A Phase 3, Multicenter, Randomized, Double-Blind, Placebo Controlled, Parallel-Group Study With an Open-Label Extension to Evaluate the Efficacy and Safety of Oral Rilzabrutinib (PRN1008) in Adults and Adolescents With Persistent or Chronic Immune Thrombocytopenia (ITP)
Phase: PHASE3
Conditions: Immune Thrombocytopenia
Sponsor: Principia Biopharma, a Sanofi Company

 
Property of the Sanofi Group - strictly confidential 
1 
AMENDED CLINICAL TRIAL PROTOCOL 05  
Protocol title: 
A Phase 3, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled, Parallel-Group Study with an 
Open-Label Extension to Evaluate the Efficacy and 
Safety of Oral Rilzabrutinib (PRN1008) in Adults and 
Adolescents with Persistent or Chronic Immune 
Thrombocytopenia (ITP) 
Protocol number: 
PRN1008-018 (EFC17093) 
Amendment number: 
05 
Compound number 
(INN/Trademark): 
PRN1008/SAR444671 
(Rilzabrutinib/Not Applicable)  
Brief title: 
LUNA 3 
Study Phase: 
3 
Sponsor name: 
Principia Biopharma Inc. 
Legal registered 
address: 
55 Corporate Drive 
Bridgewater, NJ 08807 
USA 
Monitoring team’s 
representative name 
and contact 
information: 
 
Regulatory agency 
identifier number(s): 
 
IND: 
132668 
EU trial number: 
2023-509401-71 
NCT: 
NCT04562766 
WHO: 
Not applicable 
EUDAMED: 
Not applicable 
Other 
Not applicable 
Date: 15-May-2024 
 
Total number of pages: 199 
 
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2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
Document 
Country/countries 
impacted by amendment 
Date, electronic version 
Amended Clinical Trial Protocol 05 
All 
15 May 2024, version 1 
(electronic 9.0) 
Amended Clinical Trial Protocol 04 
All 
24 Jul 2023, version 1 
(electronic 8.0) 
Amended Clinical Trial Protocol 03 
All 
11 Aug 2022, version 1 
(electronic 7.0) 
Amended Clinical Trial Protocol 02c 
All 
21 Jul 2021, version 1 
(electronic 4.0) 
Clinical Study Protocol PRN1008-018 
Version 2.0b 
All 
19 Feb 2021, electronic 
version 2.0 
Clinical Study Protocol PRN1008-018 
Version 1.2 Ukraine 
Ukraine only 
21 Jan 2021 
Clinical Study Protocol PRN1008-018 
Version 1.2 Turkey 
Turkey only 
06 Jan 2021 
Clinical Study Protocol PRN1008-018 
Version 1.3 France 
France only 
02 Jan 2021 
Clinical Study Protocol PRN1008-018 
Version 1.2 Norway 
Norway only 
15 Dec 2020 
Clinical Study Protocol PRN1008-018 
Version 1.2 France 
France only 
04 Dec 2020 
Clinical Study Protocol PRN1008-018 
Version 1.2 Austria 
Austria only 
03 Dec 2020 
Clinical Study Protocol PRN1008-018 
Version 1.2 United Kingdom 
United Kingdom only 
09 Nov 2020 
Clinical Study Protocol PRN1008-018 
Version 1.3 Canada 
Canada only 
06 Nov 2020 
Clinical Study Protocol PRN1008-018 
Version 1.2 Canada 
Canada only 
03 Nov 2020 
Clinical Study Protocol PRN1008-018 
Version 1.2 Germany 
Germany only 
28 Oct 2020 
Clinical Study Protocol PRN1008-018 
Version 1.1a 
All 
06 Aug 2020 
Clinical Study Protocol PRN1008-018 
Version 1.0 
All 
10 Jul 2020 
a First version distributed to sites; original protocol. 
b First protocol amendment. 
c Sponsor naming convention adopted. 
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Amended Clinical Trial Protocol 05 (15 May 2024) 
This amended protocol (amendment 05) is considered to be substantial based on the criteria set 
forth in Article 2(2)(13) of the Regulation No 536/2014 of the European Parliament and the 
Council of the European Union.  
OVERALL RATIONALE FOR THE AMENDMENT 
The primary reasons for this amendment are to incorporate language to comply with new 
European Union (EU) clinical trial regulations and to update the overall benefit-risk assessment. 
 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title page 
Replaced EudraCT number with EU trial number 
To comply with EU CTR requirements 
Section 1.0 Synopsis 
Section 5.1 Inclusion 
Criteria 
Inclusion #4: For estimated glomerular filtration rate 
(GFR), language modified from “Cockcroft and Gault 
method” to “Cockcroft and Gault method for adult 
and Bedside Schwartz Equation for Pediatric 
participants”. 
To Adopt “Bedside Schwartz Equation” 
to improve the calculation accuracy of 
eGFR in pediatric participants. 
 
Inclusion #6 removal of the text “with low user 
dependency” regarding the contraceptive method for 
a WOCBP  
 
To correct an error in the protocol text. 
Both Low and high user dependent 
highly effective contraception methods 
should be permitted.  
Section 1.0 Synopsis 
 
In Table 1 - Schedule of Assessments - Blinded 
Treatment Period footnote K, added “eGFR will be 
calculated using the Bedside Schwartz Equation in 
pediatric participants (10 to <18 years old) and using 
the Cockcroft and Gault method in adult 
participants.” 
To Adopt “Bedside Schwartz Equation” 
to improve the calculation accuracy of 
eGFR in pediatric participants. 
Section 2.4.1 Safety 
Removed general outdated safety information from 
the safety profile and referenced publications 
detailing safety and efficacy findings. 
To align with the investigator brochure 
(IB) and take new data into 
consideration. 
 
Added “Please refer to the most recent version of 
the IB for updated safety information.” and “For 
summary of overall benefit/risk assessment, refer to 
Section 2.7.” 
 
Section 2.7.1 Risk 
Assessment 
 
Updated Risk Assessment subsection and 
introduced uveitis as a new “important potential risk” 
of rilzabrutinib. 
To update details of liver enzyme 
increase and serious infection, which 
are known “important potential risks” of 
rilzabrutinib, as well as to introduce 
uveitis as a new “important potential 
risk” based on recent findings of 
ongoing rilzabrutinib clinical trials. 
Section 2.7.1.1 “Potential 
risks reported with other 
BTK inhibitors” 
 
Added “Class Effect” to describe specific AEs in 
subsection 2.7.1.1 “Potential risks reported with 
other BTK inhibitors”  
Section 2.7.3 “Overall 
benefit: risk conclusion” 
Updated subsection 2.7.3. “Overall benefit: risk 
conclusion” to summarize updated safety 
information. 
Section 3.1.2.2 Safety 
Objectives 
Modified description of pediatric participants from 
“(<18 years)” to “(≥10 years – <18 years)”  
To provide additional clarity on the age 
range of pediatric participants 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 4 Study Design 
Figure #1 
Modified Figure #1 “Decision tree for assessing 
response at Week 13” to remove the “continue in the 
blinded part” option.  
To correct the figure and to be 
consistent with text that 
non-responders cannot continue in the 
blinded portion of the study.  
Section 6.4.2 Destruction of 
Investigational Medicinal 
Product 
Added “No destruction of unused (not dispensed) 
IMP takes place without Sponsor’s written 
authorization. Storage conditions must be kept until 
approval from the Sponsor to remove the product 
from its storage location (eg, refrigerator). Products 
must be kept in a dedicated quarantine area until 
destruction, with a clear sign of “quarantined” until 
the Sponsor’s Site Monitor authorizes the 
destruction.” 
To be consistent with recently updated 
Pharmacist’s Manual v6.0 
 
 
Added “If a site does not have a destruction SOP, 
study drug can be returned to the depot.” 
 
Section 6.5 Treatment of 
Overdose 
Modified Section 6.5 to include clear definitions and 
guidelines for treating overdose with the IMP 
To align treatment of overdose text 
with the latest protocol template 
language  
Section 6.6.2 Particular 
Permissible Medications 
Modified “per day” to “or equivalent per day” 
regarding permitted prednisone dosing. 
To account for the fact that steroid 
medications other than prednisone 
could be used. 
Section 7.9.15 Use of 
biological samples and data 
for future research 
Updated language pertaining to “Use of biological 
samples and data for future research” 
To align with new EU CTR guidelines. 
 
Section 7.9.16 Medication 
errors or misuses of 
medicinal product 
Modified title “Overdose, medication errors, misuses 
or abuses of medicinal product” to “Medication 
errors or misuses of medicinal product” 
Template language updated to align 
with new EU CTR guidelines and as 
per the latest protocol template 
language.  
 
Definition of overdose moved to Section 6.5.  
 
 
Language added clarifying medication errors and 
misuse of medicinal product. 
 
Section 9.3.9.4 Regulatory 
reporting requirements for 
SAEs  
Added reference to safety reporting for the EU with 
direction to Appendix 10.7  
To align with new EU CTR guidelines. 
 
Section 9.3.9.6 “Adverse 
events of special interest” 
Added uveitis including Vogt‐Koyanagi‐Harada 
disease as an adverse event of special interest. 
To introduce uveitis as a new “adverse 
event of special interest” based on 
recent findings of ongoing rilzabrutinib 
clinical trials. 
 
Removed sub-bullet defining overdose 
Definition of overdose is now under 
Section 6.7 
Section 13.5 Data 
Protection 
Added subsection 13.5 “Data Protection” with 
language pertaining to the protection of participant 
personal data and personal data of professionals 
involved in the study. 
To align with new EU CTR guidelines. 
 
Section 13.6. Financial 
Disclosure 
Added subsection 13.6 “Financial Disclosure” that 
details investigator responsibilities. 
To provide additional details on 
responsibility of the investigators and 
sub-investigators. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 14.1 Regulatory 
and ethical considerations 
Modified title with removal of “Local 
Regulations/Declaration of Helsinki”  
Template language updated to align 
with new EU CTR guidelines and as 
per the latest protocol template 
language.  
Revised language to clarifying that the study will be 
conducted in accordance with EU CTR regulation 
and updated ethical considerations. 
Section 16, Appendix 10.6 
Italy country-specific 
requirements 
Removed “For pediatric participants (10 to <18 years 
old) enrolled in Italy, eGFR will be calculated using 
the Bedside Schwartz Equation.”  
To clarify that the Bedside Schwartz 
Equation will no longer be specific to 
Italy and is adopted in the inclusion 
criteria #4 and in the schedule of 
assessment footnotes for all pediatric 
participants. 
Section 16, Appendix 10.7 
EU (EEA countries) and 
UK-specific requirements 
Added safety reporting to the agency language in 
the subsection “EU (EEA countries) only” 
To align with new EU CTR guidelines. 
Section 16, Appendix 13.2 
Contraception guidance 
Added highly effective contraception methods that 
are user dependent. 
To correct an error in the contraception 
guidance text and to align with the ICF  
Section 16, Appendix 15 
Liver AND OTHER Safety: 
Suggested Actions and 
Follow-up Assessments 
Updated subsection heading to include “AND 
OTHER” 
To provide updated algorithm for 
accessing neutropenia and increase in 
ALT per the latest protocol template.  
Added figure for neutropenia assessment.  
 
Updated “Increase in ALT” figure with latest template 
version. 
Section 16, Appendix 16 
Collection, storage and 
future use of data and 
human biological samples 
Added Appendix 16 to include statement “This 
appendix is provided separately” related to the 
“Collection, storage and future use of data and 
human biological samples” 
To align with new EU CTR guidelines. 
 
