 
Three bullets with information regarding reporting 
pregnancy AEs/SAEs, including complication or 
elective termination, abnormal pregnancy 
outcomes. and post-study pregnancy-related SAEs 
considered reasonably related to the study 
intervention by the Investigator were added. 
 
 
Changes made for clarification. This 
change was made due to protocol 
amendment. 
The following text “in general” was added after “The 
long term extension endpoints will be summarized 
descriptively”. “More details will be provided in the 
SAP” was added at the end of the paragraph. 
 
 
Changes made to clarify the 
population of analysis in the testing 
order. 
The statistical testing will be done in the following 
order: 
• 
Primary endpoint based on PV patients in 
mITT population 
• 
Primary endpoint in mITT population (i.e. 
PV+PF patients) 
• 
Key secondary endpoints in mITT 
population (i.e. PV+PF patients)  
The study will be declared to be a positive study if 
the p-value for the primary endpoint based on PV 
patients in the mITT population is significant at two-
sided α = 0.05 level.  The test stops as soon as an 
endpoint is found not statistically significant at 
α=0.05 (2-sided). 
 
 
Additional analysis added 
Addition of subgroup analysis: disease diagnosis 
category (PV, PF) 
 
 
 
Changes were made for clarification. 
CS doses for efficacy analyses will be based on 
the combination of the prescribed CS doses 
collected on the “Systemic CS Daily Dosing” eCRF 
form and the CS doses collected as concomitant 
medications on the “Other Corticosteroid 
Concomitant Medications” eCRF form. The 
following process will be used to calculate the CS 
doses for efficacy endpoints 
 
 
To clarify the method of assessing 
prednisone dose of ≤ 5 mg/day for the 
primary endpoint analysis . 
The prednisone dose of ≤ 5 mg/day for the 
primary endpoint analysis will be assessed using 
the median daily dose between Week 29 and 
Week 37 with a maximum dose of ≤ 10 mg/day. 
Details are in Section 8.1 
 
 
The change was made for consistency 
purpose. 
The similar missing data imputation was applied to 
other secondary endpoints and exploratory 
endpoints as the primary and key secondary 
endpoint for CS and CR status. 
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SAP 
version  
number 
Date 
approved 
Rationale 
Description of statistical changes 
3 
29-August-
2021 
Changes were made based on FDA 
feedback on SAP 
 
• The primary efficacy endpoint was changed to 
be the proportion of patients who are in CR 
from Week 29 to Week 37 with a CS dose of 
≤ 10 mg/day 
• The analyses of efficacy endpoints involving 
CR assessment for the blinded treatment 
period are based on on-site assessments only 
(i.e. not including data collected from remote 
visits). Details are in Section 8 
• The following 3 key secondary endpoints were 
moved to other secondary endpoints: 
1. the proportion of subjects with at least one 
disease flare/relapse from initial control of 
disease activity (CDA) to Week 37,  
2. cumulative duration of CR with a CS dose 
≤ 10 mg/day from Week 37 to Week 61,  
3. cumulative duration of CR with a CS dose 
= 0 mg/day from Week 37 to Week 61 
• For multiplicy control purpose, the analyses of 
key secondary efficacy endpoints based on PV 
only subjects are added to the testing 
sequence. Details are in section 6.1.4 
• Clarified that the “time to study discontinuation” 
covariate is based on the blinded treatment 
period, in the ANCOVA model for analyzing the 
1st key secondary efficacy endpoint (i.e., 
cumulative CS dose from baseline to Week 
37). Details are in section 8.2  
 
2.3. 
Study Endpoints  
2.3.1. Safety Endpoints  
The safety endpoints of this study include the following: 
• Nature, frequency, and severity of adverse events, including serious adverse events, 
adverse events leading to discontinuation and possible corticosteroid-related adverse 
effects 
• Change from baseline in vital signs and clinical laboratory test results (including 
complete blood count and blood chemistry) 
2.3.2. Efficacy Endpoints  
For efficacy endpoints, Baseline is defined as stated in Section 6.1.1.  Unless specified 
otherwise, endpoint comparisons will be based on differences between randomized treatment 
groups.  Week 37 visit, is the planned last assessment within the Blinded Treatment Period (as 
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defined in Section 3.1) over which the primary and key secondary efficacy endpoints will be 
evaluated.  Additional endpoints may be evaluated through the Week 61 visit, or the planned last 
assessment within the Open-Label Extension Period, which begins after administration of the 
first dose of open-label PRN1008. 
2.3.2.1. 
Primary Efficacy Endpoint  
The primary efficacy endpoint of this study is the proportion of patients who are in CR from 
Week 29 to Week 37 with a CS dose of ≤ 10 mg/day.  
2.3.2.2. 
Key Secondary Efficacy Endpoints  
The key secondary efficacy endpoints of this study include the following, ranked in order of 
importance: 
1. Cumulative CS dose from Baseline to Week 37 
2. Cumulative duration of CR with a CS dose ≤ 10 mg/day, from Baseline to Week 37 
3. Time to first CR with a CS dose ≤ 10 mg/day CS, from Baseline to Week 37  
2.3.2.3. 
Other Secondary Endpoint(s)  
The other secondary efficacy endpoints of this study include the following:  
• The proportion of patients who are in CR from Week 29 to Week 37 with a CS dose of 
≤ 5 mg/day  
• The proportion of patients who have a PDAI score < 3 from Week 29 to Week 37 with a 
CS dose ≤10 mg/day 
• Cumulative duration of CR with a CS dose ≤ 10 mg/day from Baseline to Week 61, and 
from baseline to Week 109 
• Cumulative duration of CR with a CS dose = 0 mg/day from Baseline to Week 61, and 
from baseline to Week 109 
• Glucocorticoid Toxicity Index (GTI) score at Week 37 
• Change in PDAI score from baseline to Weeks 5, 13, 25, 37, 61 and 109 
• Change in Autoimmune Bullous Disease Quality of Life (ABQOL) score from baseline 
to Weeks 5, 13, 25, 37, 61, and 109 
• Proportion of patients with ABQOL Score of zero at Weeks 5, 13, 25, 37, 61, and 109 
• Change in EuroQOL-5 Dimension 5 Level (EQ-5D-5L) results (visual analog scale 
[VAS] results and individual dimension) scores from Baseline to Weeks 5, 13, 25, 37, 61, 
and 109 
• Time to first CR with a CS dose ≤ 10mg/day from Baseline to Week 61, and from 
Baseline to Week 109 
• 
Total number of disease flares/relapses from initial CDA to Week 37  
• Time to initial flare/relapse from initial CDA to Week 37  
• Proportion of patients with 3 or more lesions within 1 month that do not heal 
spontaneously within 1 week, or by the extension of established lesions, from Baseline to 
Week 37. 
• Proportion of patients with at least one disease flare/relapse from initial control of disease 
activity (CDA) to Week37. 
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• Cumulative duration of CR with a CS dose ≤ 10 mg/day, from Week 37 to Week 61. 
• Cumulative duration of CR with a CS dose = 0 mg/day, from Week 37 to Week 61 
2.3.3. Pharmacokinetic/Pharmacodynamic Endpoints  
The pharmacokinetic (PK) endpoints of the study include plasma concentrations of PRN1008 as 
follows:  
• Plasma concentrations of PRN1008 at approximately the time of maximum concentration 
at Day 1 and at varied subsequent time points. 
The pharmacodynamic (PD) endpoints of the study include 
• the change from baseline in anti-dsg1 and anti-dsg3 autoantibody levels by enzyme-
linked immunosorbent assay (ELISA) at Weeks 13, 25, 37, 49, 61, and 109. 
The calculation of parameters for population PK analysis will be described and reported  
separately. 
2.3.4. Exploratory Endpoints  
Exploratory endpoints and analyses include the following: 
• Exploratory PK/PD analysis will examine the effects, if any, of covariates on PK and/or 
PD, and the relationship between PK, PD and efficacy in this population 
• Number and type of hospitalizations, outpatient medical visits, concomitant medication 
use, adverse events and other relevant outcomes 
• Change from baseline in PDAI by visit and the temporal relationship to changes in 
quality of life and health economic variables 
• Proportion of patients with relapse after achievement of CR between Baseline and Week 
61, and between Baseline and Week 109 
• Proportion of patients initially randomized to PRN1008 that are in CR with a zero CS 
dose, from Week 53 to Week 61 (no randomized treatment comparison) 
• Proportion of patients initially randomized to placebo that are in CR with a zero CS dose, 
from Week 53 to Week 61 (no randomized treatment comparison) 
• Change in Treatment of Autoimmune Bullous Disease Quality of Life (TABQOL) score 
from Baseline to Weeks 5, 13, 25, 37, 61, and 109 
• Total number of disease flares/relapses from Week 37 to Week 61, and from Week 61 to 
Week 109 
• (Optional) Blood samples for exploratory analysis of vaccine IgG response during 
treatment. 
 