In addition, other minor editorial changes were implemented throughout the protocol. 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 05 ..........................................................................1 
I.EPROTOCOL AMENDMENT SUMMARY OF CHANGES .....................................................2 
TABLE OF CONTENTS .................................................................................................................6 
LIST OF TABLES .........................................................................................................................11 
LIST OF FIGURES .......................................................................................................................11 
LIST OF ABBREVIATIONS ........................................................................................................12 
1. 
SYNOPSIS .........................................................................................................................15 
2. 
BACKGROUND ...............................................................................................................35 
2.1. 
Overview of Immune Thrombocytopenia (ITP) ....................................................35 
2.2. 
BTK Inhibitor Rilzabrutinib ..................................................................................35 
2.3. 
Nonclinical Experience ..........................................................................................35 
2.4. 
Clinical Experience ................................................................................................36 
2.4.1. 
Safety ......................................................................................................36 
2.4.2. 
Cardiodynamic Evaluation .....................................................................37 
2.4.3. 
Pharmacokinetics and Pharmacodynamics .............................................37 
2.4.4. 
Drug-Drug Interaction Potential .............................................................37 
2.5. 
Study Design Rationale..........................................................................................38 
2.6. 
Dose Rationale .......................................................................................................39 
2.7. 
Overall Risk-Benefit Assessment ..........................................................................40 
2.7.1. 
Risk assessment ......................................................................................40 
2.7.1.1. Potential risks reported with other BTK inhibitors ..................42 
2.7.2. 
Benefit assessment ..................................................................................43 
2.7.3. 
Overall benefit: risk conclusion ..............................................................43 
3. 
OBJECTIVES AND ENDPOINTS ...................................................................................44 
3.1. 
Objectives ..............................................................................................................44 
3.1.1. 
Efficacy Objectives .................................................................................44 
3.1.2. 
Other Secondary Objectives ...................................................................44 
3.1.2.1. Efficacy Objectives ..................................................................44 
3.1.2.2. Safety Objectives .....................................................................44 
3.1.2.3. Pharmacokinetic Objectives .....................................................44 
3.1.2.4. Quality of Life (QOL) Objectives ............................................45 
3.2. 
Endpoints ...............................................................................................................45 
3.2.1. 
Primary Efficacy Endpoint (Blinded Treatment Period) ........................45 
3.2.2. 
Key Secondary Efficacy Endpoints (Blinded Treatment Period) ...........45 
3.2.3. 
Other Secondary Endpoints ....................................................................45 
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3.2.3.1. Efficacy Endpoint ....................................................................45 
3.2.3.2. Safety Endpoints ......................................................................46 
3.2.3.3. Pharmacokinetic Endpoints .....................................................46 
3.2.3.4. Quality of Life (QOL) Endpoints ............................................46 
3.2.4. 
Exploratory Endpoints ............................................................................46 
3.2.4.1. Blinded Treatment Period ........................................................46 
3.2.4.2. Open Label Period and Long-Term Extension ........................47 
4. 
STUDY DESIGN...............................................................................................................49 
4.1. 
Duration of Study Participation .............................................................................52 
4.1.1. 
Screening (Day -28 to Study Day-1 Predose) .........................................52 
4.1.2. 
Blinded Treatment Period (Weeks 1 to 25) ............................................53 
4.1.3. 
Open Label Period (Weeks 25 to 53)......................................................57 
4.1.4. 
End of Study visit (Four Weeks Post Last Dose of Study Drug) ...........63 
4.1.5. 
Long-Term Extension (LTE) ..................................................................64 
4.2. 
Study Population ....................................................................................................65 
4.3. 
Study Assessments Overview ................................................................................65 
5. 
ELIGIBILITY CRITERIA.................................................................................................66 
5.1. 
Inclusion Criteria ...................................................................................................66 
5.2. 
Exclusion Criteria ..................................................................................................67 
6. 
TREATMENTS .................................................................................................................70 
6.1. 
Treatments Administered .......................................................................................70 
6.1.1. 
Rilzabrutinib/Placebo..............................................................................70 
6.1.1.1. Packaging .................................................................................70 
6.2. 
Preparation and Administration .............................................................................70 
6.2.1. 
Rilzabrutinib/Placebo..............................................................................70 
6.3. 
Storage ...................................................................................................................70 
6.3.1. 
Rilzabrutinib/Placebo..............................................................................70 
6.4. 
Drug Management .................................................................................................70 
6.4.1. 
Drug Accountability ...............................................................................71 
6.4.2. 
Destruction of Investigational Medicinal Product ..................................71 
6.4.3. 
Treatment Compliance ............................................................................72 
6.4.4. 
Treatment Blinding/Unblinding ..............................................................72 
6.5. 
Treatment of Overdose ..........................................................................................73 
6.6. 
Concomitant Medications ......................................................................................73 
6.6.1. 
Prohibited Medications ...........................................................................73 
6.6.2. 
Particular Permissible Medications ........................................................74 
7. 
STUDY ASSESSMENTS AND PROCEDURES .............................................................76 
7.1. 
Study Recruitment Procedures ...............................................................................76 
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7.2. 
Study Enrollment Procedures ................................................................................76 
7.3. 
Temporary Discontinuation ...................................................................................76 
7.4. 
Rechallenge ............................................................................................................76 
7.5. 
Participant Exit from the Study ..............................................................................77 
7.5.1. 
Individual Participant Stopping Rules ....................................................77 
7.5.1.1. Individual Long-term Extension Participant Stopping 
Rules ........................................................................................77 
7.5.2. 
Participant Withdrawal ...........................................................................78 
7.5.3. 
Participant Lost to Follow-up .................................................................78 
7.6. 
Study Stopping Rules .............................................................................................78 
7.7. 
Sponsor Study Termination ...................................................................................78 
7.8. 
Visit Overview .......................................................................................................79 
7.8.1. 
Screening (Day -28 to Study Day -1 Predose) ........................................79 
7.8.2. 
Baseline Study Day 1 ..............................................................................79 
7.8.3. 
Blinded Treatment Period (Weeks 1 to 25) ............................................79 
7.8.4. 
Open Label Period (Weeks 25 to 53)......................................................79 
7.8.5. 
4 Week Post-Dose Follow-up Period (Weeks 53 to 56 or any 4-week 
period following the End of Treatment visit) .........................................79 
7.8.6. 
Early Termination Visit ..........................................................................80 
7.8.7. 
Long-Term Extension (LTE) ..................................................................80 
7.9. 
Study Assessments .................................................................................................80 
7.9.1. 
Body Height and Weight ........................................................................80 
7.9.2. 
Physical Examination .............................................................................80 
7.9.3. 
Medical History ......................................................................................80 
7.9.4. 
Vital Signs...............................................................................................80 
7.9.5. 
Electrocardiogram (ECG) Monitoring ....................................................81 
7.9.6. 
Clinical Laboratory Tests........................................................................81 
7.9.7. 
Pharmacokinetic Assessments ................................................................81 
7.9.8. 
Bruton’s Tyrosine Kinase (BTK) Occupancy ........................................81 
7.9.9. 
Vaccine IgG (optional) ...........................................................................81 
7.9.10. Immune Thrombocytopenia (ITP) Assessment Tools (IBLS, ITP-
PAQ, ITP-KIT) .......................................................................................82 
7.9.11. EuroQOL (EQ-5D-5L) ...........................................................................83 
7.9.12. Patient Global Impression of [Fatigue] Severity (PGIS-Fatigue) 
Scale ........................................................................................................83 
7.9.13. Patient Global Impression of Severity (PGIS) Scale ..............................83 
7.9.14. Patient Global Impression of Change (PGIC) Scal ................................83 
7.9.15. Use of biological samples and data for future research ..........................84 
7.9.16. Medication errors or misuses of medicinal product................................85 
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8. 
ASSESSMENT OF EFFICACY .......................................................................................86 
8.1. 
Specification of the Efficacy Parameters ...............................................................86 
8.2. 
Methods and Timing for Assessing, Recording, and Analyses of Efficacy 
Parameters ............................................................................................................86 
9. 
ASSESSMENT OF SAFETY ............................................................................................87 
9.1. 
Overview ................................................................................................................87 
9.2. 
Data Safety Monitoring Board (DSMB) ................................................................87 
9.3. 
Adverse Events (AEs) ............................................................................................87 
9.3.1. 
Adverse Event Collection Period ............................................................87 
9.3.2. 
Adverse Events .......................................................................................88 
9.3.3. 
Adverse Event Intensity Grading ............................................................89 
9.3.4. 
Adverse Event Relationship to Study Medication ..................................90 
9.3.5. 
Adverse Event Relationship to Standard of Care Medication ................90 
9.3.6. 
Treatment Unblinding to Determine Clinical Course .............................90 
9.3.7. 
Treatment and Follow-Up of Adverse Events (AEs) ..............................90 
9.3.8. 
Laboratory and Electrocardiogram (ECG) Abnormalities......................91 
9.3.8.1. Follow-Up of Abnormal Laboratory Test Values ....................91 
9.3.9. 
Adverse events (AEs), Serious Adverse Events (SAEs) and Other 
Safety Reporting .....................................................................................91 
9.3.9.1. Time period and frequency for collecting AE and SAE 
information ...............................................................................91 
9.3.9.2. Method of detecting AEs and SAEs ........................................92 
9.3.9.3. Follow-up of AEs and SAEs ....................................................92 
9.3.9.4. Regulatory reporting requirements for SAEs ..........................92 
9.3.9.5. Pregnancy .................................................................................93 
9.3.9.6. Adverse events of special interest ............................................93 
9.3.9.7. Guidelines for reporting product complaints ...........................94 
10. 
STATISTICAL METHODS ..............................................................................................95 
10.1. Determination of Sample Size ...............................................................................95 
10.2. Objectives and Endpoints ......................................................................................95 
10.3. Analysis Populations ..............................................................................................96 
10.3.1. Safety Population ....................................................................................96 
10.3.2. Intent-to-Treat (ITT) Population .............................................................96 
10.3.3. Modified ITT (mITT) Population ...........................................................96 
10.3.4. Pharmacokinetic (PK) Population ..........................................................96 
10.3.5. Disposition of the Study Participants......................................................96 
10.3.6. Demographic and Baseline Characteristics ............................................96 
10.3.7. Exposure to Study Treatment .................................................................96 
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10.3.8. Safety and Tolerability Analysis.............................................................97 
10.3.9. Primary Efficacy Analysis ......................................................................97 
10.3.10. Key Secondary Efficacy Analysis ..........................................................98 
10.3.11. Other Efficacy Analysis ..........................................................................98 
10.3.12. Pharmacokinetic (PK) Analysis ..............................................................98 
10.3.13. Exploratory Analysis ..............................................................................99 
10.3.14. Missing Data ...........................................................................................99 
10.4. Interim Analysis .....................................................................................................99 
11. 
INVESTIGATOR RESPONSIBILITIES ........................................................................100 
12. 
DATA QUALITY ASSURANCE ...................................................................................101 
12.1. Protocol Amendments and Study Completion .....................................................101 
12.2. Informed Consent.................................................................................................101 
13. 
DATA HANDLING AND RECORD KEEPING ...........................................................103 
13.1. Participant Confidentiality and Disclosure of Data .............................................103 
13.2. Electronic Case Report Forms (eCRF) ................................................................103 
13.3. Retention and Availability of Records .................................................................104 
13.4. Audits and Inspections .........................................................................................104 
13.5. Data Protection.....................................................................................................104 
13.6. Financial Disclosure.............................................................................................107 
14. 
ETHICAL ASPECTS ......................................................................................................108 
14.1. Regulatory and ethical considerations .................................................................108 
14.2. Institutional Review Board Review .....................................................................110 
15. 
REFERENCES ................................................................................................................111 
16. 
APPENDICES .................................................................................................................115 
Appendix 1 
ITP Disease Activity - ITP Bleeding Scale (IBLS) ..............................116 
Appendix 2 
ITP Disease Activity - ITP-PAQ ..........................................................117 
Appendix 3 
ITP Disease Activity - ITP-KIT............................................................127 
Appendix 4 
General Quality of Life Evaluation: EQ-5D-5L ...................................131 
Appendix 5 
Patient Global Impression of [Fatigue] Severity (PGIS-Fatigue), 
Patient Global Impression of Severity (PGIS), and Patient Global Impression 
of Change (PGIC) ...............................................................................................134 
Appendix 6 
Strong-to-Moderate CYP3A Inhibitors and Inducers and Sensitive 
CYP3A Substrates ..............................................................................................136 
Appendix 7 
Publication ............................................................................................137 
Appendix 8 
Guidelines to Sites for Delayed Participant Visits or Missed Visits 
due to travel restrictions and any foreseeable impacts of COVID-19 ................138 
Appendix 9 
Remote Study Visits for Active Participants ........................................141 
Appendix 10 
Country-Specific Requirements ............................................................142 
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Appendix 11 
Protocol Amendment History ...............................................................147 
Appendix 12 
AE and SAEs: Definitions and procedures for Recording evaluating, 
Follow-up, and Reporting ...................................................................................181 
Appendix 13 
Contraceptive and Barrier Guidance .....................................................187 
Appendix 14 
Patient Medication Diary ......................................................................190 
Appendix 15 
Liver AND OTHER Safety: Suggested Actions and Follow-up 
Assessments ........................................................................................................196 
Appendix 16 Collection, storage and future use of data and human biological samples 199 
 
LIST OF TABLES  
Table 1 - Schedule of Assessments - Blinded Treatment Period ...................................................28 
Table 2 - Schedule of Assessments - Open Label Period ..............................................................31 
Table 3 - Schedule of Assessments - Long-Term Extension .........................................................33 
Table 4 - Risk assessment ..............................................................................................................41 
 
LIST OF FIGURES  
Figure 1 - Decision tree for assessing response at Week 13 ..........................................................50 
Figure 2 - Study Design Flow Chart ..............................................................................................51 
 