2.3.5. Long Term Extension Endpoints  
• Nature, frequency, and severity of adverse events, including serious adverse events, 
adverse events leading to discontinuation and possible corticosteroid-related adverse 
effects during the LTE from Week 61 to Week 113  
• Average daily dose of CS from Week 61 to Week 113 
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• Time to initial flare/relapse from initial CDA to Week 109. 
3. 
Overall Study Design and Plan  
3.1. 
Overall Design  
This is a randomized, parallel-group, double-blind, placebo-controlled trial with 36 weeks of 
treatment during a Blinded Treatment Period followed by an Open-Label Extension Period of 
24 weeks and Long Term Extension Period of 48 weeks and a Follow-up Period of 4 weeks.  
Patients with moderate to severe pemphigus will be randomized in a 1:1 allocation ratio to 
receive either PRN1008 400 mg twice daily (bid) or placebo bid during a Blinded Treatment 
Period (Week 1 to Week 37). At screening, patients will be initiated on a daily dose of 
prednisone depending on disease severity. During the study, patients will undergo a moderately 
rapid CS taper regimen with the goal to reduce the CS dose to 5 mg/day by no later than Study 
Week 29, as appropriate. 
From Week 37, all patients will receive active drug in the Open-Label Extension Period for 
24 weeks. Patients who received placebo will thus receive active treatment with PRN1008 
400 mg bid. Patients requiring treatment by rituximab or other immunosuppressants (other than 
CS) for relapse during this period, must be discontinued from the study.  If a patient has a 
qualifying relapse during the Blinded Treatment Period and the second infusion from the 
rituximab course of treatment occurs during the Open-Label Extension period, the patient may 
continue in the trial.  During the Open-Label Extension Period, further tapering of CS will be 
attempted to 0 mg for patients with CR.  
After completing the Open-Label Extension Period, eligible patients (patients who are 
responding to PRN1008 treatment) may continue in the Long Term Extension Period of 48 
weeks. Patients will continue to have a 4 week follow-up visit after the patient’s last dose of 
PRN1008.  During the Long Term Extension Period, patients will continue to receive open-label 
PRN1008 400 mg bid for 48 weeks. 
3.2. 
Sample Size and Power  
The primary efficacy endpoint is the proportion of patients who are in CR from Week 29 to 
Week 37 with a CS dose of ≤10 mg/day. 
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3.3. 
Study Population  
The study population is comprised of male and female patients with newly diagnosed or 
relapsing moderate to severe pemphigus (pemphigus vulgaris [PV] or pemphigus foliaceus [PF]). 
3.4. 
Treatments Administered  
Patients will be randomized to one of two treatments in a 1:1 allocation ratio: 
• 400 mg of PRN1008  
• matching placebo 
Study investigational product (IP) taken twice daily by mouth starting on Day 1.  
Required, initial doses of CS for the duration of Screening are ≥ 0.2 mg/kg/day of CS for patients 
with relapsing disease (diagnosed > 6 months prior to Screening) and ≥ 0.5 mg/kg/day for 
patients with newly diagnosed disease (diagnosed ≤ 6 months prior to Screening). At Screening, 
patients will begin to take Sponsor-provided CS according to the minimum dose requirements, 
and as required to adequately treat the disease during the Screening period. CS doses may be 
adjusted per Investigator discretion during the Screening period, but the dose should not be 
reduced below the required minimum initial dose levels.   
Thereafter, CS will be managed per the Corticosteroid and Rituximab Management protocol 
detailed in Appendix 1 of the protocol. 
Rituximab treatment may also be administered during the Blinded Treatment Period after the 
Week 5 visit, unless contraindicated, after a second or subsequent, clinically significant 
“qualifying relapse” occurs. Full details on Rituximab treatment can be found in Appendix 1 of 
the protocol.  
3.5. 
Method of Assigning Subjects to Treatment Groups  
Patients who meet study criteria will be randomly assigned to placebo or PRN1008 in an 
approximately 1:1 allocation ratio. The randomization scheduled will be computer generated 
using a permuted block algorithm stratified by PV/PF disease type and by relapsing/newly 
diagnosed disease history (newly diagnosed defined as within 6 months of Screening). 
The randomization schedule will be prepared by Premier Research before the start of the study. 
No one involved in the study performance will have access to the randomization schedule before 
the official unblinding of treatment assignment. No subject will be randomized into this study 
more than once. 
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3.6. 
Blinding and Unblinding  
All subjects, investigators, and study personnel involved in the conduct of the study, including 
data management, will be blinded to treatment assignment, and a specified unblinded statistician 
and programmer from 
, and as part of the integration of Principia Biopharma to 
Sanofi an independent programmer from Sanofi will have access to the randomization code. The 
unblinded study personnel will not participate in study procedures or data analysis prior to 
unblinding of the study data.  
Study personnel will endeavor to safeguard the integrity of the study blind to minimize bias in 
the conduct of the study. Treatment unblinding is discouraged if knowledge of the treatment 
assignment will not materially change the planned management of a medical emergency. 
Unblinding will be permitted in a medical emergency that requires immediate knowledge of the 
subject’s treatment assignment.  
Unblinding should be discussed in advance with the medical monitor, if possible. For emergency 
unblinding, study personnel will use the interactive web response system (IWRS).  In all cases 
that are not emergencies, the investigator should discuss the event with the medical monitor prior 
to unblinding the subject’s treatment assignment. 
If treatment assignment is unblinded for an individual subject, study personnel will be notified of 
that subject’s treatment assignment without unblinding the treatment assignments for the 
remaining subjects in the study. Thus, the overall study blind will not be compromised.   
3.7. 
Schedule of Events  
A detailed schedule of events for the blinded treatment period, open label portion, open label 
extension and Long Term Extension of the study are provided in the protocol.
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4. 
Statistical Analysis and Reporting  
4.1. 
Introduction  
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed primarily using SAS (release 9.4 or higher). If the 
use of other software is warranted, the final statistical methodology report will detail what 
software was used for what purposes. 
Continuous (quantitative) variable summaries will include the number of subjects (n) with 
non-missing values, mean, standard deviation (SD), median, minimum, and maximum.  
Categorical (qualitative) variable summaries will include the frequency and percentage of 
subjects who are in the particular category or each possible value.  
Analyses will be presented by the treatment group assigned at randomization for the Blinded 
Treatment Period of the study and by double-blind treatment group and overall for the Open 
Label Phase and Long-Term Extension Phase of the study, unless stated otherwise. 
The minimum and maximum will be reported with the same degree of precision (i.e., the same 
number of decimal places) as the observed data. Measures of location (mean and median) will be 
reported to 1 degree of precision more than the observed data and measures of spread (SD) will 
be reported to 2 degrees of precision more than the observed data. 
Percentages will be presented to 1 decimal place, unless otherwise specified. 
Unless otherwise indicated, all statistical tests will be conducted at the 0.05 significance level 
using 2-tailed tests, and P values will be reported. Corresponding 95% confidence intervals (CIs) 
will be presented for statistical tests. 
Statistical testing will be performed at the 0.05 level using two-tailed tests.  
To control for the overall type I error rate, hierarchical testing based on a fixed sequence 
procedure will be used. If statistical significance is declared for the primary analysis, formal 
hypothesis testing will be done for the key secondary endpoints in sequence until a non-
significant result is reached. All other p values from key secondary and other secondary 
endpoints, after a non-significant p value is reached, will be considered nominal. 
4.2. 
Data Monitoring  
A Data Safety Monitoring Board  (DSMB) will be established to conduct reviews of subject 
safety. The DSMB reviews will occur approximately quarterly throughout the study unless the 
DSMB decides otherwise. Details of the operation of the DSMB are detailed in the DSMB 
charter. They can be modified as required. The unblinded analyses are performed by independent 
statisticians at Axio Research and the treatment codes are revealed to that party only. The 
unblinded DSMB listings will not be seen by anyone except the DSMB and the performing 
statistician. 
No interim analyses are planned. 
 
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4.3. 
Timing of Analyses  
Three sets of analyses are planned for this study.  
1. After all patients have completed the week 37 (or early termination) study visit. 
2. After all patients have completed the week 65  (or early termination) study visit. 
3. At the end of the long term extension. 
The first planned analysis will be performed after all enrolled subjects have completed the 
Week 37 (or Early Termination) study visit and will include subject activity occurring during the 
Blinded Treatment portion from Screening through Week 37. At this time, all data will be 
cleaned through Week 37 and the database will be locked prior to unblinding. A full set of 
analyses will be provided including disposition, demographics, protocol deviations, medical 
history, exposure and compliance through Week 37, all safety data summaries through Week 37, 
and all primary, secondary and exploratory efficacy endpoints through Week 37.    
The second planned analysis will be performed after all subjects who have elected to participate 
in the Open-Label Extension Period have completed the Week 65 (or Early Termination) study 
visit. A full set of TLFs will be provided after the database has been cleaned and locked which 
will include all data collected during the open label potion of the study including disposition, 
demographics, protocol deviations, exposure and compliance between Week 37 and Week 61, all 
safety data summaries between Week 37 and Week 65.  
In the above planned analyses, data collected after the target visit will also be presented either 
separately or combined with those prior to the target visit to have an overall assessment when 
appropriate (eg, exposure). 
A third analysis will be conducted similarly following the end of the Long-term Extension 
period. 
5. 
Analysis Populations  
The following analysis populations are planned for this study:  
• Safety Population (SAF): The Safety Population includes all patients who receive at 
least one dose of study medication. Safety analyses will be based on the safety 
population. Analyses of the SAF population will be presented based on actual treatment 
received. When a patient is exposed to both PRN1008 and placebo in the double blind 
period, the patient will be analyzed in the treatment group that the patient was exposed 
longer in the blinded treatment period. 
• Intent-to-Treat (ITT) Population: The ITT Population includes all randomized patients. 
• Modified Intent-To-Treat (mITT) Population: The mITT Population includes all 
patients who are randomized and receive at least one dose of study medication. Patients 
will be analyzed for efficacy according to the treatment group to which they were 
randomized. 
Pharmacokinetic and Pharmacodynamic Populations (PK and PD): The PK and PD 
Populations include all subjects in the Safety Population who have sufficient data for PK and/or 
PD analysis. 
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Analyses of the mITT Population will be presented based on the assigned treatment including 
cases in which a subject is randomized incorrectly or is administered the incorrect IP.  
6. 
General Issues for Statistical Analysis  
6.1. 
Statistical Definitions and Algorithms  
6.1.1. Baseline Definitions  
Baseline values will be the last observation recorded prior to first dose of randomized treatment.  
Baseline value derivations will include evaluations specified to have been collected Pre-Dose on 
Day 1 as specified in study schedule.  For patients from the ITT Population who are randomized 
but not treated, baseline will be based on their randomization date. 
6.1.2. Study Day  
Day 1 is defined as the date of first dose of randomized treatment. Study day is calculated 
relative to the date of Day 1.  
6.1.3. Adjustments for Covariates and Subgroup Analyses  
6.1.3.1. 
Covariates  
Disease history (newly diagnosed or relapsing) will be taken into account by including as a 
stratification variable or covariate in all of the analyses except for the Chi-Square analyses.  Due 
to the small number of PF subjects expected to be enrolled in the study, the randomization strata 
of disease type will not be included as a covariate in any of the analyses.   
6.1.3.2. 
Subgroup Analyses  
Subgroup analyses of the primary endpoint will be conducted by  
• race (White, Non-White),  
• age group (< 40, 40-64, >64),  
• gender (male, female) 
• disease history (newly diagnosed, relapsing),  
• disease diagnosis category (PV, PF) 
• disease severity (moderate [PDAI 9-45], severe [PDAI>=46])   
Key secondary endpoints will also be analyzed by the above subgroups.   
6.1.4. Multiple Comparisons  
The type I error rate of α = 0.05 will be maintained for the study by using sequential 
(hierarchical) testing for the primary and key secondary endpoints.  
The testing will be done in the following order: 
1. Primary endpoint based on PV patients in mITT population 
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2. Primary endpoint in mITT population (ie, PV+PF patients) 
3. Key secondary endpoints based on PV patients in mITT population (in the order presented 
in Section 2.3.2.2) 
4. Key secondary endpoints in mITT population (ie, PV+PF patients) (in the order presented 
in Section 2.3.2.2) 
The study will be declared to be a positive study if the p-value for the primary endpoint based on 
PV patients in the mITT population is significant at two-sided α = 0.05 level.  The test stops as 
soon as an endpoint is found not statistically significant at α=0.05 (2-sided). The nominal 
p-values for subsequent tests without adjustment will be provided in the summary tables for 
information purpose. 
All other endpoints will be considered exploratory, and no adjustments will be made for multiple 
comparisons.  
6.1.5. Handling of Dropouts or Missing Data  
All possible efforts will be made to ensure that subjects stay in the study and all data is collected 
as scheduled. Any subject who withdraws from the study or misses a scheduled visit will have 
their primary and secondary efficacy analyses missing data imputed prior to analysis according 
to criteria described in this section. Safety data (with the exception of AE and concomitant 
medication date/times as described in Section 6.1.10) will not be imputed and will be analyzed as 
observed.  
6.1.5.1. 
Imputation Procedures for the Primary Efficacy Endpoint  
For the primary efficacy endpoint (the proportion of patients who are in CR from Week 29 to 
Week 37 with a prednisone dose of ≤ 10 mg/day), patients with missing data due to study 
withdrawal will be considered as non-responders. A patient who received a rituximab dose prior 
to Week 37 will also be counted as a non-responder. 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
Tipping point analyses (Yan, 2009) will be done to investigate the impact of missing data and 
lost to follow-up (LTF). The tipping point analysis will look at all possible combination of 
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converting missing data to a responder, starting at 0 and ending at all are responders. The cases 
where the statistical significance tips from significance to non-significance (defined as a two 
sided p-value >0.05) will be listed. A complete list of all combinations will also be presented. If 
the imbalances that leads to a change in interpretation are clinically implausible then the results 
of the primary analysis will be deemed reliable   
6.1.5.2. 
 Imputation Procedures for Secondary Endpoints  
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Responder analyses: 
If a patient received a rituximab dose prior to Week 37, the patient will be counted as a non-
responder starting from the date of first dose of rituximab for following responder analyses: 
o The proportion of patients who are in CR from Week 29 to Week 37 with a CS dose 
of ≤5 mg/day  
o The proportion of patients who have a PDAI score < 3 from Week 29 to Week 37 
with a CS dose ≤10 mg/day 
For the derivation of the following parameters: 
o proportion of patients having three or more lesions within 1 month or extension of 
established lesions that do not heal within 1 week from Baseline to Week 37 
o proportion of patients with at least one disease flare/relapse from initial control of 
disease activity (CDA) to Week 37,  
A missing value will be considered as Yes with exception of the following: 
• A ‘No’ can be inferred if adjacent visits are complete and reflect this same outcome.  No 
more than one disease assessment can be imputed for this endpoint (i.e.  this imputation 
is not applicable to consecutive missing visits). Note that, this imputation is not 
applicable at Week 37 when the study treatment a patient receives before and after the 
visit could be different. 
If a patient received a rituximab dose prior to Week 37, the patient will be counted as Yes for the 
analyses of these two parameters. 
Time to event analyses: 
For the analyses of following parameters, 
o Time to first CR with a CS dose ≤ 10 mg/day CS, from Baseline to Week 37 
o Time to first CR with a CS dose ≤ 10mg/day, from Baseline to Week 61 
o Time to initial flare/relapse from initial CDA to Week 37. 
If a patient receives a rituximab therapy, the study data will be censored at the date of first 
rituximab administration for the above time to event analyses. 
Cumulative CS dose: 
o Cumulative CS dose from Baseline to Week 37 
If a patient receives a rituximab therapy, the CS dose up to the date of the first dose of rituximab 
(including CS dose  on the date of the first dose of rituximab) will be included in the analyses. 
Other analyses: 
For analyses of following parameter,  
o Change in PDAI score from baseline to Weeks 5, 13, 25, 37 and 61 
o Total number of disease flares/relapses from initial CDA to Week 37 
o Glucocorticoid Toxicity Index (GTI) score at Week 37 
o Change in Autoimmune Bullous Disease Quality of Life (ABQOL) score from baseline 
to Weeks 5, 13, 25, 37, and 61 
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o Change in EuroQOL-5 Dimension 5 Level (EQ-5D-5L) results (visual analog scale 
[VAS] results and individual dimension) scores from Baseline to Weeks 5, 13, 25, 37 and 
61. 
If a patient receives a rituximab therapy, the study data up to the date of the first dose of 
rituximab (but not including data from the date of the first dose of rituximab) will be included in 
the analyses. 
 