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LIST OF ABBREVIATIONS  
AE 
Adverse event 
AESI 
Adverse event of special interest 
AIDS 
Acquired immune deficiency syndrome 
ALT 
Alanine aminotransferase 
ALP 
Alkaline phosphatase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUClast 
Area under the plasma concentration curve 
BID 
Twice daily 
BTK 
Bruton’s tyrosine kinase 
CA 
Competent authority 
CLL 
Chronic lymphocytic leukemia 
CFR 
Codes of Federal Regulations 
CPK 
Creatinine phosphokinase 
CRA 
Clinical research associate 
CRO 
Contract research organization 
CS 
Corticosteroids 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DNA 
Deoxyribonucleic acid 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EEA 
European Economic Area 
eGFR 
Estimated glomerular filtration rate 
EOS 
End of Study 
EOT 
End of Treatment 
EQ-5D-5L 
EuroQOL-5 Dimension 5 Level 
EU 
European Union 
FDA 
United States Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
H2 
Histamine 2 
HBcAb 
Hepatitis B core antigen antibody 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
IBLS 
ITP Bleeding Scale 
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ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ID 
Identification 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
INR 
International normalized ratio 
IR 
Immediate release 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IVIg 
Intravenous immunoglobulin 
ITP 
Immune thrombocytopenia 
ITP-KIT 
Kids’ ITP Tools 
ITP-PAQ 
ITP-Patient Assessment Questionnaire 
ITT 
Intent-to-treat 
IWRS 
Interactive Web Response System 
LAR 
Legally authorized representative 
LTE 
Long-term extension 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOAEL 
No-observed adverse effect level 
PD 
Pharmacodynamics 
PGIC 
PGIS 
Patient Global Impression of Change 
Patient Global Impression of Severity 
PGIS-Fatigue 
Patient Global Impression of [Fatigue] Severity 
PK 
Pharmacokinetics 
PRN1008 
Rilzabrutinib 
PRO 
Patient response outcome 
PT 
Prothrombin time 
PV 
pemphigus vulgaris 
QOL 
Quality of life 
QTcF 
QT corrected for heart rate using Fredericia correction 
QTF Plus 
QuantiFERON®-TB Gold Plus 
RBC 
Red blood cell 
Rh 
Rhesus factor 
RNA 
Ribonucleic acid 
rSDV 
Remote source data verification 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Study day 
SoA 
Schedule of assessments 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
Tuberculosis 
T/B/NK 
T-lymphocytes/ B-lymphocytes/natural killers 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time of observed maximum plasma concentration 
TPO 
Thrombopoietin 
TPO-RA 
Thrombopoietin receptor agonist 
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UK 
United Kingdom 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WC 
World Courier 
WHO 
World Health Organization  
WOCBP 
Woman of childbearing potential 
WONCBP 
Woman of nonchildbearing potential 
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1. 
SYNOPSIS  
PROTOCOL TITLE 
A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study with an 
Open-Label Extension to Evaluate the Efficacy and Safety of Oral Rilzabrutinib (PRN1008) in Adults 
and Adolescents with Persistent or Chronic Immune Thrombocytopenia (ITP) 
PROTOCOL NUMBER  
PRN1008-018 (EFC17093) 
SPONSOR  
Principia Biopharma Inc. 
STUDY MEDICATION 
The investigational drug product is rilzabrutinib (PRN1008/SAR444671). 
PHASE 
This is a Phase 3 pivotal study. 
STUDY POPULATION 
Participants with refractory or relapsed ITP of >3 months duration (age 18 years and above) or with 
>6 months duration (age ≥12 to <18 years; see Appendix 10.2, Appendix 10.3, and Appendix 10.7 for 
country-specific criteria). 
DURATION OF STUDY PARTICIPATION 
For each participant, the study will last up to 60 weeks from the start of the screening period to the End 
of Study (EOS) visit. This includes screening (up to 4 weeks) through a 12 to 24-week blinded 
treatment period followed by a 28-week open label period. Followed by a 4-week post-dose follow-up. 
For adult participants, the maximum duration of the long-term extension (LTE) period will be 
12 months from the date of the last adult participant to enter the LTE. 
For pediatric participants, the maximum duration of the LTE period will be 12 months from the date of 
the last pediatric participant to enter the LTE. 
NUMBER OF STUDY SITES 
Approximately 150 sites worldwide. 
OBJECTIVES 
Primary Efficacy Objective (Blinded Treatment Period) 
• 
To demonstrate the efficacy of rilzabrutinib versus placebo in participants with 
refractory/relapsed ITP, based on the durability of platelet response during the last 12 weeks of 
the 24-week blinded treatment period in the absence of rescue therapy. 
Key Secondary Efficacy Objectives (Blinded Treatment Period) 
• 
To evaluate the effect of rilzabrutinib versus placebo on the number of weeks with platelet 
count ≥50,000/μL OR between ≥30,000/μL and <50,000/μL and at least doubled from 
baseline, over the 24-week blinded treatment period in the absence of rescue therapy  
• 
To evaluate the effect of rilzabrutinib versus placebo on the number of weeks with platelet 
counts ≥30,000/μL and at least doubled from baseline over the 24-week blinded treatment 
period in the absence of rescue therapy 
• 
To evaluate the effect of rilzabrutinib versus placebo on the time to first platelet count of 
≥50,000/μL OR between ≥30,000/μL and <50,000/μL and at least doubled from baseline 
• 
To evaluate the effect of rilzabrutinib versus placebo on the proportion of participants 
requiring rescue therapy 
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• 
To evaluate the effect of rilzabrutinib versus placebo on the change from baseline on Item 
10 of the ITP-Patient Assessment Questionnaire (ITP-PAQ) (ie, physical fatigue) in adult 
participants (≥18 years) at Week 13 
See Appendix 10.7 for EU (EEA countries) and UK-specific requirements. 
Other Secondary Objectives 
Efficacy Objectives 
• 
To evaluate the stability of platelet response of rilzabrutinib 
Safety Objectives  
• 
To evaluate the safety and tolerability of rilzabrutinib in pediatric participants (<18 years) and 
in adult participants (≥18 years) with refractory/relapsed ITP 
Pharmacokinetic (PK) Objectives  
• 
To characterize the PK of rilzabrutinib in pediatric participants (<18 years) and in adult 
participants (≥18 years) with refractory/relapsed ITP 
Quality of Life (QOL) Objectives  
• 
To evaluate the effect of rilzabrutinib on the general and disease specific QOL of adult 
participants (≥18 years) with refractory/relapsed ITP 
• 
To evaluate the effect of rilzabrutinib on disease specific QOL in pediatric participants with 
refractory/relapsed ITP 
Refer to Appendix 10.7 for EU (EEA countries) specific age ranges. 
INVESTIGATIONAL PLAN 
Study Design 
This is a global, randomized, parallel-group, double-blind, multicenter clinical study in participants 
with primary ITP who had a response to either intravenous immunoglobulin (IVIg) or corticosteroid 
(CS) that was not sustained. 
After providing informed consent, participants will enter a 28-day screening period. Upon completion 
of the screening period, participants who satisfy all the inclusion criteria and none of the exclusion 
criteria of this protocol will be randomized in a 2:1 allocation ratio to one of two study arms: 
rilzabrutinib or placebo.  
Randomization will be carried out separately for the two age groups. For the adult group, stratified 
permuted block randomization will be implemented; for the pediatric group, dynamic randomization 
algorithm (minimization) will be implemented. The factors used for stratification (for adult 
participants), or balance (for pediatric participants) are splenectomy status (yes/no), and by severity of 
thrombocytopenia (Inclusion Criteria #3 platelet counts <15,000/μL or ≥15,000/μL). 
After randomization, participants will start a blinded treatment period of up to 25 weeks followed by an 
open-label period of 28 weeks during which all participants will receive rilzabrutinib, and then a 
4-week safety follow-up period or long-term extension. 
At the end of 12 weeks of treatment, participants will be assessed for achieving a platelet response 
defined as:  
a) platelet count of ≥50,000/μL OR a platelet count between ≥30,000/μL and <50,000/μL and at least 
doubled from baseline at any time during the first 12 weeks and 
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b) absence of rescue medication in the 4 weeks prior to the elevated platelet count that meets platelet 
response criteria. 
Figure 1 depicts the decision process for assessing response. The baseline value of platelet count is 
defined as the average of all the participant’s Predose platelet counts (Screening and Study Day 1). 
• 
Participants who respond will continue the blinded treatment period for a total of 24 weeks 
before entering the open label period. 
• 
Participants who do not respond (including participants who receive rescue medication after 
8 weeks of treatment) may discontinue from the study or enter the 28-week open label period 
at the end of Week 12, receiving treatment with 400 mg twice daily (BID) of rilzabrutinib. The 
initial study medication assignment will remain blinded.  
Concomitant ITP medications (an oral CS and/or a thrombopoietin receptor agonist [TPO-RA]) will be 
permitted in both treatment arms and must be maintained at stable doses from 14 days before Study 
Day 1 until the last dose of study medication. Reductions in the doses of concomitant ITP medications 
will be permitted for associated safety concerns only. 
The use of rescue medications (one of IVIg, high-dose CSs, platelet infusion, or anti-D 
immunoglobulin infusion) intended to increase platelet counts or prevent bleeding when platelet counts 
are less than 20,000/μL, or for bleeding or wet purpura, will be allowed.  
After completing the open label period, participants who demonstrate a platelet response defined as 
platelet counts ≥50,000/μL or ≥30,000/μL and at least doubled from baseline at ≥50% of the visits 
without receiving rescue therapy while on treatment during the last 8 weeks of the open label period, 
will be allowed to enter the LTE. 
Participant(s) may continue in the LTE until: 
a) The participant is no longer responding (platelet counts <30,000/µL or less than 20,000/µL above 
baseline on two consecutive visits)  
b) The drug is no longer being developed by the Sponsor for ITP  
c) The program is stopped for safety reasons or  
d) The drug becomes commercially available in the participant’s country. 
Safety Measures Due to Coronavirus (COVID-19) Pandemic 
Due to the COVID-19 pandemic, safety measures have been implemented to ensure continued supply 
of study medication and safety monitoring for participants. These measures are described in the 
“Guidelines to Sites for Delayed Participant Visits or Missed Visits due to travel restrictions and any 
foreseeable impacts of COVID-19.” 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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STUDY DRUG AND DOSING REGIMEN 
Participants will receive one 400 mg tablet of rilzabrutinib, or placebo BID in the double-blind portion 
of the study. Participants will receive one 400 mg tablet of rilzabrutinib BID in the open label portion 
of the study and the LTE. 
Tablets should be taken with (~8oz/250mL) of water and may be taken with or without food. 
PLANNED NUMBER OF PARTICIPANTS: 
• 
Up to 30 pediatric participants aged 12 to <18 years; pediatric participants 10 to <12 years will 
be enrolled only in EEA countries; see Appendix 10.2, Appendix 10.3, and Appendix 10.7 for 
country-specific age ranges). 
• 
Approximately 194 participants aged 18 years or older. 
INDIVIDUAL PARTICIPANT STOPPING RULES 
• 
Life-threatening or Common Terminology Criteria for Adverse Events (CTCAE) Grade 4 
rilzabrutinib-related treatment-emergent adverse event (TEAE) except for adverse events 
(AEs) related to the disease under study or other underlying medical conditions 
• 
Serious allergic reaction to rilzabrutinib or placebo, including anaphylactic reaction 
• 
Pregnancy 
• 
Any medical condition or personal circumstance that, in the opinion of the Investigator, 
exposes the participant to risk if the participant continues with rilzabrutinib or placebo or that 
prevents the participant’s adherence to the protocol 
• 
Human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), viral 
hepatitis (B and C) infection occurring during the study 
• 
Violation of protocol inclusion or exclusion criteria, that in the opinion of the Sponsor, would 
significantly compromise data interpretation 
• 
Discontinuation of study intervention for abnormal liver tests is required by the Investigator 
when a participant meets one of the conditions outlined in Appendix 15 or in the presence of 
abnormal liver chemistries not meeting protocol-specified stopping rules if the Investigator 
believes that it is in best interest of the participant.  
STUDY STOPPING RULES 
Study stopping rules will include, however not be limited to: 
• 
More than one rilzabrutinib-related death 
• 
Two or more life-threatening or CTCAE Grade 4 rilzabrutinib-related TEAEs except for AEs 
related to the disease under study (lack of efficacy) 
• 
The Sponsor elects to stop the study.  
INCLUSION CRITERIA 
Participants may be included in the study if ALL of the following criteria are met: 
1. Participants will be male and female with primary ITP with duration of >6 months in pediatric 
participants aged 12 to <18 years (pediatric participants aged 10 to <12 years will be enrolled 
in the EU [EEA countries] only; refer to Appendix 10.2, Appendix 10.3, and 
Appendix 10.7 for country-specific requirements) and duration of >3 months in adults aged 
≥18 years 
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2. Participants who had a response (achievement of platelet count ≥50,000/µL) to IVIg/anti-D or 
CSs that was not sustained and who have documented intolerance, insufficient response, or any 
contraindication to any appropriate courses of standard of care ITP therapy  
3. An average of 2 platelet counts at least 5 days apart of <30,000/µL during the screening period, 
and no single platelet count >35,000/µL, within 14 days prior to the first dose of study drug 
• 
Pediatric participants must additionally be determined to need treatment for ITP as per 
clinical assessment by the Investigator (see Appendix 10.7 for EU [EEA countries] specific 
requirements). 
4. Adequate hematologic, hepatic, and renal function (absolute neutrophil count ≥1.5 × 109/L, 
aspartate aminotransferase/alanine aminotransferase ≤1.5 × upper limit of normal [ULN], 
albumin ≥3 g/dL, total bilirubin ≤1.5 × ULN [unless the participant has documented Gilbert 
syndrome], glomerular filtration rate >50 [Cockcroft and Gault method for adult and Bedside 
Schwartz Equation for Pediatric participants]). 
5. Hemoglobin >9 g/dL within 1 week prior to Study Day 1 
6. All contraceptive use by men and women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies 
A) Male participants 
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 13 weeks after the last administration of study intervention: 
• 
Refrain from donating or cryopreserving sperm 
Plus, either: 
- 
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent 
OR 
- 
Must agree to use contraception/barrier as detailed below 
- 
A male condom; the participant should also be advised of the benefit for a female 
partner to use a highly effective method of contraception (as described in 
Appendix 13 Contraceptive and barrier guidance of the protocol) as a condom may 
break or leak when having sexual intercourse with a woman of childbearing potential 
(WOCBP) who is not currently pregnant 
B) Female participants 
A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of 
the following conditions applies: 
• 
Is a woman of nonchildbearing potential (WONCBP) as defined in Appendix 13 of the 
protocol. 
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OR 
• 
Is a WOCBP and agrees to use a contraceptive method that is highly effective (with a 
failure rate of <1% per year), as described in Appendix 13 of the protocol, during the 
study intervention period (to be effective before starting the intervention) and for at least 
4 weeks after the last administration of study intervention AND agrees not to donate or 
cryopreserve eggs (ova, oocytes) for the purpose of reproduction during this period. 
• 
A WOCBP must have a negative highly sensitive pregnancy test (serum) as required by 
local regulations) within 3 days before the first administration of study intervention  
- 
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive. 
7. Participants must be able to provide written informed consent or informed assent with 
corresponding informed consent obtained from the participant’s guardian and agree to the 
schedule of assessments (SoA). 
EXCLUSION CRITERIA 
Participants will be excluded from the study if any of the following criteria are met: 
1. Participants with secondary ITP 
2. Pregnant or lactating women  
3. Electrocardiogram (ECG) findings for participants:  
o Aged ≥10 and <16 years: QTcF >449 msec (males) or >457 msec (females) 
o Aged ≥16 and <18 years: QTcF >450 msec (males) or >460 msec (females) 
o Aged ≥18 years, of QTcF >450 msec (males) or >470 msec (females), poorly controlled 
atrial fibrillation (ie, symptomatic participants or a ventricular rate above 100 beats/min on 
ECG), or other clinically significant abnormalities  
4. History (within 5 years of Study Day 1) or current, active malignancy requiring or likely to 
require chemotherapeutic or surgical treatment during the study, with the exception of 
non-melanoma skin cancer  
5. Transfusion with blood, blood products, plasmapheresis, or use of any other rescue 
medications with intent to increase platelet count within 14 days before Study Day 1 
6. Change in CS and/or TPO-RA dose within 14 days prior to Study Day 1 (more than 
10% variation from current doses) 
7. Immunosuppressant drugs other than CSs within 5 times the elimination half-life of the drug or 
14 days of Study Day 1, whichever is longer 
8. Treatment with rituximab or splenectomy within the 3 months prior to Study Day 1 
- 
Participants treated with rituximab will have normal B-cell counts prior to enrollment 
9. Ongoing need for the use of proton pump inhibitor drugs such as omeprazole and 
esomeprazole (it is acceptable to change participant to histamine 2 receptor blocking drugs 
prior to Study Day 1) 
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10. Use of known strong-to-moderate inducers or inhibitors of cytochrome P450 (CYP) 3A within 
14 days or 5 half-lives (whichever is longer) of Study Day 1 and until the end of the active 
treatment period 
11. Planned or concomitant use of any anticoagulants and platelet aggregation inhibiting drugs 
such as aspirin (except for low dose aspirin up to 100 mg per day), nonsteroidal 
anti-inflammatory drugs, and/or thienopyridines within 14 days of Study Day 1 and until the 
end of the active treatment period 
12. Has received any investigational drug within the 30 days before receiving the first dose of 
study medication, or at least 5 times elimination half-life of the drug (whichever is longer); 
participant should not be using an investigational device at the time of dosing 
o Participants who previously received treatment with Bruton’s Tyrosine Kinase (BTK) 
inhibitors (except rilzabrutinib) within 30 days before the first dose of study drug are not 
eligible  
o Participants who previously received rilzabrutinib at any time are not eligible  
13. Current drug or alcohol abuse 
14. Refractory nausea and vomiting, malabsorption, external biliary shunt, significant bowel 
resection, or any other condition that would preclude adequate study drug absorption 
15. History of solid organ transplant 
16. Positive at Screening for HIV, hepatitis B virus (HBV) (surface and core antibodies unrelated 
to vaccination), or hepatitis C virus (anti-HCV antibody confirmed with Hep C RNA) 
- 
Participants who are hepatitis B virus surface antigen (HBsAg) positive will not be 
eligible.  
- 
Participants who are HBsAg negative and hepatitis B core antigen antibody (HBcAb) 
positive will be tested for HBV surface antibody (HBsAb) and HBV DNA. If HBV DNA 
is negative and HBsAb titer is ≥100 IU/L, participants may be enrolled. Monthly HBV 
DNA monitoring will be required while on treatment and for 6 months after the last dose 
of the study drug. Positive HBV DNA results will be managed appropriately as per local 
standard of care.  
- 
Participants who are HBcAb positive and HBsAg negative with HBsAb titer <100 IU/L or 
negative, are not eligible. 
17. Positive QuantiFERON®-TB Gold, or QuantiFERON®-TB Gold Plus (QFT Plus) at 
Screening unless all of the following 3 conditions are true (see Appendix 10 country-specific 
requirements): 
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 one of the following prophylactic treatment regimens: 
i. Oral daily Isoniazid for 6 months or 
ii. Oral daily Rifampin for 4 months or 
iii. Isoniazid and Rifapentine weekly for 3 months (3HP) 
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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 
participant may be enrolled using the local result upon approval of the Sponsor.  
18. History of recurring (2 or more) serious infections requiring intravenous antibiotic, antivirals, 
or antifungals therapy within the last 3 months before Study Day 1 or active serious or 
moderate infection ongoing on the day of randomization 
19. Myelodysplastic syndrome 
20. Live vaccine within 28 days prior to Study Day 1 or plan to receive one during the study 
21. Planned surgery in the time frame of the dosing period 
22. Any other clinically significant disease, condition, known allergy to any of the study 
medications, their analogues, or excipients in the various formulations of any agent (please see 
Section 6.1.1 for information on excipients), or medical history that, in the opinion of the 
Investigator or Sponsor’s medical monitor, would interfere with participant safety, study 
evaluations, and/or study procedures 
23. Positive severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) molecular test (if 
COVID-19 testing required per local guidelines to be determined for each site) 
24. The COVID-19 vaccine within 14 days prior to Study Day 1 or planned during the last 
12 weeks of the blinded treatment period 
RANDOMIZATION PROCEDURE 
Participants will be randomized in a 2:1 ratio to either active rilzabrutinib or placebo. The study is 
designed so that randomization will be carried out separately for the two age groups. For the adult 
group, stratified permuted block randomization will be implemented; for the pediatric group, dynamic 
randomization algorithm (minimization) will be implemented. The factors used for stratification or 
balance are splenectomy status (yes/no), and by severity of thrombocytopenia (Inclusion Criteria 3 
platelet counts <15,000/μL or ≥15,000/μL). 
STUDY ASSESSMENTS 
Clinical assessments will include: 
• 
Physical examination; assessment of vital signs, height, and weight; 12-lead ECG, collection of 
medical history, collection of concomitant medication information, assessment of bleeding 
with ITP Bleeding Scale (IBLS) and/or other bleeding scales, QOL questionnaires, collection 
of AEs. 
Laboratory assessments will include: 
• 
Hepatitis B and C, HIV, pregnancy test, follicle-stimulating hormone (FSH), urinalysis, ABO 
and Rh, hemolysis panel (Coombs and haptoglobin), mean platelet volume, serum chemistry, 
hematology, platelet counts, prothrombin time (PT)/international normalized ratio (INR), 
thrombopoietin (TPO) level, PK sampling, T-lymphocytes/ B-lymphocytes/natural killers 
(T/B/NK) count, Immunoglobulin levels, activated partial thromboplastin time (aPTT), 
fibrinogen, and BTK occupancy (at select sites). 
SAFETY AND TOLERABILITY ASSESSMENTS 
Safety and tolerability will be assessed by collection of frequency, severity, and causal relationship of 
TEAEs. 
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Data Safety Monitoring Board 
An independent Data Safety Monitoring Board will review unblinded participant safety data. 
ENDPOINTS 
Primary Efficacy Endpoint (Blinded Treatment Period) 
• 
Durable platelet response defined as the proportion of participants able to achieve platelet 
counts at or above 50,000/μL for ≥ two-thirds of at least 8 non-missing weekly scheduled 
platelet measurements during the last 12 weeks of the 24-week blinded treatment period in the 
absence of rescue therapy, provided that at least 2 non-missing weekly scheduled platelet 
measurements are at or above 50,000/μL during the last 6 weeks of the 24-week blinded 
treatment period; see Appendix 10.7 for country-specific definition of durable platelet response 
(EU [EEA countries] and UK). 
Key Secondary Efficacy Endpoints (Blinded Treatment Period) 
• 
Number of weeks with platelet count ≥50,000/μL OR between ≥30,000/μL and <50,000/μL 
and at least doubled from baseline over the 24-week blinded treatment period in the absence of 
rescue therapy 
• 
Number of weeks with platelet counts ≥30,000/μL and at least doubled from baseline over the 
24-week blinded treatment period in the absence of rescue therapy  
• 
Time to first platelet count of ≥50,000/μL OR between ≥30,000/μL and <50,000/μL and 
doubled from baseline 
• 
Proportion of participants requiring rescue therapy during the 24-week blinded treatment 
period 
• 
Change from baseline on Item 10 of the ITP-PAQ (ie, physical fatigue) in adult participants 
(≥18 years) at Week 13 
See Appendix 10.7 for EU (EEA countries) and UK-specific requirements. 
Other Secondary Endpoints 
Efficacy Endpoint 
• 
Stability of response defined as the proportion of participants able to achieve stable platelet 
response, which is defined as no 2 scheduled visits, at least 4 weeks apart, with a platelet count 
less than 50,000/µL, without an intervening visit with a platelet count ≥50,000/µL, within a 
period of 24 weeks following initial achievement of the platelet response (initial platelet 
response defined as platelet count ≥50,000/μL within 12 weeks of initiation of treatment with 
rilzabrutinib during the study)   
Safety Endpoints 
• 
Frequency and severity of TEAEs 
• 
Frequency and severity of bleeding TEAEs  
• 
Change from baseline in physical examination, ECG, vital signs, and clinical laboratory tests 
results: serum chemistry and hematology (except for platelet counts included in the primary 
efficacy endpoint) 
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Pharmacokinetic Endpoints 
• 
Plasma concentrations of rilzabrutinib 
Quality of Life (QOL) Endpoints 
• 
Change from baseline on the Symptoms, Bother and Activity domains of the ITP-PAQ in adult 
participants (≥18 years) 
• 
Change from baseline in disease-specific QOL as measured by the Kids’ ITP Tools (ITP-KIT) 
score in pediatric participants  
Exploratory Endpoints (Blinded Treatment Period): 
• 
Proportion of participants able to achieve platelet counts ≥50,000/μL for 4 out of last 8 weeks 
of the 24-week treatment period 
• 
Percentage of weeks with platelet count ≥50,000/μL OR between ≥30,000/μL and <50,000/μL 
and at least doubled from baseline over the 24-week blinded treatment period in the absence of 
rescue therapy 
• 
Proportion of participants with complete response (defined as platelet count ≥100,000/μL) on 
2 consecutive visits at least 5 days apart and no bleeding or rescue ITP therapy use on and 
through these two visits. 
• 
Proportion of participants with platelet count ≥50,000/μL on 2 consecutive visits at least 5 days 
apart and no rescue ITP therapy use on and through these two visits. 
• 
Proportion of participants who have a platelet count that exceeds 250,000/μL or 450,000/µL 
(for participants on TPO-RAs) 
• 
Change from baseline in IBLS assessment at Week 13 and Week 25 
• 
Change from baseline and change from Week 13 on the Fatigue (Item 10 of the IT-PAQ; 
physical fatigue), Psychological, Fear, Social Activity, Women’s Reproductive Health and 
Work domains of the ITP-PAQ in adult participants (≥18 years) at Week 25 
• 
Change from baseline on the Psychological, Fear, Social Activity, Women’s Reproductive 
Health and Work domains of the ITP-PAQ in adult participants (≥18 years) at Week 13 
• 
Change from baseline in QOL as measured by the EuroQOL-Dimensions-5 Level in adult 
participants (≥18 years)  
• 
Change from baseline in disease-related symptom severity as measured by the Patient Global 
Impression of Severity (PGIS) scale 
• 
Change from baseline in disease-related fatigue severity as measured by the Patient Global 
Impression of [Fatigue] Severity (PGIS-Fatigue) scale 
• 
Patient perception of disease-related symptom improvement as measured by the Patient Global 
Impression of Change (PGIC) scale 
• 
PK parameters as assessed by population PK analysis 
• 
BTK occupancy 
• 
Changes from baseline in TPO levels, T/B/NK counts, immunoglobulin (IgG, IgG1, IgG4, 
IgM, IgE) levels  
• 
(Optional) Vaccine-specific IgG response during treatment 
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See Appendix 10 (Appendix 10.5) for China-specific requirements. 
Exploratory Endpoints (Open Label Period and Long-Term Extension): 
The following exploratory endpoints will be assessed at the end of the open label period (Week 53) and 
after 12 months on the LTE period. 
• 
Proportion of participants who received placebo during the blinded part and able to achieve 
durable platelet response during the open label part. Durable platelet response is defined as 
platelet counts at or above 50,000/μL for ≥ two-thirds of at least 10 non-missing weekly 
scheduled platelet measurements during the last 16 weeks of the 28 of the open label period in 
the absence of rescue therapy, provided that at least 3 non-missing weekly scheduled platelet 
measurements are at or above 50,000/μL during the last 8 weeks of the 28-week open label 
period 
• 
Percentage of weeks with platelet count ≥50,000/μL OR between ≥30,000/μL and <50,000/μL 
and at least doubled from baseline 
• 
Proportion of participants with complete response (defined as platelet count ≥100,000/μL) on 
2 consecutive visits at least 5 days apart and no bleeding or rescue ITP therapy use on and 
through these two visits 
• 
Proportion of participants who have a platelet count that exceeds 250,000/μL or 450,000/µL 
(for participants on TPO-RAs) 
• 
Proportion of participants requiring rescue therapy 
• 
Change from baseline on the Fatigue (Item 10 of the ITP-PAQ; physical fatigue), 
Psychological, Fear, Social Activity, Women’s Reproductive Health and Work domains of the 
ITP-PAQ in adult participants (≥18 years) 
• 
Change from baseline in IBLS assessment 
• 
Change from baseline on the Psychological, Fear, Social Activity, Women’s Reproductive 
Health and Work domains of the ITP-PAQ in adult participants (≥18 years) 
• 
Change from baseline in QOL as measured by the EuroQOL-Dimensions-5 Level in adult 
participants (≥18 years)  
• 
Percent change from baseline on CS dose 
• 
Percent change from baseline on TPO-RA dose. 
• 
Proportion of participants who switch to rilzabrutinib as a monotherapy during the first year of 
the LTE period 
• 
Proportion of participants who decrease their CS dose >50% relative to baseline values during 
the first year of the LTE  
• 
Proportion of participants who manage to reduce their dose or stop TPO-RA agonists during 
the first year of the LTE 
See Appendix 10.7 for EU (EEA countries) and UK-specific requirements. 
SAFETY ASSESSMENTS 
Safety will be assessed by the incidence, severity, and causal relationship of TEAEs, including 
clinically significant changes in physical examination, vital signs, ECG, laboratory parameters.  
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PHARMACOKINETICS 
Blood samples for the determination of plasma rilzabrutinib (and metabolites, if applicable) 
concentrations will be collected at specified timepoints. Concentrations will be summarized by 
timepoint. PK data may also be analyzed using a nonlinear mixed effects (population PK) model in 
isolation and/or pooled with PK data from other studies. Exploratory analyses will be conducted to 
evaluate potential relationships between PK and PD, safety, and efficacy endpoints. The results of 
these analyses may be reported outside of the main clinical study report. 
SAMPLE SIZE 
The adult sample size chosen for this study was selected to achieve enrollment of 129 adult participants 
(≥18 years) on rilzabrutinib and 65 adult participants on placebo. The pediatric sample size of up to 
30 participants (20 participants on rilzabrutinib and 10 participants on placebo) was determined based 
on clinical practice and is adequate to descriptively describe the safety and efficacy in pediatric 
participants. With a sample size of 20 pediatric participants on rilzabrutinib the maximum width of an 
exact 90% CI on response rate would be 40%.  
A sample size of approximately 194 (129 versus 65 adult participants in the rilzabrutinib versus 
placebo arms, respectively) will provide 95% power to detect a 20% difference in response rates as 
defined in the primary endpoint (Section 3.2.1) between the 2 arms (25% vs 5%, in the rilzabrutinib 
versus placebo arms, respectively), using the Fisher’s Exact test with a 0.05 two-sided significance 
level.  
PRIMARY EFFICACY ANALYSIS 
The primary analysis will compare the proportion of participants in the adult intent-to-treat (ITT) 
population who achieve durable platelet response defined as  platelet counts at or above 50,000/μL for 
≥ two-thirds of at least 8 non-missing weekly scheduled platelet measurements during the last 
12 weeks of the 24-week blinded treatment period in the absence of rescue medication (with at least 
2 platelet counts at or above 50,000/μL during the last 6 weeks of the 24-week blinded treatment 
period) between rilzabrutinib and placebo with a Cochran-Mantel-Haenszel test using the two 
stratification factors at a 2-sided alpha level of 0.05 (See Appendix 10.7 for country-specific definition 
of durable platelet response (EU [EEA countries] and UK). Participants who do not respond in the first 
12 weeks and enter the open label period will be treated as non-responders in the primary analysis. 
The primary endpoint will be analyzed for adult and pediatric participants separately. 
Platelet counts conducted locally will be used for the primary endpoint analysis. Platelet counts 
conducted centrally at Clinic Visits will be used as a back-up for missed or non-analyzable local lab 
samples. 
KEY SECONDARY EFFICACY ANALYSES 
The following five comparisons will be conducted between rilzabrutinib and placebo in the adult ITT 
population using sequential (hierarchical) testing with a fixed sequence, which controls the family-wise 
error for multiple comparisons at alpha level of 0.05 (two-sided): 
• 
Compare the number of weeks with platelet count ≥50,000/μL OR between ≥30,000/μL and 
<50,000/μL and at least double from baseline over the 24-week blinded treatment period 
(platelet counts will be censored for 4 weeks after the use of rescue therapy, if any) 
• 
Compare the number of weeks with platelet counts ≥30,000/μL and at least double from 
baseline over the 24-week blinded treatment period 
• 
Compare the time to first platelet count of ≥50,000/μL OR between ≥30,000/μL and 
<50,000/μL and at least double from baseline 
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• 
Compare the proportion of participants requiring rescue therapy during the 24-week blinded 
treatment period 
• 
Compare the change from baseline on Item 10 of the ITP-PAQ (physical fatigue) in adult 
participants at Week 13 
See Appendix 10.7 for EU (EEA countries) and UK-specific requirements. 
OTHER EFFICACY ANALYSES 
• 
Estimate the predictive value of platelet count for each of the three predictors separately or in 
combination: 
- 
≥30,000/μL on Study Day 8 
- 
≥20,000/μL above baseline on Study Day 8 
- 
≥50,000/μL at any time over first 8 weeks of the treatment period to achieve the primary 
endpoint 
OTHER STATISTICAL CONSIDERATIONS 
The primary endpoint will be analyzed for adult and pediatric participants separately. The primary 
analysis will be based on the adult population. An early analysis may be performed with the cutoff 
when the last adult participant has completed the blinded treatment period. As the primary analysis for 
the study is based on the adult population, the results at the early analysis will be considered as final 
and served as basis for regulatory submissions. 
The pediatric participants will not be tested, and descriptive statistics will be done on these 
participants. Additional statistical analyses on these pediatric participants may be provided for specific 
regulatory requests. 
The primary efficacy analysis will be conducted when all adult participants aged ≥18 years have 
completed the Blinded Study Week 25 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, 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.  
No formal interim analysis is planned for the double-blind part of the study.  
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Table 1 - Schedule of Assessments - Blinded Treatment Period  
 
Screening 
Blinded Treatment Periodw  
 
Early Terminationx/ 
Unscheduled visit 
(D-28 to 
Study 
Day -1 
Predose)a 
 
WK 1 
SD1 
WK5  
SD29 
WK9 
SD57 
WK13 
SD85 
WK17 
SD113 
 
 
WK21 
SD141 
Weekly Lab 
Visits Between 
Clinic Visits 
Visit Window 
 
±3  
days 
±3  
days 
±3  
days 
±3  
days 
±3  
days 
±3  
days 
±3  
days 
 
Informed Consent 
Xt 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
 
X 
Review of Platelet Counts for 
Responseb 
 
 
 
 
X 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
 
X 
Height (cm)c 
X 
 
 
 
X 
 
 
 
 
Weight (kg) 
X 
X 
X 
X 
X 
X 
X 
 
X 
Physical exam/medical historyd 
X 
X 
X 
X 
X 
X 
X 
 
X 
ECG (12-lead, single) 
X 
Xe 
 
 
 
 
 
 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
 
X 
Urinalysisf 
X 
X 
X 
X 
X 
X 
X 
 
X 
Hep B & C, HIVg 
X 
 
 
 
 
 
 
 
 
QuantiFERON-TB Test 
X 
 
 
 
 
 
 
 
 
Pregnancy Testh 
X 
X 
X 
X 
X 
X 
X 
 
X 
FSHi 
X 
 
 
 
 
 
 
 
 
ABO and Rh Blood Typej 
X 
 
 
 
 
 
 
 
 
Serum Chemistryk 
X 
X 
X 
X 
X 
X 
X 
 
X 
Hematology, differential, 
reticulocytesl 
X 
X 
X 
X 
X 
X 
X 
Xu 
X 
T/B/NK countsr 
 
X 
X 
 
X 
 
 
 
 
PT/INR, aPTTm 
X 
X 
X 
X 
X 
X 
X 
 
 
TPO levelsr 
 
X 
X 
X 
X 
X 
X 
 
 
Hemolysis paneln, r 
 
X 
X 
X 
X 
X 
X 
 
 
Immunoglobulin Levelsr 
 
X 
X 
 
X 
 
 
 
 
PK sampleo 
 
X 
 
 
X 
 
 
 