Other responder analysis: 
o Proportion of patients with ABQOL Score of zero at Weeks 5, 13, 25, 37, and 61 
the patient will be counted as a non-responder starting from the date of first dose of rituximab for 
the responder analysis. 
6.1.6. Analysis Visit Windows  
For all analyses presented by study week, unscheduled and/or repeated measurements will only be 
included if a scheduled measurement is not available and the unscheduled/repeated measurement 
falls within the analysis visit windows as described below (Table 2 and Table 3). Otherwise, visits 
will be analyzed as scheduled.  
Table 2:  Analysis Visit Windows – Blinded Treatment Period  
Analysis 
Visit 
Name 
Target 
Day of 
Planned 
Visit 
Assessment Window 
(Days) 
Week 3 
15 
Post-dose ─ Day 21 
Week 5 
29 
22 ─ 42 
Week 9 
57 
43 ─ 70 
Week 13 
85 
71 ─ 98 
Week 17 
113 
99 ─ 126 
Week 21 
141 
127 ─ 154 
Week 25 
169 
155 ─ 182 
Week 29 
197 
183 ─ 210 
Week 33 
225 
211 ─ 238 
Week 37 
253 
239 ─ Pre-open label 
dose 
If more than 1 visit occurs within a single visit window, then the analysis will use the visit 
closest to the target day. If 2 visits within the same visit window are equidistant from the target 
day, then the analysis will use the later visit. 
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Table 3:  Analysis Visit Windows – Open-Label and Long Term Period Extension Periods  
Analysis 
Visit 
Name 
Target 
Day of 
Planned 
Visit 
Assessment Window (Days) 
Week 39 
267 
Post-open label dose – 273 
Week 41 
281 
274 ─ 294 
Week 45 
309 
295 ─ 322 
Week 49 
337 
323 ─ 350 
Week 53 
365 
351 ─ 378 
Week 57 
393 
379 ─ 406 
Week 61 
421 
407 ─ Pre-long term extension 
dose 
Week 65 
449 
Post-long term extension dose 
- 462 
Week 69  
477 
463 – 490 
Week 73 
505 
491 - 546 
Week 85 
589 
547 - 630 
Week 97 
673 
631 - 714 
Week 109 
757 
715 - 770 
6.1.7. Pooling of Sites  
Data from all investigative sites will be pooled for all planned analyses.  Analysis of individual 
site findings will be considered if necessary. 
6.1.8. Derived Variables  
Variables associated with primary or key efficacy analyses will be derived based on data imputed 
as identified in Section 6.1.5. 
• Time from Pemphigus diagnosis to enrollment (years) = (screening date - first date of 
pemphigus diagnosis +1)/365.25 
• Duration calculations are generally produced as: end date – start date + 1. 
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Table 4: Event and Censoring Details for Time to First CR with a CS dose at or below 
10 mg/day  
Situation 
Date of First CR/ 
Date of Censoring 
Censored/ 
Event 
No post baseline assessments 
Date of first dose   
Censored 
Patient in CR status and with a CS 
dose of ≤ 10 mg/day 
First date that patient is in CR 
status and with a CS dose of 
≤ 10 mg/day as identified in 
Section 6.1.9. 
Event 
Rituximab administered  
Date of first Rituximab 
administration  
Censored 
No CR with a CS dose of ≤ 10 
mg/day during  the Blinded 
Treatment Period 
Date of last efficacy 
assessment during blinded 
treatment phase (through 
Week 37) 
Censored 
Study discontinuation  
Date of last efficacy 
assessment prior to or on the 
date of treatment 
discontinuation 
Censored 
Death before CR  
Date of death  
Censored  
Note:  Patients will be censored prior to a CR event at the earliest date of the censored events above should a 
censoring reason occur.  Censoring reasons may be categorized for reporting (eg, by discontinuation reason). 
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• Three or more lesions within 1 month that do not heal spontaneously within 1 week or 
extension of established lesions = Yes if any of the following conditions are satisfied: 
o eCRF entry “Have new lesions appeared within a month that did not heal 
spontaneously within 1 week? OR Have there been extension of established 
lesions?” = Yes for any visits from Baseline up to Week 37. 
o At this visit, Has a Relapse occurred or is continuing? 
The number of instances with investigator assessments of disease worsening will also be 
derived and categorized for reporting as 0, 1, 2, and ≥ 3. After the first worsening, a patient 
can have additional worsening, but only after the patient returns to CDA first, and then the 
next worsening can happen. 
• PDAI score <3 from Week  29 to Week 37 with a CS dose of ≤ 10 mg/day = Yes if the 
following conditions are both satisfied: 
o PDAI <3  = Yes for all visits from Week 29 through Week 37  
o Daily prednisone dose is ≤ 10 mg/day from Week 29 through Week 37 as defined 
in Section 6.1.9. 
o No Rituximab therapy prior to Week 37. 
After applying the CS dose imputation as described in Section 6.1.5.2, a patient with partial 
missing data  (missing PDAI assessment or CS dose) or complete missing data at any 
scheduled visit will be considered as a non-responder. 
• Change from baseline = value at current time point – value at Baseline. 
• PDAI Total Score = the Total PDAI activity score as reported on the PDAI Total Score 
CRF (possible range of 0 to 250) as  the sum of the individual skin activity, scalp activity 
and mucosal activity scores, higher score corresponding to worsening.  
• PDAI activity subscores for skin (range 0 to 120), scalp (range from 0 to 10) and mucosal 
(range from 0 to 120) 
• ABQOL Score of zero, = Yes if zero; = No if ABQOL is present and nonzero; missing 
otherwise.  
• TABQOL = Sum of the 17 items of the ABQOL Questionnaire. Each item is scored on a 
scale of 0-3 for each of the 4 options (all the time, sometimes, occasionally and never), 
with 0 being the least severe and 3 being the most severe. No imputation will be done for 
missing item, therefore the total score will be missing if any item is missing10. 
• EQ-5D-5L: The EQ-5D-5L comprises the EQ-5D 5 dimensions (mobility, self-care, usual 
activities, paint/discomfort and anxiety/depression) and a visual analogue scale (VAS). 
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Each dimension has 5 levels: no problems, slight problems, moderate problems, severe 
problems and extreme problems. Overall health state is then defined as a 5-digit number. 
The health utility index value will be calculated using the crosswalk value sets provided 
in the EQ-5D-5L Index Value Calculator created by the EuroQol Group and using 
mapping function developed by Van Hout et al.11.  The values sets based on UK 
population12 will be used for all countries.  The health utility score will be missing if 
response to one or more dimension is missing.  
• The EQ VAS records the respondent’s self-rated health on a 20 cm vertical VAS with 
endpoints labelled 0 (‘the worst health you can imagine’) to 100 (‘the best health you can 
imagine’). This information can be used as a quantitative measure of health as judged by 
the individual respondents. EQ VAS will be described as given by patient. Missing data 
will not be imputed.  
• At least one relapse/flare after initial CDA to Week 37 = Yes if the following condition is 
satisfied: 
o eCRF entry “At this visit, Has a Relapse occurred or is continuing?” = Yes for any 
visits from CDA to Week 37. 
o If a patient received a rituximab dose prior to Week 37, the patient will be counted 
as Yes. 
Relapse/flare can only happen following an initial CDA, subjects never achieve CDA 
prior to Week 37 will not be included in analysis. After the first initial flare, a patient can 
have additional relapse/flares, but only after the patient returns to CDA first, and then the 
next relapse/flare can happen.  A similar method will be used to identify the number of 
relapses/flares from Week 37 to Week 61.   
• Time to initial flare/relapse after initial CDA: Outcomes and durations for specific cases 
will be based on Table 5. The date of the event/censoring is considered the end date and 
the date of initial CDA is considered the start date, for duration calculations. 
Table 5: Event and Censoring Details for Time to First flare/relapse after initial CDA  
Situation 
Date of First flare/relapse 
or 
Date of Censoring 
Censored/ 
Event 
No assessments after first CDA 
Date of  first CDA 
Censored 
Flare/relapse before Week 37 
Date of first relapse 
Event 
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Situation 
Date of First flare/relapse 
or 
Date of Censoring 
Censored/ 
Event 
Rituximab administered  
Date of first Rituximab 
administration  
Censored 
No flare/relapse during the 
Blinded Treatment Period 
Date of last efficacy 
assessment during blinded 
treatment phase (through 
Week 37) 
Censored 
Study discontinuation  
Date of last efficacy 
assessment prior to or on the 
date of treatment 
discontinuation  
Censored 
Death before flare/relapse  
Date of death  
Censored  
• 
Note:  Patients will be censored prior to a flare/relapse event should a censoring reason occur.  
Censoring reasons may be categorized for reporting (e.g. by discontinuation reason).  A patient must 
have a CDA in order to be included in this analysis. 
• Complete remission for ≥8 weeks on zero CS at Week 61 = Yes if complete remission 
status is achieved at Weeks 53, 57, and 61 with no recorded CS usage during this time; 
No otherwise, provided all data is complete for the specified visits.  For patients with 
missing data at the specified visits this endpoint value will be missing unless there are a 
documented CR both before and after the missing visit. 
• TEAE = any adverse event with an onset date on or after the first dose of study drug, 
having been absent pre-treatment or worsening relative to pre-treatment state. 
• TEAE (Blinded Treatment Period) = any TEAE with an onset date on or after the first 
dose of study drug and occurring before enrollment into the open-label portion of the 
study. TEAEs that are ongoing at the time of enrollment into the open-label portion are 
considered part of the double-blind portion of the study.  
• TEAE (Open-Label Extension Period) = any TEAE with an onset date on or after 
enrollment into the open-label extension portion of the study, having been absent during 
the double-blind portion or worsening relative to double-blind portion state. Since the 
TEAE time is not collected for the study, any AE started or worsened on the first day of 
the open-label period is considered a TEAE for the blinded treatment period. 
• TEAE (Long Term Extension Period) = any TEAE with an onset date on or after 
enrollment into the long term extension portion of the study, having been absent during 
the double-blind/open-label extension portion or worsening relative to double-blind/open-
label extension portion state.  Since the TEAE time is not collected for the study, any AE 
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started or worsened on the first day of the long term extension period is considered a 
TEAE for the open-label extension period. 
• Treatment duration (days) =  
Date of last dose of study drug – Date of first dose of study drug + 1 
For subjects who are missing the date of last study drug application, the last visit date 
will be used in the calculation of treatment duration.  
• Study Drug Compliance (%) =  
(Total number of tablets taken during the treatment/Total number of tablets 
planned during the treatment) x 100% 
The total number of tablets taken will be calculated by subtracting the number of tablets 
returned from the number of tablets dispensed. The total number of tablets planned will be 
calculated by multiplying the total number of days of planned exposure to study drug by 2. 
• Corticosteroid compliance (%) = amount (mg) of systemic corticosteroid prescription 
doses taken divided by amount (mg) of corticosteroid expected to be taken, as collected 
on the “Prednisone/Prednisolone Accountability” eCRF form. 
6.1.9. Corticosteroid Dose Derivation for Efficacy Analyses  
At screening, subjects will be prescribed required initial doses of oral corticosteroid (prednisone 
or prednisolone) at 0.5 mg/kg/day for newly diagnosed patients (diagnosed ≤6 months prior to 
Screening)  with PDAI total activity score of ≥ 15, and 0.2 mg/kg/day for relapsing, chronic 
patients (diagnosed >6 months prior to Screening) with a PDAI total activity score of ≥9. Up-
titration of CS during the screening period will be permitted if the starting dose had been 
insufficient to prevent worsening disease. During the treatment period, CS will be tapered once 
the subject reached End of Consolidated Phase (ECP) towards a goal of ≤5 mg/day by 
≤Week 29. Once the 5 mg level is achieved, it will be kept at that level until the time of the 
primary endpoint at Week 37 is assessed. From Week 37, further tapering to 0 mg CS will be 
attempted in patients with CR unless medically contraindicated. Up-titration of CS will also be 
permitted during the treatment period in cases of worsening disease. Further details of the 
corticosteroid management plan can be found in Appendix 1 of the protocol.  
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6.1.10. GTI Scores  
The Glucocorticoid Toxicity Index is a proprietary licensed instrument from Massachusetts 
General Hospital (Miloslavsky 2017). It was developed to assess glucocorticoid (GC)-related 
morbidity and GC-sparing ability of other therapies. 
The GTI is composed of two components, the Composite GTI and the Specific List. The 
Composite GTI consists of nine domains (body mass index (BMI), glucose tolerance, blood 
pressure,  lipid,  bone mineral density, glucocorticoid-induced myopathy,  skin toxicity,  
Neuropsychiatric toxicity, and infection) on common steroid-related adverse events anticipated 
to occur in ≥5% of patients treated in a clinical trial involving glucocorticoids. Note that for this 
study bone mineral density was not collected, and therefore not included in the derivation. The 
Specific List consists of 23 items (11 domains) that are mainly less common but serious adverse 
effects, serving as a complementary tool to the Composite GTI to ensure that all important 
elements of glucocorticoid toxicity were captured. 
The domains of the Composite GTI and the specific list of the GTI will be assessed at Day 1, 
Week 13, Week 25, Week 37. The details on the derivations of baseline glucocorticoid toxicity 
score are provided in Appendix 2.  
Domain-specific score for each patient at a visit is defined as the weight assigned based on the 
change in severity level as described for each domain in Appendix 3. 
Composite GTI score for each patient at a visit is the sum of 8 domain-specific scores at each 
visit. 
Cumulative GTI score is the sum of composite GTI score across visits. Two cumulative GTI 
scores, CWS and AIS, will be defined. 
• Cumulative worsening score (CWS)  
CWS is designed to assess cumulative GC toxicity, regardless of whether the toxicity has 
lasting effects or is transient. New toxicities that occur are added, but toxicities that 
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appear to resolve on follow-up are not removed. Thus, the CWS serves as a lasting record 
of GC toxicity observed and can only increase or remain the same over time. 
CWS will be lower in the treatment arm compared to the placebo arm at the end of trial, 
if the treatment is effective at decreasing GC toxicity over time. 
• Aggregate improvement score (AIS)  
Patients are anticipated to have some GC toxicity at baseline, the AIS would be important 
in establishing that the new therapy is effective at diminishing any baseline GC toxicity 
over time. With the AIS, toxicities can be removed if improvement occurs, and added if 
worsening occurs. 
AIS decrease over time means that the treatment is effective in decreasing GC toxicity 
level, compared to placebo which may show fluctuation of CIS over time. Negative score 
reflects that toxicities present at baseline (or occurring during the trial) resolved over the 
treatment period. 
The steps to calculate the CWS and AIS at Weeks 25 and 37 are described below.  
Step 1: Calculate domain-specific worsening score (for computing CWS in Step 2) and 
improvement score (for computing AIS in Step 2) at each visit. 
For Domains without sub-items (Body Weight, Glucose Metabolism, Blood Pressure, Lipid 
Metabolism, Steroid Myopathy), 
a) For worsening score, only consider positive domain-specific score at each visit. For domain 
with a negative domain-specific score, the worsening score will be 0. 
b) For improvement score, all domain-specific scores (could be positive or negative) at each 
visit will be considered. 
The Skin and Neuropsychiatric domains both have sub-items. For the Skin domain, these are 
Acneiform Rash, Easy Bruising, Hirsutism, Atrophy/Striae, and Erosions/tears/ulcerations. For 
the Neuropsychiatric domain, these are Insomnia, Depression, Mania, and Cognitive Impairment. 
a) For worsening score, only the item with the highest weight is scored for any GTI interval 
(typically three months) with the CWS.  As an example, if neither insomnia nor depression 
were present at the baseline visit but there is now mild Insomnia and moderate depression 
present at follow-up, then only the moderate depression is scored (+63 points). 
b) For improvement score, improvement as well as worsening can be recorded. Because it is 
conceivable that one item might improve while another worsens, the item of greatest 
improvement (highest absolute weight) and the item of greatest worsening (highest weight) 
are recorded for given GTI interval. 
For Infection Domain, the worsening score and improvement score handle the scoring of 
infections differently, because the CWS and AIS reflect reciprocal measures of GC toxicity. 
a) For worsening score, the most severe infection in every GTI interval is scored. 
b) For improvement score, only the most severe infection occurring among Week 13, Week 25, 
and Week 37 is scored. 
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Step 2: Calculate composite worsening score and improvement score at each visit by summing 
the 8 domain-specific score. 
a) For composite worsening score, sum the 8 domain-specific worsening scores. 
b) For composite improvement score, sum the 8 domain-specific improvement scores. 
Step 3: Calculate cumulative GTI scores by summing composite scores across visits.  
a) For CWS at Week 37, summing composite GTI worsening score at Week13, Week 25 and 
Week 37. 
b) For AIS at Week 37, summing composite GTI improvement score at Week 13, Week 25 and 
Week 37.  
The detailed information for the derivation of Glucocorticoid Toxicity Index are presented in 
Appendix 3. 
6.1.11. Data Adjustments/Handling/Conventions  
All p-values will be displayed in four decimals and rounded using standard scientific notation (eg, 
0.XXXX). If a p-value is less than 0.0001 occurs it will be shown in tables as <0.0001. 
If a patient has both non missing screening value and re screening value for a parameter, then the 
re screening value will be used in the analyses as the screening value. 
Adverse events will be coded using the MedDRA Version 24.0. 
For CS medications recorded as concomitant medications on “Other Corticosteroid Concomitant 
Medications” eCRF form, partial end date recorded will be imputed to a date as late as possible 
based on the available partial date information, but no later than the date of last dose of study 
drug.  This date imputation will be applied prior to implementation of the imputation method 
described in Section 6.1.5.2. 
Other than the above CS dose end date imputation, no actual imputation of other medication 
start/end dates will be performed.  If a medication start date or end date is missing or partially 
missing , and available information is not enough to determine whether CM was taken prior to 
first dose of study drug or only concomitantly with study drug,  the CM will assumed to be both 
a prior and concomitant medication, and across as many treatment period as possible based on 
the available information. These data imputations are for categorization purpose only and will 
not be used in listings. 
Missing or partial AE onset dates will be imputed so that if the partial date information is not 
sufficient enough to determine whether or not the AE started prior to first dose of study drug, the 
AE will be classified as treatment-emergent. However, if the question “Did this AE occur before 
the first dose of study drug?” in the AE eCRF form has the answer of “Yes”, then the AE will be 
counted as pre-treatment AE instead of TEAE. If the partial date information is not sufficient 
enough to determine during which period the AE stared, the AE will be counted in the earlier 
period. These data imputations are for categorization purpose only and will not be used in 
listings.  No imputation is planned for date of adverse event resolution. 
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7. 
Study Patients/Subjects and Demographics  
7.1. 
Disposition of Patients/Subjects and Withdrawals  
The number and percentage of subjects randomized, completing, and withdrawing, along with 
reasons for withdrawal, and included in each population will be tabulated overall and by 
treatment group. The number of screened subjects will also be reported. This summary will be 
presented by trial Phase (Blinded Treatment Period,  Open-Label Extension Period, and Long 
Term Extension separately).  A summary of the number of patients enrolled, randomized, and 
treated at each site will also be produced. 
Disposition and analysis population data will be listed.  A listing of randomization codes and 
treatment values will also be provided.   
7.2. 
Protocol Violations and Deviations  
Protocol violations will be identified and finalized prior to database lock.  The number and 
percentage of subjects with any important protocol deviations will be tabulated by treatment 
group and overall for the mITT population. Important protocol deviations will be further broken 
down by category. Subjects with one or more important deviations within each category will 
only be counted once.  
All protocol deviations will be listed. 
7.3. 
Demographics and Other Baseline Characteristics  
Demographic and baseline characteristics variables will include age, sex, ethnicity, race, BMI, 
disease category, disease status (newly diagnosed/relapsing), Total PDAI Activity score, Total 
PDAI Activity Score category (<15, 15-45, ≥46), Total Anti-DSG1, Total Anti-DSG1 category 
(<100, ≥100), Total Anti-DSG, Total Anti-DSG category (<100, ≥100), and time since 
Pemphigus diagnosis (years). Summary statistics for demographic and baseline characteristics 
will be presented separately by treatment group as well as overall.  
For the continuous variables, the number of non-missing values and the mean, standard 
deviation, minimum, median and maximum will be tabulated.  
For the categorical variables, the counts and proportions of each value will be tabulated.    
The number and percentage of subjects reporting various medical histories, grouped by 
MedDRA system organ class and preferred term (coded using MedDRA v24.0), will be tabulated 
by treatment group. Pemphigus procedure history will be presented separately from non-
pemphigus medical history.  
These analyses will be conducted for ITT  population. 
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7.4. 
Exposure and Compliance  
The following parameters will be summarized by treatment group for the safety population, and 
for blinded treatment period and open-label extension period: 
• Treatment exposure  
• Study drug compliance  
• Corticosteroid compliance  
• Number of times that CS was not returned during blinded and open-label periods,  
Study exposure will also be summarized for long term extension period. 
For subjects who are missing the date of last study drug administration, for any reason, the last 
study visit date will be used in the calculation of treatment duration, and exposure will be 
calculated up to that date. Study drug compliance will not be calculated for those subjects whose 
date of last study drug administration is unknown. The number and percentage of patients with 
compliance between 80% and 125% will be tabulated for both study drug and CS.  
The compliance for CS is based on systemic prescription doses collected on 
“Prednisone/Prenisoline Accountability” eCRF form. CS doses collected as concomitant 
medications on “Other Corticosteroid Concomitant Medications” eCRF form are not included in 
the compliance calculations.  
For the blinded period, CS doses collected from Day 1 until Week 37 Visit (until early 
termination visit for patients prematurely discontinued study prior to Week 37 visit) are included 
in the derivation.  For open label extension period, CS doses collected from beginning of open 
label extension period until Week 61 Visit (until early termination visit for patients prematurely 
discontinued study during the open label extension period) are included in the derivation. For 
long term extension period, CS doses collected from beginning of long term extension period 
until Week 109 Visit (until early termination visit for patients prematurely discontinued study 
during the open label extension period) are included in the derivation. 
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8. 
Efficacy Analysis  
A summary of the study endpoints and their corresponding analysis methods are presented in 
Table 6. Further details of each analysis are presented in the following sections. 
Table 6: Efficacy Endpoints and Analysis Methods  
 