X 
BTK Occupancy (at select sites)p, r 
 
X 
 
 
X 
 
 
 
 
(Optional) sample for 
vaccine-specific IgGr, s 
 
===============================================→ 
X 
QOL Questionnairesq 
X 
X 
X 
X 
X 
X 
X 
 
X 
IBLS 
X 
X 
X 
X 
X 
X 
X 
 
X 
Rilzabrutinib or Placebo dispensed 
 
X 
X 
X 
X 
X 
X 
 
 
Patient Medication Diary 
 
X 
X 
X 
X 
X 
X 
 
 
SARS-CoV-2 test 
Xa,v 
X r  
 
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AE = adverse event; aPTT = activated partial thromboplastin time; BTK = Bruton’s tyrosine kinase; D = day; ECG = electrocardiogram; EQ-5D-5L = EuroQOL-5 Dimension 5 Level; 
FSH = follicle-stimulating hormone; HBV = hepatitis B virus; HBsAg = hepatitis B surface antigen; Hep = hepatitis; HIV = human immunodeficiency virus; IBLS = ITP Bleeding Scale; 
IgG = immunoglobulin G; INR = international normalized level; IMP = investigational medicinal product; ITP = immune thrombocytopenia; ITP-PAQ = ITP- Patient Assessment Questionnaire; 
ITP- KIT = Kids’ ITP Tools; PGIC = Patient Global Impression of Change; PGIS = Patient Global Impression of Severity; PGIS-Fatigue = Patient Global Impression of [Fatigue] Severity; 
PK = pharmacokinetics; PT = Prothrombin time; QOL = Quality of Life; Rh = rhesus factor; SARS-CoV-2 = severe acute respiratory syndrome–related coronavirus-2; SD = study day; 
TB = tuberculosis; T/B/NK = T-lymphocytes/B-lymphocytes/natural killers; TPO = Thrombopoietin; WK = Week. 
a Participants may be re-screened once. The screening period can be up to -31 days of Study Day 1. 
b At the Week 13 visit review previous platelet counts for response during the first 12 weeks. If the participant met the criteria for response continue with the Week 13 visit assessments, the 
participant should continue in the blinded part. If the participant did not meet the criteria for response, complete the Week 25 visit assessments and the participant may start the open label period 
or discontinue from the study. Platelet response is defined as a) a platelet count of ≥50,000/μL OR a platelet count of between ≥30,000/μL and <50,000/μL and at least doubled from baseline at 
any time during the first 12 weeks and b) absence of rescue medication in the 4 weeks prior to the latest elevated platelet count that meets platelet response criteria.) Participants who receive 
rescue medication during the last 12 weeks also may join the open-label part or discontinue from the study. See Figure 1 for decision tree for assessing response at Week 13 and for calculation 
of baseline platelet count. 
c For pediatric participants (see Appendix 10.7 for EU [EEA countries] age ranges) height is recorded at Screening, Week 13, Week 25, Week 37, and Week 53. For participants aged 18 years 
and older height is recorded at Screening only. 
d Full physical examination at Screening, 4-week follow-up and early termination; abbreviated physical examination at all other visits. Medical history should include vaccine history. See 
Appendix 10.6 for Italy-specific requirements. 
e ECG for pediatric participants (see Appendix 10.7 for EU [EEA countries] age ranges) will be performed predose and 2 hours postdose (±15 mins) at the Week 1 and Week 25 visits.  
f 
Urinalysis: pH, specific gravity, protein, glucose, ketones, bilirubin, blood, nitrites, urobilinogen, and leukocytes. 
g Participants enrolled with positive HBV core antibody test result and HBsAb titer ≥100 IU/L will have HBV DNA monitored monthly while on treatment and for 6 months after treatment has 
ended. 
h For women of childbearing potential only. Serum pregnancy test must be performed at Screening; a urine pregnancy test must be performed at all other study timepoints. 
i 
To confirm postmenopausal status for women who are not surgically sterile and of reproductive potential. 
j 
Historical lab results may be used for ABO and Rh Blood Type. 
k 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) and estimated glomerular filtration rate (eGFR) is to be 
performed at Screening only. eGFR will be calculated using the Bedside Schwartz Equation in pediatric participants (10 to <18 years old) and using the Cockcroft and Gault method in adult 
participants. 
l 
Hematology will include the following: hemoglobin, hematocrit, erythrocyte count (red blood cell [RBC] count), thrombocyte count (platelets), mean platelet volume, leukocyte count (white blood 
cell [WBC] count) with differential in absolute counts (including neutrophils, eosinophils, basophils, lymphocytes, and monocytes). Local laboratories will be used for platelet analysis required at 
ALL visits (ie, Clinic Visits and Weekly Lab Visits in between Clinic Visits). 
The central laboratory will be used for the analyses required at Clinic Visits including hematology, differential, and reticulocytes. The results of hematology, differential and reticulocytes obtained 
at local laboratories will be used only if the central lab results of Clinic Visits are missing due to any reason. Central platelet counts assessed at Clinic Visits will be used if local platelet results 
are missing for any reason. 
m Coagulation will include: PT/INR, thrombin time, activated partial thromboplastin time (aPTT), and fibrinogen level. 
n Hemolysis panel: consisting of Coombs test, haptoglobin levels. 
o PK samples for participants aged 18 years or older will be collected predose (within 1.5 hours predose) and 2 hours postdose (±15 minutes) at the Week 1 visit. PK samples for pediatric 
participants  (see Appendix 10.7 for EU [EEA countries] age ranges) will be taken Predose (within 1.5 hours predose) and postdose at the following timepoints: 0.5 hours (±5 mins), 2 hours 
(±5 mins) and 4 hours (±15 mins), 6 hours (±15 mins) at the Week 1 visit. At the Week 13 visit a sample will be taken Predose only. At these visits, participants will wait to take their morning 
dose until they complete the blood draw of pre-dose sample.  
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p BTK Occupancy samples for participants aged 18 years or older will be collected Predose (within 1.5 hours predose) and 2 hours postdose (±15 mins) at the Week 1 visit. BTK Occupancy 
samples for pediatric participants (see Appendix 10.7 for EU [EEA countries] age ranges) will be taken Predose (within 1.5 hours predose) and postdose at the following timepoints: 0.5 hours 
(±5 mins), 2 hours (±5 mins) and 4 hours (±15 mins), 6 hours (±15 mins) at the Week 1 visit. At the Week 13 visit a sample will be taken Predose only. At these visits, participants will wait to 
take their morning dose until they complete the blood draw of pre-dose sample. 
q QOL Questionnaires include EQ-5D-5L, ITP-Patient Assessment Questionnaire (ITP-PAQ) or Kids’ ITP Tools (ITP-KIT), and PGIS-Fatigue/PGIS/PGIC. ITP-PAQ,  
EQ-5D-5L and PGIS-Fatigue/PGIS/PGIC (in that order) will be administered for adults 18 years or older. ITP-KIT and EQ-5D-5L (in that order) will be administered for pediatric participants (see 
Appendix 10.7 for EU (EEA countries) age ranges). Questionnaires should be completed prior to all other study procedures and interactions with site staff. Note: The PGIC will be 
collected starting after Day 1. 
r 
See Appendix 10 for country-specific requirements. 
s Optional collection of 2 blood samples for vaccine-specific IgG in serum (See Section 7.9.9 for a list of routine vaccines). 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. 
t 
Participants enrolled into the pediatric portion of the trial will still be considered as part of the pediatric group with all the planned assessments when they turn 18 years old, unless specified, and 
they should be re-consented with an adult consent. See Appendix 10.7 for EU (EEA countries) age ranges. 
u This visit is for platelet count assessment and can be conducted on-site or remotely. After the end of treatment (EOT) visit, weekly platelet count assessment is not required; however, it is up to 
the Investigator to decide whether to conduct weekly platelet assessments using unscheduled visits, if deemed necessary for participant safety. 
v SARS-CoV-2 molecular test (if COVID-19 testing is required per local guidelines to be determined for each site). 
w During the blinded treatment period (Week 13 to Week 24): Participants who discontinue from the blinded treatment period due to safety (or other) reasons and choose to join the open label 
period will attend the Week 25 assessments at their next scheduled visit. 
x All participants who discontinue treatment during the blinded or open-label period need to have an Early Termination visit as specified in Table 1 and an End of Study visit (4 weeks 
after last IMP intake) as specified in the End of Study visit in Table 2 (See End of Study Table 2). 
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Table 2 - Schedule of Assessments - Open Label Period  
 
Open Label Period 
 
 
Early Termination/ 
Unscheduled visit 
First Day 
of WK25o, p 
SD169 
WK 29 
SD197 
WK33  
SD225 
WK37 
SD253 
WK41 
SD281 
WK45 
SD309 
 
 
WK49 
SD337 
First 
Day of 
WK53q 
SD365 
End of 
Study 
4 weeks 
post-last 
dose 
SD393 
Weekly Lab 
Visits Between 
Clinic Visitsr 
Visit Window 
±3  
days 
±3  
days 
±3  
days 
±3  
days 
±3  
days 
±3  
days 
±3  
days 
±3  
days 
±3  
days 
±3  
days 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Height (cm)a 
X 
 
 
X 
 
 
 
X 
 
 
 
Weight (kg) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Physical examb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
ECG (12-lead, single) 
Xc 
 
 
 
 
 
 
X 
X 
 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Urinalysisd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pregnancy teste 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Serum Chemistryf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Hematology, differential, 
reticulocytesg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xr 
X 
T/B/NK countsm 
X 
X 
X 
 
X 
 
 
X 
X 
 
 
PT/INR, aPTTh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
TPO levels m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Hemolysis paneli, m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Immunoglobulin Levelsm 
X 
X 
X 
 
X 
 
 
X 
X 
 
 
PK samplej  
X 
 
 
 
 
 
 
X 
 
 
X 
BTK Occupancy (at 
select sites)k, m 
X 
 
 
 
 
 
 
X 
 
 
 
(Optional) sample for 
vaccine-specific IgG m, n 
=======================================================→ 
X 
QOL Questionnairesl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
IBLS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Rilzabrutinib dispensed 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Patient Medication Diary 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
SARS-CoV-2 test (see 
Appendix 10 for 
country-specific 
requirements) 
X 
 
AE = adverse event; aPTT = activated partial thromboplastin time; BTK = Bruton’s tyrosine kinase; ECG = electrocardiogram; EQ-5D-5L = EuroQOL-5 Dimension 5 Level; IBLS = ITP Bleeding 
Scale; IgG = immunoglobulin G; INR = international normalized level; ITP = immune thrombocytopenia; ITP-PAQ = ITP-Patient Assessment Questionnaire; ITP- KIT = Kids’ ITP Tools; 
PGIC = Patient Global Impression of Change; PGIS = Patient Global Impression of Severity; PGIS-Fatigue = Patient Global Impression of [Fatigue] Severity; PK = pharmacokinetics; 
PT = Prothrombin time; QOL = Quality of Life; SARS-CoV-2 = severe acute respiratory syndrome–related coronavirus-2; SD = study day; T/B/NK = T-lymphocytes/ B-lymphocytes/natural killers; 
TPO = Thrombopoietin; WK = Week. 
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a For pediatric participants (see Appendix 10.7 for EU [EEA countries] age ranges) height is recorded at Screening, Week 13, Week 25, Week 37, and Week 53. For participants aged 18 and 
older height is recorded at Screening only. 
b Full physical examination at Screening, 4-week follow-up and early termination; abbreviated physical examination at all other visits. See Appendix 10.6 for Italy-specific requirements. 
c ECG for pediatric participants (see Appendix 10.7 for EU [EEA countries] age ranges) will be performed predose and 2 hours postdose (±15 minutes) at the Week 25 visit. Adult participants are 
also required to complete ECG at Week 25. 
d Urinalysis: pH, specific gravity, protein, glucose, ketones, bilirubin, blood, nitrites, urobilinogen, and leukocytes. 
e For women of childbearing potential only. A urine pregnancy test must be performed at all study timepoints. 
f 
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). 
g Hematology will include the following: hemoglobin, hematocrit, erythrocyte count (red blood cell [RBC] count), thrombocyte count (platelets), mean platelet volume, leukocyte count (white blood 
cell [WBC] count) with differential in absolute counts (including neutrophils, eosinophils, basophils, lymphocytes, and monocytes). Local laboratories will be used for platelet analysis required at 
ALL visits (ie, Clinic Visits and Weekly Lab Visits in between Clinic Visits). 
The central laboratory will to be used for the analyses required at Clinic Visits including hematology, differential, and reticulocytes. The results of hematology, differential and reticulocytes 
obtained at local laboratories will be used only if the central lab results of Clinic Visits are missing due to any reason. Central platelet counts assessed at Clinic Visits will be used if local platelet 
results are missing for any reason. 
h Coagulation will include: PT/INR, thrombin time, activated partial thromboplastin time (aPTT), and fibrinogen level. 
i 
Hemolysis panel: consisting of Coombs test, haptoglobin levels. 
j 
At Week 25 visit, PK samples for participants aged 18 years or older will be collected Predose (within 1.5 hours predose) and 2 hours postdose (±15 minutes). At the Week 25 visit, PK samples 
for pediatric participants (see Appendix 10.7 for EU [EEA countries] age ranges) will be taken Predose (within 1.5 hours predose) and postdose at the following timepoints: 0.5 hours 
(±5 minutes), 2 hours (±5 minutes) and 4 hours (±15 minutes), 6 hours (±15 minutes). At these visits, participants will wait to take their morning dose until they complete the blood draw of 
pre- dose sample. At Week 53 and early termination visits, a random timepoint PK samples will be collected and the time of sample and time of the last dose of rilzabrutinib will be captured.  
k At Week 25 visit, BTK occupancy samples for participants aged 18 years or older will be collected Predose (within 1.5 hours predose) and 2 hours postdose (±15 minutes). At Week 25 visit, 
BTK Occupancy samples for pediatric participants (see Appendix 10.7 for EU [EEA countries] age ranges) will be taken Predose (within 1.5 hours predose) and postdose at the following 
timepoints: 0.5 hours (±5 minutes), 2 hours (±5 minutes) and 4 hours (±15 minutes), 6◦hours (±15 minutes). At these visits, participants will wait to take their morning dose until they complete 
the blood draw of pre-dose sample. At Week 53, a random timepoint BTK occupancy sample will be collected and the time of sample and time of the last dose of rilzabrutinib will be captured. 
l 
QOL Questionnaires include EQ-5D-5L, ITP-PAQ or ITP-KIT, and PGIS-Fatigue/PGIS/PGIC. ITP-PAQ, EQ-5D-5L and PGIS-Fatigue/PGIS/PGIC (in that order) will be administered for adults 
18 years or older. ITP-KIT and EQ-5D-5L (in that order) will be administered for pediatric participants (see Appendix 10.7 for EU [EEA countries] age ranges). Questionnaires should be 
completed prior to all other study procedures and interactions with site staff.  
m See Appendix 10 for country-specific requirements. 
n Optional collection of 2 blood samples for vaccine-specific IgG in serum (see Section 7.9.9 for a list of routine vaccines). 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. 
o Week 25/SD169 visit is the last visit of the blinded treatment period and may also serve as the start of the open label period. 
p For participants who will enter the open label period directly after 12 weeks of blinded treatment, they will attend the Week 13/SD85 visit which corresponds to the Week 25/SD169 visit (Table 2), 
this would be their last visit of the blinded treatment period and also the start of the open label period. They will follow the open label period schedule of assessments from Week 29 (Table 2) 
starting at their next scheduled visit for a total of 28 weeks. 
q For participants who will enter the open label period directly after 12 weeks of blinded treatment, they will follow the open label period schedule of assessments (Week 25 to  Week 53) which 
means that they will be treated on the open-label part for a total of 28 weeks. After Week 53, the participants will follow the schedule of assessments according to their eligibility for the LTE 
period. 
r 
This visit is for platelet count assessment and can be conducted on-site or remotely. Lab visits will occur weekly from Week 25 to Week 53. The Investigator can request that the participant visits 
the clinic for additional platelet monitoring during unscheduled visits if needed. After the end of treatment (EOT) visit, weekly platelet count assessment is not required; however, it is up to the 
Investigator to decide whether to conduct weekly platelet assessments using unscheduled visits, if deemed necessary for participant safety. 
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Table 3 - Schedule of Assessments - Long-Term Extension  
 