Endpoint 
Analysis Method 
Primary 
Proportion of patients who are in CR 
from Week  29 to Week 37 with a CS 
dose of ≤ 10 mg/day 
Cochran-Mantel-Haenszel test 
stratified by disease history 
(newly diagnosed or relapsing).  
Secondary 
Endpoints 
(in 
hierarchy) 
Cumulative CS dose from Baseline to 
Week 37 
Analysis of covariance, with CS 
dose duration (in days) during the 
blinded treatment period time to 
study discontinuation as the 
covariate, with terms for 
treatment group,  and disease 
history.  
Cumulative duration of CR with CS 
dose ≤ 10 mg/day from Baseline to 
Week 37 (days)   
Zero-inflated negative binomial 
with terms for treatment group 
and disease history with an offset 
term based on the number of days 
on study during the Blinded 
Treatment Period  
Time (Days) to first CR with a dose of 
≤ 10 mg/day from Baseline to Week 37 
Log rank test stratified by disease 
history 
Proportion of patients with at least one 
disease flare/relapse from initial control 
of disease activity (CDA) to Week 37 
Cochran-Mantel-Haenszel test 
stratified by disease history  
Cumulative duration of CR with CS 
dose ≤ 10 mg/day from Week 37 to 
Week 61 (days)   
Zero-inflated negative binomial 
with terms for treatment group 
and disease history with an offset 
term based on the number of days 
on study during the Blinded and 
unblinded Treatment Period 
Cumulative duration of CR with CS 
dose = 0 mg/day from Week 37 to 
Week 61 (days)   
Zero-inflated negative binomial 
with terms for treatment group 
and disease history with an offset 
term based on the number of days 
on study during the Blinded and 
unblinded Treatment Period 
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Endpoint 
Analysis Method 
Secondary 
Endpoints 
(not in 
hierarchy, 
family-wise 
error rate 
not 
controlled) 
The proportion of patients who are in 
CR from Week 29 to Week 37 with a 
CS dose of ≤ 5 mg/day   
Cochran-Mantel-Haenszel test 
stratified by disease history  
The proportion of patients who have 
PDAI score < 3 from Week 29 to Week 
37 with CS ≤10 mg/day 
Cochran-Mantel-Haenszel test 
stratified by disease history  
Cumulative duration of CR with a CS 
dose of ≤ 10 mg/day (days) from 
Baseline to Week 61 
Zero-inflated negative binomial 
with terms for treatment group 
and disease history with an offset 
term based on the number of days 
on study during the Open-Label 
Extension Period 
Cumulative duration of CR with a  CS 
dose = 0 mg/day (days) from Baseline 
to Week 61 
Zero-inflated negative binomial 
with terms for treatment group 
and disease history with an offset 
term based on the number of days 
on study during the Open-Label 
Extension Period 
 