On-treatment clinic visits 
Early Termination/ 
Unscheduled Visit 
Week 53/Rollover to 
LTEn 
Clinic Visits Every 
28 Days for the first 
year of LTE then 
every 3 months 
thereafter 
Last Day of Active 
Rilzabrutinib 
Treatment 
End of Study 
(4 weeks post-last 
dose) 
Visit Windows 
±7 days 
±7 days 
±7 days 
±7 days 
 
AEs 
X 
X 
X 
X 
X 
Concomitant Medicationsa 
X 
X 
X 
X 
X 
Weight (kg) 
X 
X 
X 
X 
X 
Physical Examb 
X 
X 
X 
X 
Xm 
ECG (12-lead, single) 
X 
 
 
X 
Xm 
Vital Signs 
X 
X 
X 
X 
X 
Urinalysisc 
X 
X 
X 
X 
X 
Pregnancy testd 
X 
X 
X 
X 
X 
Serum Chemistrye 
X 
X 
X 
X 
X 
Hematology, differential, reticulocytesf 
X 
X 
X 
X 
X 
T/B/NK countsg, k 
X 
X 
 
X 
 
PT/INR aPTTh 
X 
X 
X 
X 
 
TPO levelsk 
X 
X 
X 
X 
 
Hemolysis paneli, k 
 
 
 
X 
 
Immunoglobulin Levelsk 
 
 
 
X 
 
(Optional) sample for vaccine-specific IgGk, l 
=============================================→ 
X 
QOL Questionnairesj 
X 
X  
X 
X 
X 
IBLS 
X 
X 
X 
X 
X 
Rilzabrutinib dispensed 
X 
X 
 
 
 
Patient Medication Diary 
X 
X 
 
 
Xm 
SARS-CoV-2 test (see Appendix 10 for country-specific 
requirements) 
X 
Xm 
AE = adverse event; aPTT = activated partial thromboplastin time; CS = corticosteroids; ECG = electrocardiogram; EQ-5D-5L = EuroQOL-5 Dimension 5 Level; IBLS = ITP Bleeding Scale; 
IgG = immunoglobulin G; INR = international normalized level; ITP = Immune thrombocytopenia; ITP-PAQ = ITP-Patient Assessment Questionnaire; ITP-KIT = Kids’ ITP Tools; PGIS = Patient 
Global Impression of Severity PGIS-Fatigue = Patient Global Impression of [Fatigue] Severity; QOL = Quality of Life; SD = study day; T/B/NK = T-lymphocytes/B-lymphocytes/natural killers; 
PGIC = Patient Global Impression of Change; PT = prothrombin time; TPO = Thrombopoietin; TPO- RA = thrombopoietin receptor agonist 
a Reductions in the doses or withdrawal of concomitant ITP medications will be permitted if the participant achieves platelet count of ≥50,000/μL in three scheduled visits (over 12 weeks). 
Retreatment with the same medication(s) and doses of ITP concomitant medication(s) used at baseline (an oral CS and/or a TPO-RA), changing the dose or initiation of new ITP medications (an 
oral CS and/or a TPO-RA) will also be allowed. Tapering of concomitant CS and/or TPO-RA should be performed in accordance with the schedule in Section 6.6.2. 
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b Full physical exam at End of Study, abbreviated physical exam at all other visits. See Appendix 10.6 for Italy-specific requirements. 
c Urinalysis: pH, specific gravity, protein, glucose, ketones, bilirubin, blood, nitrites, urobilinogen, and leukocytes. 
d Urine pregnancy test for women of childbearing potential only. 
e 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).  
f 
Hematology will include the following: hemoglobin, hematocrit, erythrocyte count (red blood cell [RBC] count), thrombocyte count (platelets), mean platelet volume, leukocyte count (white blood 
cell [WBC] count) with differential in absolute counts (including neutrophils, eosinophils, basophils, lymphocytes, and monocytes). Local laboratories will be used for platelet analysis required at 
ALL visits (ie, Clinic Visits and Unscheduled Lab Visits in between Clinic Visits). The central laboratory will to be used for the analyses required at Clinic Visits including hematology, differential, 
and reticulocytes. The results of hematology, differential and reticulocytes obtained at local laboratories will be used only if the central lab results of Clinic Visits are missing due to any reason. 
Central platelet counts assessed at Clinic Visits will be used if local platelet results are missing for any reason. After the end of treatment (EOT) visit, weekly platelet count assessment is not 
required; however, it is up to the Investigator to decide whether to conduct weekly platelet assessments using unscheduled visits, if deemed necessary for participant safety. 
g T-lymphocytes/ B-lymphocytes/natural killers (T/B/NK) counts at Week 53, every 6 months during the long-term extension period and at End of Study. 
h PT/INR, aPTT: only if needed to follow-up on bleeding adverse events. 
i 
Hemolysis panel: consisting of Coombs test, haptoglobin levels. 
j 
QOL Questionnaires include EQ-5D-5L, ITP-PAQ or ITP-KIT, and PGIS-Fatigue/PGIS/PGIC to be completed every 3 months. ITP-PAQ, EQ-5D-5L and PGIS-Fatigue/ PGIS/PGIC (in that order) 
will be administered for adults 18 years or older. ITP-KIT and EQ-5D-5L (in that order) will be administered for pediatric participants (see Appendix 10.7 for EU [EEA countries] age ranges). 
Questionnaires should be completed prior to all other study procedures and interactions with site staff. 
k See Appendix 10 for country-specific requirements. 
l 
Optional collection of 2 blood samples for vaccine-specific IgG in serum (see Section 7.9.9 for a list of routine vaccines). 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. 
m Early Termination Visit only. 
n Assessments performed at the open label period Week 53 Visit will be used at the starting visit (Week 53) of the LTE. 
 