 
GTI scores at Week 37 
Analysis of covariance, with 
treatment, disease history as fixed 
effects, and baseline GTI score, 
baseline CS dose as covariates 
Change from Baseline in PDAI Score at 
Weeks 5, 13, 25, 37, and 61 
MMRM with terms for treatment, 
week, baseline score, disease 
history, and treatment by week 
interaction 
Change from Baseline in ABQOL  
Score at Weeks 5, 13, 25, 37, and 61 
MMRM with terms for treatment, 
week, baseline score, disease 
history, and treatment by week 
interaction 
Proportion of patients with ABQOL 
Score of zero at Weeks 5, 13, 25, 37, 
and 61 
Cochran-Mantel-Haenszel test 
stratified by disease history at 
each visit 
Change from Baseline in EQ-5D-5L 
visual analog scale [VAS] results and 
individual dimension score categories 
at Weeks 5, 13, 25, 37 and 61 
Continuous outcomes: MMRM 
with terms for treatment, week, 
baseline score, disease history, 
and treatment by week 
interaction. 
Categorical outcomes: 
Cochran-Mantel-Haenszel test 
stratified by disease history  
 
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Endpoint 
Analysis Method 
 
Time to first flare/relapse from initial 
CDA to Week 37 
Log rank test stratified by disease 
history 
 
Time to first CR with a CS dose ≤ 
10mg/day, from Baseline to Week 61 
Log rank test stratified by disease 
history 
 
Proportion of patients with 3 or more 
lesions within 1 month or extension of 
established lesions that do not heal 
spontaneously within 1 week from 
Baseline to Week 37  
Cochran-Mantel-Haenszel test 
stratified by disease history  
 
Total number of disease flares/relapses 
from initial CDA to Week 37 
Zero-inflated negative binomial 
with terms for treatment group 
and disease history with an offset 
term based on the number of days 
on Post initial CDA 
To ensure the overall type I error rate of α = 0.05 will be maintained for the study, hierarchical 
testing, based on a fixed sequence procedure, will be used for the primary endpoint and 
continuing for the key secondary endpoints. The CMH primary analysis, as described in  
Section 8.1, will be the starting point for the hierarchical testing. If statistical significance is 
declared for the primary analysis, formal hypothesis testing will continue for the key secondary 
endpoints in sequence (see Section 6.1.3 for sequence of testing) until a non-significant result is 
reached. All other p-values from secondary and exploratory endpoints, after a non-significant p-
value is reached, will be considered nominal. All statistical tests will be performed using two-
tailed tests.  
For Cochran-Mantel-Haensel tests, if stratum cell sizes are too small based on the Mantel-Fleiss 
criterion (Mantel, 1980) a Pearson Chi-square test will be used instead without stratification for 
disease history.  If expected cell counts for the unstratified test are less than 5, a Fisher’s Exact 
test will be used. 
Analysis of covariance model residuals for the key secondary endpoint evaluated graphically for 
normality (e.g. quantile-quintile plot) and variance homogeneity (residual plots); additionally, a 
Kolmogorov-Smirnov test will be performed.  A non-parametric will be considered appropriate 
if the two-sided p-value for the test is significant at the 0.01 level.  If a parametric analysis is 
indicated, a rank analysis of covariance (Stokes, Davis, and Koch, 2000) will be used. 
All analyses will be performed on the mITT Population as described in Section 5.  Due to the 
small number of PF subjects expected to be enrolled in the study, the randomization strata of 
disease type (PV, PF) will not be included as a covariate in any of the analyses.  
The analyses for efficacy endpoints involving clinical assessment CR in the blinded treatment 
period will be performed based on data collected on on-site visits (i.e., not including data 
collected from remote visits) as the primary analyses. Supportive analysis will be performed by 
using data collected from all visits including visits performed remotely. 
 
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8.1. 
Primary Efficacy Analysis  
The primary efficacy endpoint is the proportion of patients who are in CR from Week 29 to 
Week 37 with a prednisone dose of ≤ 10 mg/day in patients treated with PRN1008 compared 
with placebo.  
Allow p0 to represent the proportion of responders in the placebo group; p1 will represent the 
proportion of responders in the PRN1008 group.  The null and alternative hypotheses are: 
H0:  
p1 - p0 = 0 
The proportion of patients who are in CR from Week 29 to Week 37 with a 
prednisone dose of ≤ 10 mg/day does not differ between the two treatment 
groups.  
H1:  
p1 - p0 ≠ 0 
The proportion of patients who are in CR from Week 29 to Week 37 with a 
prednisone dose of ≤ 10 mg/day differs between the two treatment groups. 
The primary endpoint will be analyzed using a CMH test, stratified by disease history.  The 
observed number and proportion of subjects meeting the primary endpoint as well as the 
proportion difference (PRN1008 – placebo), estimated standard error (SE), 95% CI and the 
associated p-value will be reported.  
Descriptive summaries of patients who are in CR with a CS dose of ≤ 10 mg/day will also be 
provided by visit through Week 37.  
These analyses will be performed on the mITT Population as well as in study subgroups as 
described in Section 6.1.3.2.As a sensitivity analysis to the primary endpoint, disease type will 
be included as an additional stratification factor in the CMH test. 
Tipping point analyses (Yan, 2009) will be done to investigate the impact of missing data and 
lost to follow-up (LTF). The tipping point analysis will look at all possible combination of 
converting missing data to a responder, starting at 0 and ending at all are responders. The cases 
where the statistical significance tips from significance to non-significance (defined as a two 
sided p-value > 0.05) will be listed. A complete list of all combinations will also be presented.  If 
the imbalances that leads to a change in interpretation are clinically implausible then the results 
of the primary analysis will be deemed reliable.   
In addition, the following endpoints will be analyzed as supportive analyses to primary endpoint: 
• Time to first CDA from Baseline to Week 37 
• Time to CR from Baseline to Week 37 
8.2. 
Key Secondary Efficacy Analyses  
The key secondary endpoint of Cumulative CS dose from baseline to Week 37, adjusted for time 
to study discontinuation will be calculated using the summation of the CS data as described in 
Section 6.1.9 and will be analyzed using an ANCOVA model with terms for treatment group and 
disease history. The estimated mean difference in cumulative CS usage (PRN1008 minus 
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placebo) and the associated 95% CI will be reported. Missing data for this endpoint is described 
in Section 6.1.5.2 . The “time to study discontinuation” covariate is up to study discontinuation, 
first Rituximab administration if any,  or the end of the blinded treatment period whichever happens 
first. 
If outliers or skewed data is present,  sensitivity analysis will be conducted on this secondary 
endpoint of average weekly CS usage over 36 weeks in which the data will be rank-transformed 
prior to analysis.  
Cumulative CS dose from Week 37 to Week 61 will be analyzed similarly. 
Cumulative duration of CR with CS dose ≤10mg/day from Baseline to Week 37, will be based 
on a zero-inflated negative binomial model with terms for treatment group and disease history.  
The p-value and estimated treatment difference (parameter difference of PRN1008 minus 
placebo) from the negative binomial component will be reported, along with the 95% CI for the 
estimated parameter.  The difference estimate will also be back-transformed (e.g. exponentiated) 
to demonstrate the relative difference in the number of pemphigus free days between treatment 
groups.  Cumulative duration of CR with CS dose ≤10mg/day from Baseline to Week 37 will 
also be summarized based on descriptive statistics.   
A Kaplan Meier analysis will be used to estimate the median and other quartiles for Time (Days) 
to first CR with a dose of ≤ 10 mg/day, along with two-sided 95% confidence intervals. The 
number of events and censored observations will be presented as well as graphical 
representations of estimated survival curves.  A hazard ratio for treatment comparisons will be 
presented, along with its 95% confidence interval, based on a Cox regression model with terms 
for treatment group and disease history. The endpoint will be evaluated based on a p-value from 
a log-rank test stratified by disease history for treatment group comparison. In addition, a 
landmark analysis will be done at Week 37 in the key secondary analysis and at Week 61 for the 
other secondary analysis.  
All key secondary endpoints will be analyzed based on the subgroups presented in 
Section 6.1.3.2.  
8.3. 
Other Secondary Analyses  
The following endpoints will be analyzed in a manner similar to that described for the primary 
endpoint in Section 8.1, with exception of the additional subgroup analyses described in 
Section 6.1.3.2: 
• The proportion of patients who are in CR from Week 29 to Week 37 with a CS dose of 
≤5 mg/day  
• The proportion of patients who have a PDAI score < 3 from Week 29 to Week 37 with 
CS ≤10 mg/day 
Cumulative duration of CR with a CS dose ≤ 10 mg/day from Baseline to Week 61; cumulative 
duration of CR with a zero CS dose from Baseline to Week 61 and the cumulative duration of 
CR with a zero CS dose from Week 37 to Week 61 will be analyzed based on the same methods 
described for the cumulative duration of CR with CS dose ≤ 10mg/day from Baseline to 
Week 37. 
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Change from baseline to Weeks 5, 13, 25, 37, and 61 in PDAI will be analyzed using restricted 
maximum likelihood (REML)-based mixed model for repeated measures (MMRM) with fixed 
effects for treatment, week, baseline PDAI and treatment by week interaction. For the analysis of 
the differences at Weeks 5, 13, 25, and 37, only all data up to Week 37 will be included in the 
model.  For the analyses of the difference at 61 weeks, only data collected during the Open-Label 
Extension Period will be included in the model (from Week 39  onward).  A contrast will be 
written within the MMRM model to get each Week-specific treatment difference (least squares 
treatment means, treatment difference estimates and 95% CIs). ABQOL and EQ-5D-5L overall 
VAS scores will be analyzed similarly. 
Descriptive summaries presenting the raw scores and change from baseline will be presented for 
ABQOL, PDAI, and EQ-5D-5L  and EQ-5DVAS scores by treatment group at each study visit. 
Additionally, descriptive summaries for responses to the EQ-5D-5L dimensions of mobility, self-
care, usual activities, pain/discomfort, and anxiety/depression will be displayed as frequency 
counts by category and treatment group for each study visit (Week 37, as well as Weeks 5, 13, 
25 and 61). Results will be analyzed using a CMH test, stratified by disease history.  The 
observed number and proportion of subjects reporting No Problems, as well as the resulting 
Mantel-Haenszel risk difference (PRN1008 – placebo), estimated SE, 95% CI and the associated 
p-value will be reported.  Descriptive summaries will be presented separately for the blinded 
treatment, open label, and long term extension periods of the study.  
The proportion of patients with 3 or more lesions within 1 month or extension of established 
lesions that do not heal spontaneously within 1 week from Baseline to Week 37 will be analyzed 
using the same methodology as the primary endpoint as described in Section 8.1.  The total 
number of disease flares/relapses from initial CDA to Week 37 will be analyzed based on the 
same methodology described for the cumulative duration of CR with CS dose ≤ 10mg/day from 
Baseline to Week 37 in Section 8.2. 
A Kaplan Meier analysis will be used to estimate the median and other quartiles for Time to first 
flare/relapse from initial CDA to Week 37, along with two-sided 95% confidence intervals. The 
number of events and censored observations will be presented as well as graphical 
representations of estimated survival curves.  A hazard ratio for treatment comparisons will be 
presented, along with its 95% confidence interval, based on a Cox regression model with terms 
for treatment group and disease history. The endpoint will be evaluated based on a p-value from 
a log-rank test stratified by disease history for treatment group comparison. 
Descriptive statistics including number, mean, SD, SE, median, minimum, and maximum will be 
provided by treatment group and by visit for domain-specific GTI scores, composite GTI total 
score, CWS and AIS. For CWS and AIS at Week 37, analysis of covariance model with 
treatment, disease history as fixed effects, and baseline GTI score, baseline CS dose as 
covariates, will be used to test the difference of the least-square means (LS means) between the 
treatment groups. Difference in LS means and the corresponding 95% CI along with the p-value 
will be provided.   
Proportion of patients with at least one disease flare/relapse from initial control of disease 
activity (CDA) to Week37 will be analyzed using the same methodology as the primary 
endpoint as described in Section 8.1. 
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Cumulative duration of CR with a CS dose ≤10 mg/day from Week 37 to Week 61, and 
cumulative duration of CR with a CS dose = 0 mg/day from Week 37 to Week 61 will be 
analyzed similarly to cumulative duration of CR with CS dose ≤ 10mg/day from Baseline to 
Week 37. 
8.4. 
Exploratory Analyses  
The number and percentage of patients with relapse after achievement of CR through Week 61 
Yes/No) will be presented by treatment group. A similar summary will be presented for patients 
that reached CR with a zero CS dose by from Week 53 to Week 61 (Yes/No). 
Observed values and changes from Baseline in Treatment of Autoimmune Bullous Disease 
Quality of Life (TABQOL) will be presented at each study visit based on summary statistics by 
treatment group.  Descriptive summaries for the Open-Label and Long Term Extension periods 
will report data by treatment group in double-blinded portion and overall. 
The total number of disease flares/relapses from initial Week 37 to Week 61 will be analyzed 
based on the same methodology described for the cumulative duration of CR with CS dose 
≤10mg/day from Baseline to Week 37 in Section 8.2, using an offset term representing the time 
of patient participation in the Open-Label Treatment Period. 
During the COVID-19 pandemic, measures to ensure continued drug supply and safety 
monitoring for patients were implemented. In-clinic study visits, as outlined in the protocol 
schedule of assessments, may be changed to a remote visit (e.g., telephone call, video call) as 
needed to address the COVID-19 restrictions. As a result, statistical analyses of efficacy 
endpoints involving CR assessment for the blinded treatment period will not include data 
collected from these remote visits. The incidence of remote visits and the corresponding reason 
for missing the onsite visits will be summarized by visit. Supportive analysis will be performed 
by including data collected remotely. 
The analyses of the following endpoints will be documented and reported separately: 
• Exploratory PK/PD analysis will examine the effects, if any, of covariates on PK and/or 
PD, and the relationship between PK, PD and efficacy in this population 
• Cost utilities based on the number and type of hospitalizations, outpatient medical visits, 
concomitant medication use, adverse events and other relevant outcomes 
• the temporal relationship of change in PDAI with changes in quality of life and health 
economic variables. 
9. 
Safety and Tolerability Analysis  
Safety will be evaluated from reported TEAEs, changes in clinical laboratory values, changes in 
vital signs and physical exam results. All safety analyses will be performed on the Safety 
population. All summaries of safety will be presented for the blinded treatment potion of the 
study separately from the open-label portion of the study. The long term extension period will 
also be separately reported.  All safety and tolerability data summaries will be reported by 
treatment group in double-blinded portion and overall.  No statistical tests will be performed for 
any of the safety assessments. 
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9.1. 
Adverse Events  
All AEs, TEAEs, and SAEs will be coded using the MedDRA dictionary version 24.0. 
A TEAE is defined as any AE with an onset date/time on or after the first dose of study drug, 
having been absent pre-treatment or worsening relative to pre-treatment state. TEAEs will be 
broken down into Blinded Treatment Period TEAEs; Open-Label Extension Period TEAEs; and 
Long Term Extension TEAEs. A double-blind TEAE is defined as any TEAE with an onset date 
on or after the first dose of study drug and occurring before enrollment into the open-label 
portion of the study. TEAEs that are ongoing at the time of enrollment into the open-label 
portion are considered part of the double-blind portion of the study. An open-label TEAE is 
defined as any TEAE with an onset date on or after enrollment into the open-label portion of the 
study, having been absent during the double-blind portion or worsening relative to double-blind 
portion state.  TEAEs for the long-term extension study will be determined similarly, based on 
the relative timing and severity of an event with respect to the end of the open-label period and 
start of the long term extension. 
All summaries of TEAEs will be presented separately for the double-blind and open-label 
portions of the study for the Safety Population.  
An overall summary of TEAEs will be presented including the total number of events, frequency 
counts, and percentages for: 
• Any TEAEs 
• Any treatment-related TEAEs  
• Any TEAE leading to study discontinuation 
• Any SAEs 
• TEAEs resulting in death 
• TEAEs by Grade (severity)  
• Action Taken with Study Drug for all TEAEs (Study Drug Dose Not Changed, Study 
Drug Dose Interrupted, Study Drug Discontinued) 
• TEAEs related to Corticosteroids 
Summaries of the incidence of TEAEs and SAEs will be displayed by: 
• SOC and PT 
• SOC, PT, and maximum severity grade 
• SOC, PT, and maximum causality (not related, related) to the study drug 
In the case of multiple occurrences of the same TEAE within the same subject, each subject will 
only be counted once a preferred term. In the summaries showing severity and relationship to 
study medication the event with the maximum severity grade or strongest relationship (not 
related < related) will be reported. If an event is missing the severity, then severe will be used in 
the summary analyses (severity = severe);  If an event is missing the relationship, then related 
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will be assumed for summary analyses (relationship = related). These data imputations are for 
categorization purpose only and will not be used in listings. 
All TEAEs summarized by system organ class (SOC) and preferred term (PT) will be sorted in 
order of descending frequency of the SOC and then by descending frequency order (total across 
treatment groups) of the PT within each SOC. 
In addition, summaries of TEAEs will be displayed by: 
• SOC, HLGT, HLT and PT 
In the AE data listings, all AEs will be displayed. AEs that are not treatment-emergent will be 
flagged. 
9.1.1. Adverse Events Related to Corticosteroid Use  
A summary of incidence rates (frequencies and percentages) of TEAEs related to CS use, SOC, 
and preferred term will be prepared for the Safety Population.  
9.1.2. Adverse Events Leading to Withdrawal  
A summary of incidence rates (frequencies and percentages) of TEAEs leading to withdrawal of 
study drug, by SOC, and preferred term will be prepared for the Safety Population. 
A data listing of AEs leading to withdrawal of study drug will also be provided, displaying 
details of the event(s) captured on the CRF. 
9.1.3. Deaths and Serious Adverse Events  
Any deaths that occur during the study will be listed. 
Serious adverse events will be listed and also tabulated by system organ class and preferred term 
and presented. 
9.2. 
Clinical Laboratory Evaluations  
Absolute values and changes from baseline will be summarized for clinical laboratory chemistry, 
hematology and coagulation results using descriptive statistics. The number of subjects with 
clinical laboratory values below, within, or above the normal range by time point will be 
tabulated for each clinical laboratory analyte. Shift tables for each clinical laboratory test will 
cross-tabulate the number of subjects with values below the laboratory reference range (low), 
values within the laboratory reference range (normal) or above the laboratory range (high) at 
baseline with the number of subjects with low, normal or high values at each post-baseline time 
point. Normal ranges and values outside the normal ranges will be identified by the central 
laboratory. A separate listing of out of normal range laboratory results will be provided. 
A listing of all randomized subjects with pre-treatment and treatment-emergent laboratory values 
our of normal range will be presented.  
Patients with positive urine pregnancy test results will be presented in by-subject listings. 
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9.3. 
Vital Signs  
Descriptive summaries of actual values and changes from baseline will be calculated for systolic 
blood pressure, diastolic blood pressure, pulse rate, respiratory rate, oral body temperature, body 
weight, height and BMI.  Height will be presented at baseline only. 
9.4. 
Physical Examinations  
Abbreviated physical examinations will be summarized using descriptive statistics at Baseline 
and at each post-baseline time point. Shifts from Baseline will also be summarized.  
Abnormal physical examination findings will be displayed in a by-subject listing. 
9.5. 
Electrocardiograms  
Descriptive summaries will be presented for ECG measures of PR interval, RR interval, QRS 
Duration interval, QTcF interval, and HR. These summaries will be presented by study visit. 
Shift tables comparing baseline ECG investigator interpretation (normal; abnormal, not clinically 
significant; or abnormal, clinically significant) and unable to evaluate,  to each study visit will be 
provided. 
9.6. 
Prior and Concomitant Medication  
Prior and concomitant medication use will be summarized descriptively using counts and 
percentages by ATC Class Level 2 and preferred term (ATC Class Level 5). 
Prior medications will be presented separately from concomitant medications. Medications that 
started prior to Day 1 will be considered prior medications whether or not they were stopped 
prior to Day 1. Any medications continuing or starting after Day 1 will be considered to be 
concomitant. If a medication starts prior to Day 1 and continues after Day 1 it will be considered 
both prior and concomitant. 
• Medications will be coded using the World Health Organization Drug Dictionary 
Version March 2021. 
Medications will be summarized separately for non-corticosteroid medications and other 
corticosteroid (i.e. not Prednisone/Prednisolone) medications.  
9.7. 
Long Term Extension Analysis  
The Long Term Extension endpoints will be summarized descriptively. Summaries of patient 
disposition, demographics, and baseline characteristics will be provided. The number of received 
doses and treatment duration will be described. Safety data including adverse events, laboratory 
evaluations and vital signs assessments will also be summarized. Specifically, 
• Nature, frequency, and severity of adverse events, including serious adverse events, 
adverse events leading to discontinuation and possible corticosteroid-related adverse 
effects during the LTE from Week 61 to Week 113, will be summarized descriptively 
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in a manner similar to that described in Section 9.1. 
• Average daily dose of CS from Week 61 to Week 113 will be summarized by 
treatment group in double-blinded portion and overall. 
• Time to relapse from Week 61 (beginning of LTE) during the LTE will be 
summarized using Kaplan Meier estimates of the median and other quartiles along 
with two-sided 95% confidence intervals. The number of events and censored 
observations will be presented as well as graphical representations of estimated 
survival curves. 
10. 
Changes from Planned Analysis  
Not applicable. 
11. 
Other Planned Analysis  
11.1. Pharmacokinetic and Pharmacodynamic Analysis  
Individual and group PK (PRN1008 and metabolites as applicable) and PD (anti-desmoglein-1 
and -3) data will be summarized, displayed graphically, and by descriptive statistics for each visit, 
where measured. Additional analyses may be described and reported separately.  
11.2. Questionnaires and health economic Analysis  
Analyses of the following two exploratory endpoints will be performed outside of CSR under the 
responsibility of the Health Economics Outcomes Research (HEOR) department of Sanofi. 
• Number and type of hospitalizations, outpatient medical visits, concomitant medication 
use, adverse events and other relevant outcomes 
• Change from baseline in PDAI by visit and the temporal relationship to changes in 
quality of life and health economic variables 
12. 
References  
1. U. S. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). 
Center for Biologics Evaluation and Research (CBER). (1998). Guidance for Industry E9 
Statistical Principles for Clinical Trials. https://www.fda.gov/regulatory-information/search-
fda-guidance-documents/e9-statistical-principles-clinical-trials 
2. ASA. (2016) Ethical Guidelines for Statistical Practice. Prepared by the Committee on 
Professional Ethics, April 2016. http://www.amstat.org/about/ethicalguidelines.cfm 
3. RSS. (2014) The Royal Statistical Society: Code of Conduct, 2014. 
http://www.rss.org.uk/Images/PDF/join-us/RSS-Code-of-Conduct-2014.pdf. 
 