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2. 
BACKGROUND  
2.1. 
Overview of Immune Thrombocytopenia (ITP)  
Immune Thrombocytopenia (ITP) is characterized by autoantibody-mediated destruction of 
platelets and impaired platelet production, which result in thrombocytopenia and a predisposition 
to bleeding associated with morbidity and mortality. 
In general, pharmacotherapy (corticosteroids [CSs], intravenous immunoglobulin [IVIg] or 
anti-D) is used for symptomatic participants with low platelet counts for reducing platelet 
destruction. While a majority of participants respond initially to CSs, the rate of continued 
remission is low. Second line therapies include rituximab and splenectomy and are associated 
with risk of sepsis and immune suppression. Thrombopoietin (TPO) mimetics (Bussel 2007) are 
approved for the treatment of participants with chronic ITP who have not had sufficient 
responses to CSs, IVIg, or splenectomy. Second-line treatment with TPO-RAs have a clinical 
response rate of 80%, however approximately one-third of participants discontinue TPO-RAs 
due to lack of response (Ghanima 2019). Novel, safe, and effective oral treatments to maintain 
platelet counts in this setting would be a significant therapeutic advantage. Thus, there remains a 
high unmet medical need for novel, safe, and effective oral therapies for ITP. 
2.2. 
BTK Inhibitor Rilzabrutinib  
Bruton’s 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. BTK is also expressed in other cells of hematopoietic lineage with the 
exception of T cells, natural killer cells and plasma cells (Sideras 1995, Rip 2018). 
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-mediated B-cell 
pathways, FcR-induced cytokine release from monocytes and macrophages, FcR-induced mast 
cell degranulation and granulocyte migration and mediator release. 
There is preliminary evidence to support the role of BTK inhibition in participants with 
autoimmune cytopenias (Rogers 2016, Montillo 2017), where sequential episodes of severe 
autoimmune hemolytic anemia and ITP ceased after initiation of treatment with ibrutinib, a 
BTK/epidermal growth factor receptor /interleukin-2-inducible T-cell kinase inhibitor, in 
participants with chronic lymphatic leukemia (CLL). 
Rilzabrutinib is a high-affinity inhibitor of BTK. Pertinent to the treatment of ITP, rilzabrutinib 
treatment in vitro profoundly inhibited human B-cell activation and blocked antibody (IgG, IgE) 
mediated activation of immune cells via Fc receptor signaling. 
2.3. 
Nonclinical Experience  
The nonclinical safety profile of rilzabrutinib has been well-characterized in safety 
pharmacology studies and repeat-dose oral toxicity studies in multiple animal species. Orally 
administered rilzabrutinib did not affect the gross behavioral, physiological, or neurological state 
of rats at dose levels up to 500 mg/kg/day and the no-observed-adverse-effect level (NOAEL) of 
the cardiovascular and respiratory systems in dogs considered to be 500 mg/kg/day. 
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Rilzabrutinib was well-tolerated in rats and dog studies of up to 6- and 9-month duration, 
respectively. In 6-month oral rat study, the NOAEL for female rats was 50 mg/kg/day (area 
under the plasma concentration curve [AUClast] 5480 hr.ng/mL) and 150 mg/kg/day in males 
(AUClast 5327 hr.ng/mL), based on lethality, decreased body weight gain, macroscopic and 
microscopic changes in the gastrointestinal (GI) tract, and neutrophilic inflammation in the brain. 
In a 9-month oral dog study, the NOAEL was 30 mg/kg/day (AUClast 963 hr.ng/mL), based on 
body weight loss and the euthanasia of 1 male dog at 50 mg/kg/day. The estimated human 
exposure of 400 mg twice daily (BID) at steady state is 890 hr.mg/mL. Rilzabrutinib was not 
genotoxic and did not demonstrate toxicities in fertility and early embryo-fetal development 
reproductive studies. Overall, the nonclinical safety profile of rilzabrutinib supports continuation 
of clinical studies. Additional nonclinical information on rilzabrutinib is provided in the current 
version of the rilzabrutinib (PRN1008) Investigator's Brochure (IB). 
Please refer to the IB for more details. 
2.4. 
Clinical Experience  
As of the data cut-off date of 22 April 2021, Rilzabrutinib was administered to 289 healthy 
volunteers and was well-tolerated. 
Details of clinical experience with rilzabrutinib in the PRN1008-005 (NCT02704429) study in 
participants with pemphigus and PRN1008-010 study in participants with ITP can be found in 
the IB. Preliminary efficacy results of PRN1008-010 Part A of the study were presented at 
European Hematology Association 2020 (Kuter 2020). 
2.4.1. 
Safety  
As of the data cut-off date of 22 April 2021, in 8 completed Phase 1 studies and 4 ongoing Phase 
1 studies (more than 280 healthy volunteers), the completed Phase 2 study in participants with 
pemphigus (41 participants, PRN1008-005), and ongoing Phase 1/2 studies in ITP  
(61 participants, PRN1008-010), and IgG4 (4 participants, PRN1008-017), rilzabrutinib 
demonstrated a safety profile characterized by predominantly mild-to-moderate adverse events 
(AEs) such as GI disturbance and headache, no rilzabrutinib-related deaths, and no evidence of 
increased risk of infections. There have been no related thrombotic or major bleeding events in 
the clinical experience with rilzabrutinib to date. In addition, there are no patterns or clinically 
significant findings from physical examinations, laboratory parameters, electrocardiograms 
(ECG), or vital signs in healthy-volunteers and in participants from studies conducted to date. 
The most common treatment-related AEs as of 22 April 2021 were GI in nature, including 
nausea, vomiting, and diarrhea. The majority of treatment-emergent adverse events (TEAEs) 
were mild to moderate in severity. There was 1 serious adverse event (SAE) in 
Study PRN1008-005 that was assessed by the Sponsor as related to the study drug (cellulitis). 
Safety and efficacy findings of Study PRN1008-010 (main treatment periods) and LTE-Part A 
interim analysis were published (Kuter et al 2022, Cooper et al 2023, Kuter et al 2024). Please 
refer to the most recent version of the IB for updated safety information.    
The marketed BTK inhibitor, ibrutinib, has been studied in combination with rituximab in the 
treatment of chronic lymphocytic leukemia without published evidence of increased drug-related 
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AEs (Burger 2019). There is no a priori drug interaction potential between anti-CD20 biologic 
drugs and the small molecule rilzabrutinib. 
PRN1008-010 (Part A and Part B) study results demonstrated a rapid and sustained platelet 
response in patients with primary ITP who failed multiple prior therapies and showed a favorable 
safety profile (Kuter et al 2022, Cooper et al 2023). For summary of overall benefit/risk 
assessment, refer to Section 2.7. 
2.4.2. 
Cardiodynamic Evaluation  
A cardiodynamic evaluation of rilzabrutinib was conducted in healthy volunteer subjects in 
which 400 mg rilzabrutinib, 400 mg rilzabrutinib plus ritonavir, placebo, and moxifloxacin 
(positive control) were given in separate, randomized periods to healthy volunteer subjects in a 
4-way crossover design. Serial ECGs were extracted from continuous Holter monitors at baseline 
(predose) and for 24 hours post-dose on Day 1 in each period  
(Cardiac Safety Report PRN1008-014). Rilzabrutinib at the studied doses did not have a 
clinically relevant effect on cardiac conduction (ie, the PR and QRS intervals). 
In summary, rilzabrutinib at the studied doses did not have a clinically relevant effect on the 
studied ECG parameters. 
2.4.3. 
Pharmacokinetics and Pharmacodynamics  
Rilzabrutinib is rapidly cleared from the plasma, with a terminal half-life of approximately 
4 hours, maximum concentration time of approximately 2 hours after ingestion, and a volume of 
distribution of 149 L after intravenous administration. No significant accumulation was observed 
after multiple dosing. Approximately 3% of rilzabrutinib is excreted unchanged in the urine. 
Rilzabrutinib is available in a tablet formulation for investigation in-patient populations in 
clinical studies. Food delays the time of observed maximum plasma concentration (Tmax) by 
1.5 hours and decreases AUC and Cmax of rilzabrutinib by 20% and 30%, respectively, which is 
not considered to be clinically relevant. Rilzabrutinib showed approximately linear increases in 
exposure between doses of 150 mg and 600 mg. 
Rilzabrutinib demonstrated sustained, dose-dependent occupancy of BTK in peripheral blood 
mononuclear cells in healthy volunteers. Twice daily dosing with 400 mg tablet is expected to 
result in BTK occupancy that is within the therapeutic range. 
Additional details of the clinical pharmacokinetics (PK) and safety information of rilzabrutinib 
are provided in the current version of the IB. 
2.4.4. 
Drug-Drug Interaction Potential  
Rilzabrutinib is a substrate of the cytochrome P450 (CYP) 3A isoenzyme. In a clinical drug-drug 
interaction study, the CYP3A inhibitor ritonavir increased plasma rilzabrutinib concentrations 
(PRN1008-014) and the CYP3A inducer rifampin decreased plasma rilzabrutinib concentration 
(PRN1008-024); therefore, concomitant use of strong and moderate CYP3A inhibitors or 
inducers should be avoided. Rilzabrutinib is also a substrate of P-gp from in-vitro studies. 
However, the P-gp inhibitor quinidine didn’t change plasma concentrations of rilzabrutinib 
(PRN1008-024); thus, rilzabrutinib could be administered with P-gp inhibitors clinically. 
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In healthy volunteers, 400 mg of rilzabrutinib given simultaneously or two hours prior to the 
CYP3A substrate midazolam increased the AUC of midazolam by approximately 2-fold, 
classifying rilzabrutinib as a “weak CYP3A inhibitor” (PRN1008-011). Appropriate caution 
should be used when co-administering CYP3A “sensitive” substrates with rilzabrutinib, 
including an assessment of medical risk-benefit for each medication. Consideration should also 
be given to avoidance of high doses, dose reduction, or replacement of “sensitive” CYP3A 
substrate drugs. Rilzabrutinib is not an inhibitor of other CYP enzymes. Concomitant 
administration of rilzabrutinib immediate release (IR) tablet with a proton pump inhibitor, 
esomeprazole, decreased its exposure by approximately 50%. Concomitant administration of 
rilzabrutinib IR tablet with famotidine, a histamine 2 (H2) receptor antagonist, modestly reduced 
(by ~36%) its exposure. When rilzabrutinib IR tablet was dosed at least 2 hours prior to 
famotidine, no significant exposure change of rilzabrutinib was observed; hence, H2 receptor 
antagonists should be administered at least 2 hours after rilzabrutinib. 
Additional details are provided in the current version of the rilzabrutinib (PRN1008) IB. 
2.5. 
Study Design Rationale  
Study PRN1008-018 is a randomized, double-blind, parallel-group, multicenter, 
placebo-controlled study with a blinded treatment period of up to 24 weeks followed by an open 
label period of 28 weeks, and a safety follow-up period of 4 weeks, which is intended to evaluate 
the efficacy and safety of oral rilzabrutinib in participants with refractory or relapsed ITP of 
>3 months duration in participants aged 18 years and above, and of >6 months duration in 
pediatric participants aged 12 to <18 years (see Appendix 10.7 for EU [EEA countries], where an 
age range of 10 to <18 years is applicable). Participants who are eligible at the end of the open 
label period can be considered for a long-term extension (LTE). 
Placebo has been selected as the comparator to rilzabrutinib, as there are no globally approved 
medicinal products, other than CS (approved in EU but not United States [US]) that could serve 
as a suitably rapid-acting and active comparator. Use of placebo is ethical in this context, as 
participants who are on concomitant ITP medications (an oral CS and/or a thrombopoietin 
receptor agonist [TPO-RA]) will be eligible for the study. Participants have to have an 
inadequate response to these medications as evidenced by the average of two platelet counts 
below 30,000/μL (with no platelet count greater than 35,000/μL) and will have to maintained 
stable doses of these medications from 14 days before Study Day 1 and until the last dose of 
study medication. In addition, the use of rescue medications (limited to IVIg, anti-D, CS, and 
platelet infusion only) will be permitted to increase platelet counts or prevent bleeding when 
platelet counts are less than 20,000/μL, or for bleeding or wet purpura. 
The marketed BTK inhibitor, ibrutinib, has been studied in combination with rituximab in the 
treatment of chronic lymphocytic leukemia without evidence of increased drug-related AEs 
(Burger 2017). There is no prior drug interaction potential between anti-CD20 biologic drugs and 
the small molecule rilzabrutinib. 
The primary purpose of the 28-week, open label period is to allow access to study drug for 
participants who were on placebo medication as well as to evaluate durability of clinical 
response and accrue additional long-term data on the safety of rilzabrutinib. 
The LTE is designed to further evaluate durability of clinical response and accrue additional 
long-term data on the safety of rilzabrutinib. 
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During the COVID-19 pandemic, measures to ensure continued drug supply and safety 
monitoring for participants are described in the “Guidelines to Sites for Delayed Participant 
Visits or Missed Visits due to travel restrictions and any foreseeable impacts of 
COVID- 19” (Appendix 8). These measures include remote study visits, enrollment procedures, 
direct to participant delivery of study medication and urine pregnancy tests, as well as handling 
of protocol deviations, and remote site monitoring (where allowed by local regulations). 
Enrollment of pediatric participants 
Inclusion of participants aged 10 to <18 years in the study is possible based on clinical and 
pathophysiological similarities between persistent/chronic ITP with adult participants. These 
similarities include presenting platelet counts (mean, 18.1 × 109/L in children and 25.4 × 109/L in 
adults), incidence and type of bleeding when platelet counts are <20 × 109/L, family history of 
thrombocytopenia (2% in children and 3% in adults), rates of treatment (80% of children and 
71% of adults at presentation and 58% of children and adults at 6 months, with similarly 
decreasing rates within both groups at 12 and 24 months) (Kühne 2001, Schifferli 2018) and 
similar late remission rates among children and adults with persistent and chronic ITP at 12 and 
24 months (Schifferli 2018). Lowe and Buchanan confirmed that pediatric patients with ITP (age 
10 to 18 years) had chronic disease with a chronicity rate up to 57%, which is higher than the 
rate of chronic ITP in younger children (<10 years of age) (Lowe 2002). Moreover, it has been 
reported that children diagnosed with ITP between 10 and18 years of age showed only a 32% 
recovery rate (Lowe 2002, Kühne 2003). The pathological mechanism of ITP 
(antibody-mediated platelet destruction) as well, is not different between children and adults. It 
can be expected that rilzabrutinib acts in the same way in adults and children with 
persistent/chronic ITP. It is well known that that the immune system matures and significantly 
changes throughout childhood (Blanco 2018, Comans-Bitter 1997, Simon 2015). The most 
significant changes were observed in the first 10 years of life 
(Duchamp 2014, Ghraichy 2020, Piatosa 2010). B-cells percentage declined between the ages of 
6 months and 8 years, after which it remained stable at about 70-80%. Memory B-cells are 
already present at birth and their numbers increase throughout childhood, stabilizing between the 
ages of 12 and 18 years (Duchamp 2014). Literature reports indicate that total B-cell counts 
increase 2-fold immediately after birth, remain high until the age of 2 years, and then gradually 
decrease approximately 6.5-fold until adulthood (Blanco 2018). The percentage of naive B-cells 
among total B-cells decrease steadily from birth to the age of 12 years and the memory B-cell 
numbers stabilize between the ages of 12 to 18 years (Duchamp 2014). Total serum IgG levels 
gradually increase at early ages, and IgG3 and IgG1 levels reach adult like concentrations at 5 to 
10 years of age (Blanco 2018). In addition, renal function and drug metabolizing enzymes are 
fully developed by age 12 (Fernandez 2011). Thus, the developmental immunological and 
physiological characteristics justify the inclusion of children ages 10 to <18 years in the current 
study. 
2.6. 
Dose Rationale  
A dosing regimen of 400 mg rilzabrutinib BID has been selected for evaluation in participants 
with ITP based on the observed safety and efficacy profile in Study PRN1008-005. In addition, 
Phase 1 dose-ranging data indicate that the plasma concentrations associated with this dose level 
are sufficient to maintain near-maximal BTK occupancy over the entire dosing interval, thereby 
robustly testing the efficacy of BTK inhibition. 
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Dose-response analyses conducted on preliminary data from Study PRN1008-010 indicate that 
the 400 mg rilzabrutinib BID dosing regimen was associated with a faster and more pronounced 
increase in platelet count compared to lower doses. After 28 days of rilzabrutinib treatment, 
increases in mean platelet count ranged from 7.59 × 109/L at the low dose of 200 mg once daily 
to 22.5 × 109/L at the high dose of 400 mg BID. In addition, patients treated with lower daily 
doses were less likely to achieve the primary endpoint (Kuter 2019). Patient responses were 
improved in patients who started the study at the 400 mg BID dose with 43.8% achieving the 
primary endpoint of 2 or more consecutive platelet counts, separated by at least 5 days of 
≥50 × 109/L AND an increase of platelet count of ≥20 × 109/L from baseline (Kuter 2020). This 
evidence of treatment effect supports the evaluation of 400 mg BID in the Phase 3 PRN1008-018 
study under this protocol. 
The same dosing regimen (400 mg rilzabrutinib BID) has been selected for evaluation in 
pediatric participants (10 to <18 years of age) as the PK of rilzabrutinib are expected to be 
similar in pediatric participants (10 to <18 years old) and adults. Rilzabrutinib is metabolized by 
the CYP3A isoenzyme; the clearance of CYP3A substrates has been observed to be similar in 
adolescents and adults (Ginsberg 2002), suggesting that the clearance of rilzabrutinib will also be 
similar in adolescents (12 to <18 years old) and adults, and the adult and adolescent doses were 
found to be equivalent in the majority of approved drugs in a recent US Food and Drug 
Administration (FDA) survey (Momper 2013). A body weight ≥30 kg is added as inclusion 
criteria, to ensure the body weight of pediatric participants (10 to <12 years old) is within the 
95% percentile body weight of pediatric participants at 12 years old, so that the PK exposure for 
participants 10 to <12 years is not anticipated to be higher than that for participants at 12 years 
old, and the same dose (400 mg BID tablet) could be used in the entire pediatric population 
(10 to <18 years old) (See Appendix 10.7). This dosing regimen is therefore expected to be 
associated with a comparable benefit-risk profile in adolescent participants with ITP relative to 
adult participants, and evaluation in this study may expedite the availability of an efficacious 
treatment to the adolescent population. 
Please refer to the IB for more details. 
2.7. 
Overall Risk-Benefit Assessment  
2.7.1. 
Risk assessment  
Based on the review of the cumulative data, as of 02 January 2024, with an estimated exposure 
of 1137 participants who received at least one dose of rilzabrutinib or placebo across multiple 
disease conditions (826 participants on rilzabrutinib with approximately 545 patient-years, 
estimated based on randomization ratio), there are no important identified risks for rilzabrutinib. 
The following are considered as important potential risks for rilzabrutinib: 
• Serious infections 
• Liver enzyme elevation 
• Uveitis 
Details of important potential risks together with a summary of the cumulative clinical safety 
data are provided below. 
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Table 4 - Risk assessment  
Important Potential risk  Summary of data/rationale for 
risk 
Mitigation Strategy 
Serious infection 
Rilzabrutinib may increase the risk of 
serious infection due to inhibition of 
human B-cell activation and antibody 
mediated activation of immune cells via 
FC receptor signaling. Refer to the latest 
IB for additional detail on the 
pharmacology of rilzabrutinib. 
As of 02-Jan-2024, the overall exposure 
was 1137 participants in Phase 2/3 
studies (rilzabrutinib/ placebo) in whom 
2 SUSARs of serious infections have 
been reported in studies of pemphigus 
(n=1) and ITP (n=1). 
Most patients have recovered while on 
treatment with either rilzabrutinib or 
blinded IMP and cases are confounded 
by underlying disease and/or treatment 
with high dose corticosteroids. No 
imbalance observed between rilzabrutinib 
arm and the placebo arm for participants 
treated for Pemphigus (10-May-2022) and 
CSU (19-Jul-2023). No serious infections 
were observed in the atopic dermatitis 
randomized controlled clinical trial 
(20-Jul-2023). A causal association 
between IMP and these conditions has 
not been established. 
• Participants with evidence suggestive of 
active tuberculosis or non-tuberculous 
mycobacterial infections are excluded. 
• Participants with a history of serious 
infection requiring IV therapy within 4 weeks 
of randomization or with active moderate-to-
severe infections at screening are excluded. 
• Risk management includes screening, 
regular monitoring, and identification of early 
signs of infections (HBV, HCV, HIV, or 
active COVID-19) or with active moderate-
to-severe infection.  
• Routine collection of AEs  
• Designation of severe or serious infection as 
an AESI 
Liver enzyme elevation 
As of 02-Jan-2024, the overall exposure 
was 1137 participants in Phase 2/3 
(rilzabrutinib/ placebo) studies in whom 
26 events of elevations of liver enzymes 
have been observed in studies with 
pemphigus, ITP, Asthma, CSU, AD, and 
IgG4-RD participants. The majority were 
of mild/moderate severity; few events 
resulted in interruption of IMP. Most 
patients had alternative etiologies or 
confounding factors for the elevations 
observed. As of 02-Jan-2024, there is 
insufficient evidence for a causal 
relationship between liver enzyme 
elevations and rilzabrutinib. There were 
no Hy’s Law or hepatic failure cases 
reported. 
• Participants with AST/ALT > 1.5 × ULN or 
total bilirubin >1.5 × ULN are excluded. 
• Participants with acute or chronic liver 
disease (other than the disease under 
investigation) are excluded. 
• Routine collection of AEs 
• Routine monitoring of AST, ALT, and total 
bilirubin 
• Designation of ALT > 3 × ULN as an AESI 
and suggested actions and follow up 
assessments. 
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Important Potential risk  Summary of data/rationale for 
risk 
Mitigation Strategy 
Uveitis 
As of 02-Jan-2024, the overall exposure 
was 1137 participants in Phase 2/3 
(rilzabrutinib/ placebo) studies in which 
cases of uveitis (n=5) occurred, including 
2 Vogt-Koyanagi-Harada disease (VKHD) 
cases. The events of uveitis were 
observed in different indications across 
the rilzabrutinib program in studies of 
pemphigus (n=2), ITP (n=1), and CSU 
(n=2). All events resolved; 4 of the 
5 events resolved with treatment, while 
continuing rilzabrutinib. A definitive causal 
association between rilzabrutinib and 
these ocular conditions has not been 
established. 
• Participants are advised to report new onset 
or worsening eye symptoms to the site study 
doctor in ICF. 
• Inclusion of eye-assessment in all physical 
examinations  
• Designation of uveitis as an AESI 
• Examination by an ophthalmologist should 
be considered for patients who develop 
ocular symptoms, eg, eye erythema, pain, or 
blurred vision suggestive of uveitis, as 
appropriate. 
Abbreviations: AE=adverse event; AESI=adverse event of special interest; ALT=alanine aminotransferase; BID=twice daily; BTK=Bruton’s 
tyrosine kinase; CMV=Cytomegalovirus; COVID-19=Coronavirus disease 2019; CSU=chronic spontaneous urticaria; HBV=hepatitis B virus; 
HCV=hepatitis C virus; HIV=human immunodeficiency virus; IMP=investigational medicinal product; ITP=immune thrombocytopenic purpura; 
SARS-CoV-2=severe acute respiratory syndrome coronavirus-2; SUSAR=suspected unexpected serious adverse reaction; ULN=upper limit 
normal. 
2.7.1.1. 
Potential risks reported with other BTK inhibitors  
There are AEs that have been reported during the administration of other drugs from the same 
therapeutic class (BTK inhibitors) as rilzabrutinib, however primarily for oncologic indications, 
including B-cell malignancies (Lipsky 2020). 
These Class Effect AEs include: 
• Cytopenia  
• Bleeding 
• Atrial fibrillation 
Rilzabrutinib has characteristics that may solve many of the selectivity- and reversibility-related 
concerns accompanying currently available BTK inhibitors. Rilzabrutinib binds in a covalent 
manner, increasing selectivity by forming a chemical bond to a specific cysteine residue present 
in BTK. This durable covalent engagement allows for maximal efficacy. However, 
rilzabrutinib’s unique binding mechanism provides the opportunity for a tailored residence time 
while reducing safety concerns associated with irreversible inhibitors such as ibrutinib and 
acalabrutinib (Langrish 2021). 
There are important differences between the background safety risk profiles of chronic 
autoimmune and/or inflammatory disease populations versus the oncologic population (where 
these events have been observed). Taken together, it is postulated that there is a low probability 
of occurrence of the above-mentioned “BTK inhibitor class” AEs during the administration of 
rilzabrutinib. 
 