4. Yan X., Lee, S., and Li, N. (2016) Missing Data Handling Methods in Medical Device 
Clinical Trials, Journal of Biopharmaceutical Statistics, 19:6, 1085-1098. 
 
5. Mantel N, Fleiss JL (1980) Minimum expected cell size requirements for the Mantel-
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Haenszel one-degree-of-freedom chi-square test and a related rapid procedure.  American 
Journal of Epidemiology, 112:1, 129-134. 
 
6. Stokes ME, Davis CS, Koch GG (2000). Categorical data analysis using the SAS system. 
Second edition. SAS Institute, Inc., Cary, N.C. 
 
7. Beissert S, Werfel T, Frieling U, Böhm M, Sticherling M, Stadler R, et al. A comparison of 
oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of 
pemphigus. Arch Dermatol. 2006 Nov;142(11):1447-54.  
 
8. Joly P, Maho-Vaillant M, Prost-Squarcioni C, Hebert V, Houivet E, Calbo S, et al. First-line 
rituximab combined with short-term prednisone versus prednisone alone for the treatment of 
pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial. 
Lancet. 2017 May 20;389(10083):2031-2040. 
 
9. Miloslavsky EM, Naden RP, Bijlsma JW, Brogan PA, Brown ES, Brunetta P, et al. 
Development of a Glucocorticoid Toxicity Index (GTI) using multicriteria decision analysis. 
Ann Rheum Dis. 2017 Mar;76(3):543-546. 
 
10. Tjokrowidjaja A, Daniel BS, Frew JW, Sebaratnam DF, Hanna AM, Chee S, Dermawan A, 
Wang CQ, Lim C, Venugopal SS, Rhodes LM, Welsh B, Nijsten T, Murrell DF. The 
development and validation of the treatment of autoimmune bullous disease quality of life 
questionnaire, a tool to measure the quality of life impacts of treatments used in patients with 
autoimmune blistering disease. Br J Dermatol. 2013 Nov;169(5):1000-6. doi: 
10.1111/bjd.12623. Erratum in: Br J Dermatol. 2014 Feb;170(2):481-3. PMID: 24102329. 
11. Van Hout B, Janssen MF, Feng YS, Kohlmann T, Busschbach J, Golicki D et al. 
Interim scoring for the EQ-5D-5L: Mapping the EQ-5D-5L to EQ-5D-3L value 
sets. Value in Health. 2012;15(5):708-15. 
12. Dolan P. Modeling valuations for EuroQol health states. Med Care. 1997 
Nov;35(11):1095-108. doi: 10.1097/00005650-199711000-00002. PMID: 
9366889. 
13. Murrell DF, Peña S, Joly P, Marinovic B, Hashimoto T, Diaz LA, et al. Diagnosis 
and management of pemphigus: Recommendations of an international panel of 
experts. J Am Acad Dermatol. 2020;82(3):575-85.
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