 
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2.7.2. 
Benefit assessment  
ITP is associated with an increased risk of mortality due to bleeding, thrombosis, and reduced 
quality of life (QOL) (Trotter and Hill 2018). The disease burden is more significant in patients 
with severe and chronic thrombocytopenia and those who are unresponsive to current therapy. 
Patients with such severe thrombocytopenia have a high risk of hemorrhage which increases with 
age. Intracranial hemorrhage is the major cause of death which is reported to occur in 1.5% of 
adult patients (Neunert et al 2015). Besides the high risk of bleeding, patients with chronic ITP 
experience significant fatigue, cognitive impairment, fear of bleeding and a negative impact on 
social and work activities (Frith et al 2012; Trotter and Hill 2018). Treatment with rilzabrutinib 
may induce durable platelet response in participants not responsive to prior therapies. 
2.7.3. 
Overall benefit: risk conclusion  
The safety of rilzabrutinib to date (02-Jan-2024), and the resulting benefit risk balance profile, 
supports the continued investigation in participants with ITP. There is no important identified 
risk associated with the use of rilzabrutinib. The important potential risks of “increased risk for 
serious infections”, “liver enzyme elevation”, and “uveitis” have been characterized and 
appropriate risk mitigation procedures have been defined. The AEs seen with other BTK 
inhibitors (cytopenia, bleeding, atrial fibrillation) will continuously closely monitored and their 
risk-evaluation will continuously be reassessed, and if needed mitigations will be adjusted as the 
safety profile matures. Overall, benefit/risk balance is in favor of continuing evaluation of 
rilzabrutinib in patients with persistent or chronic ITP.   
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3. 
OBJECTIVES AND ENDPOINTS  
3.1. 
Objectives  
3.1.1. 
Efficacy Objectives  
Primary Efficacy Objective (Blinded Treatment Period) 
• To demonstrate the efficacy of rilzabrutinib versus placebo in participants with 
refractory/relapsed ITP, based on the durability of platelet response during the last 
12 weeks of the 24-week blinded treatment period in the absence of rescue therapy 
Key Secondary Efficacy Objectives (Blinded Treatment Period) 
• To evaluate the effect of rilzabrutinib versus placebo on the number of weeks with 
platelet count ≥50,000/μL OR between ≥30,000/μL and <50,000/μL and at least doubled 
from baseline, over the 24-week blinded treatment period in the absence of rescue 
therapy 
• To evaluate the effect of rilzabrutinib versus placebo on the number of weeks with 
platelet counts ≥30,000/μL and at least doubled from baseline over the 24-week blinded 
treatment period in the absence of rescue therapy 
• To evaluate the effect of rilzabrutinib versus placebo on the time to first platelet count of 
≥50,000/μL OR between ≥30,000/μL and <50,000/μL and at least doubled from baseline 
• To evaluate the effect of rilzabrutinib versus placebo on the proportion of participants 
requiring rescue therapy 
• To evaluate the effect of rilzabrutinib versus placebo on the change from baseline on Item 10 
of the ITP-Patient Assessment Questionnaire (ITP-PAQ) (ie, physical fatigue) in adult 
participants (≥18 years) at Week 13 
See Appendix 10.7 for EU (EEA countries) and UK-specific requirements. 
3.1.2. 
Other Secondary Objectives  
See Appendix 10.7 for EU (EEA countries) specific requirements. 
3.1.2.1. 
Efficacy Objectives  
• To evaluate the stability of platelet response of rilzabrutinib 
3.1.2.2. 
Safety Objectives  
• To evaluate the safety and tolerability of rilzabrutinib in pediatric participants (≥10 years 
– <18 years) and in adult participants (≥18 years) with refractory/relapsed ITP 
3.1.2.3. 
Pharmacokinetic Objectives  
• To characterize the PK of rilzabrutinib in pediatric participants (<18 years) and in adult 
participants (≥18 years) with refractory/relapsed ITP 
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3.1.2.4. 
Quality of Life (QOL) Objectives  
• To evaluate the effect of rilzabrutinib on the general and disease specific QOL of adult 
participants (≥18 years) with refractory/relapsed ITP 
• To evaluate the effect of rilzabrutinib on disease specific QOL in pediatric participants 
with refractory/relapsed ITP 
3.2. 
Endpoints  
3.2.1. 
Primary Efficacy Endpoint (Blinded Treatment Period)  
Durable platelet response defined as the proportion of participants able to achieve platelet counts 
at or above 50,000/μL for ≥ two-thirds of at least 8 non-missing weekly scheduled platelet 
measurements during the last 12 weeks of the 24-week blinded treatment period in the absence 
of rescue therapy, provided that at least 2 non-missing weekly scheduled platelet measurements 
are at or above 50,000/μL during the last 6 weeks of the 24-week blinded treatment period (See 
Appendix 10.7 country-specific definition of durable platelet response (EU [EEA countries] and 
UK). 
3.2.2. 
Key Secondary Efficacy Endpoints (Blinded Treatment Period)  
• Number of weeks with platelet count ≥50,000/μL OR between ≥30,000/μL and 
<50,000/μL and at least doubled from baseline over the 24-week blinded treatment period 
in the absence of rescue therapy 
• Number of weeks with platelet counts ≥30,000/μL and at least doubled from baseline 
over the 24-week blinded treatment period in the absence of rescue therapy  
• Time to first platelet count of ≥50,000/μL OR between ≥30,000/μL and <50,000/μL and 
doubled from baseline 
• Proportion of participants requiring rescue therapy during the 24-week blinded treatment 
period 
• Change from baseline on Item 10 of the ITP-PAQ (ie, physical fatigue) in adult 
participants (≥18 years) at Week 13 
See Appendix 10.7 for EU (EEA countries) and UK-specific requirements. 
3.2.3. 
Other Secondary Endpoints  
3.2.3.1. 
Efficacy Endpoint  
• Stability of response defined as the proportion of participants able to achieve stable 
platelet response, which is defined as no 2 scheduled visits, at least 4 weeks apart, with a 
platelet count less than 50,000/µL, without an intervening visit with a platelet count 
≥50,000/µL, within a period of 24 weeks following initial achievement of the platelet 
response (initial platelet response defined as platelet count ≥50,000/μL within 12 weeks 
of initiation of treatment with rilzabrutinib during the study). 
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3.2.3.2. 
Safety Endpoints  
• Frequency and severity of TEAEs 
• Frequency and severity of bleeding TEAEs 
• Change from baseline in physical examination, ECG, vital signs, and clinical laboratory 
test results: serum chemistry and hematology (except for platelet counts included in the 
primary efficacy endpoint) 
3.2.3.3. 
Pharmacokinetic Endpoints  
• Plasma concentrations of rilzabrutinib  
3.2.3.4. 
Quality of Life (QOL) Endpoints  
• Change from baseline on the Symptoms, Bother and Activity domains of the ITP-PAQ in 
adult participants (≥18 years) 
• Change from baseline in disease specific QOL as measured by the Kids’ ITP Tools 
(ITP-KIT) score in pediatric participants 
3.2.4. 
Exploratory Endpoints  
3.2.4.1. 
Blinded Treatment Period  
• Proportion of participants able to achieve platelet counts ≥50,000/μL for 4 out of last 
8 weeks of the 24-week treatment period 
• Percentage of weeks with platelet count ≥50,000/μL OR between ≥30,000/μL and 
<50,000/μL and at least doubled from baseline over the 24-week blinded treatment period 
in the absence of rescue therapy 
• Proportion of participants with complete response (defined as platelet count 
≥100,000/μL) on 2 consecutive visits at least 5 days apart and no bleeding or rescue ITP 
therapy use on and through these two visits. 
• Proportion of participants with platelet count ≥50,000/μL on 2 consecutive visits at least 
5 days apart and no rescue ITP therapy use on and through these two visits. 
• Proportion of participants who have a platelet count that exceeds 250,000/μL or 
450,000/µL (for participants on TPO-RAs) 
• Change from baseline in ITP Bleeding Scale (IBLS) assessment at Week 13 and Week 25 
• Change from baseline and change from Week 13 on the Fatigue (Item 10 of the IT-PAQ; 
physical fatigue), Psychological, Fear, Social Activity, Women’s Reproductive Health 
and Work domains of the ITP-PAQ in adult participants (≥18 years) at Week 25 
• Change from baseline on the Psychological, Fear, Social Activity, Women’s 
Reproductive Health and Work domains of the ITP-PAQ in adult participants (≥18 years) 
at Week 13 
• Change from baseline in QOL as measured by the EuroQOL-5 Dimensions-5 Level 
(EuroQOL-5D-5L) in adult participants (≥18 years) 
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• Change from baseline in disease-related symptom severity as measured by the Patient 
Global Impression of Severity (PGIS) scale 
• Change from baseline in disease-related fatigue severity as measured by the Patient 
Global Impression of [Fatigue] Severity (PGIS-Fatigue) scale 
• Patient perception of disease-related symptom improvement as measured by the Patient 
Global Impression of Change (PGIC) scale 
• PK parameters as assessed by population pharmacokinetic analysis 
• BTK occupancy 
• Changes from baseline in TPO levels, T-lymphocytes/ B-lymphocytes/natural killers 
(T/B/NK) counts, immunoglobulin (IgG, IgG1, IgG4, IgM, IgE) levels 
• (Optional) Vaccine-specific IgG response during treatment 
See Appendix 10 (Appendix 10.5) for China-specific requirements. 
3.2.4.2. 
Open Label Period and Long-Term Extension  
The following exploratory endpoints will be assessed at the end of the open label period 
(Week 53) and after 12 months of the LTE period. 
• Proportion of participants who received placebo during the blinded part and able to 
achieve durable platelet response during the open label part. Durable platelet response 
is defined as platelet counts at or above 50,000/μL for ≥ two-thirds of at least 
10 non-missing weekly scheduled platelet measurements during the last 16 weeks of the 
28 of the open label period in the absence of rescue therapy, provided that at least 
3 non-missing weekly scheduled platelet measurements are at or above 50,000/μL during 
the last 8 weeks of the 28-week open label period. 
• Percentage of weeks with platelet count ≥50,000/μL OR between ≥30,000/μL and 
<50,000/μL and at least doubled from baseline. 
• Proportion of participants with complete response (defined as platelet count 
≥100,000/μL) on 2 consecutive visits at least 5 days apart and no bleeding or rescue ITP 
therapy use on and through these two visits. 
• Proportion of participants who have a platelet count that exceeds 250,000/μL or 
450,000/µL (for participants on TPO-RAs). 
• Proportion of participants requiring rescue therapy 
• Change from baseline on the Fatigue (Item 10 of the ITP-PAQ; physical fatigue), 
Psychological, Fear, Social Activity, Women’s Reproductive Health and Work domains 
of the ITP-PAQ in adult participants (≥18 years) 
• Change from baseline in IBLS assessment 
• Change from baseline on the Psychological, Fear, Social Activity, Women’s 
Reproductive Health and Work domains of the ITP-PAQ in adult participants (≥18 years) 
• Change from baseline in QOL as measured by the EuroQOL-Dimensions-5 Level in adult 
participants (≥18 years) 
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• Percent change from baseline on CS dose 
• Percent change from baseline on TPO-RA dose  
• Proportion of participants who switch to rilzabrutinib as a monotherapy during the first 
year of the LTE period 
• Proportion of participants who decrease their CS dose >50% relative to baseline values 
during the first year of the LTE  
• Proportion of participants who manage to reduce their dose or stop TPO-RA agonists 
during the first year of the LTE 
See Appendix 10 for country-specific requirements of endpoints. 
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4. 
STUDY DESIGN  
This is a global, randomized, parallel-group, double-blind, multicenter clinical study in patients 
with primary ITP who had a response to either IVIg or CS that was not sustained. 
After providing informed consent, participants will enter a 28-day screening period. Upon 
completion of the screening period, participants who satisfy all the inclusion criteria and none of 
the exclusion criteria of this protocol will be randomized in a 2:1 allocation ratio to one of two 
study arms: rilzabrutinib or placebo. Randomization will be carried out separately for the two 
age groups. For the adult group, stratified permuted block randomization will be implemented; 
for the pediatric group, dynamic randomization algorithm (minimization) will be implemented. 
The factors used for stratification (for adult participants), or balance (for pediatric participants) 
are splenectomy status (yes/no), and by severity of thrombocytopenia 
(Inclusion Criteria #3 platelet counts <15,000/μL or ≥15,000/μL). 
After randomization, participants will start a blinded treatment period of up to 24 weeks 
followed by an open label period of 28 weeks during which all participants will receive 
rilzabrutinib, and then a 4-week safety follow-up period or LTE. 
At the end of 12 weeks of treatment, participants will be assessed for achieving a platelet 
response defined as a) platelet count of ≥50,000/μL OR a platelet count of between ≥30,000/μL 
and <50,000/μL and at least doubled from baseline at any time during the first 12 weeks and 
b) absence of rescue medication in the 4 weeks prior to the elevated platelet count that meets 
platelet response criteria.  
Figure 1 depicts the decision process for assessing response. The baseline value of platelet count 
is defined as the average of all the participant’s Predose platelet counts (Screening and Study 
Day 1). 
• Participants who respond will continue the blinded treatment period for a total of 
24 weeks before entering the open label period. 
• Participants who do not respond (including participants who receive rescue medication 
after 8 weeks of treatment) may discontinue from the study or enter the 28-week open 
label period at the end of Week 12, receiving treatment with 400 mg BID of rilzabrutinib. 
The Initial study medication assignment will remain blinded. 
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Figure 1 - Decision tree for assessing response at Week 13  
 
 
 
During the blinded treatment period (Week 13 to Week 24): 
• Participants who discontinue from the blinded treatment period due to safety or other 
reasons and choose to join the open label period will undergo the Week 25 assessments at 
their next scheduled visit. 
Participants who discontinue the blinded treatment period and choose not to join the open label 
period, should attend an Early Termination (ET) visit as shown in the Schedule of Assessments 
(SoA) (Table 1) for collection of data at the time of study discontinuation and complete the 
follow-up (EOS visit) and any further evaluations in need of completion. 
Concomitant ITP medications (an oral CS and/or a TPO-RA) will be permitted in both treatment 
arms and must be maintained at stable doses from 14 days before Study Day 1 and until the last 
dose of study medication. Reductions in the doses of concomitant ITP medications will be 
permitted for associated safety concerns only. In the LTE portion of the trial, reductions in dose 
or withdrawal of concomitant ITP medications (an oral CS and/or a TPO-RA) will also be 
permitted if the participant achieves platelet count of ≥50,000/μL in three scheduled visits (over 
12 weeks). Retreatment with the same medication(s) and doses of ITP concomitant medication(s) 
used at baseline (an oral CS and/or a TPO-RA), changing the dose or initiation of new ITP 
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medications (an oral CS and/or a TPO-RA) will also be allowed. Tapering of concomitant CS 
should be performed in accordance with the schedule in Section 6.6.2. 
The use of rescue medications (one of IVIg, high-dose CSs, platelet infusion, or anti-D 
immunoglobulin infusion) intended to increase platelet counts or prevent bleeding when platelet 
counts are less than 20,000/μL, or for bleeding or wet purpura, will be allowed. 
Figure 2 - Study Design Flow Chart  
 
BID = twice daily; CS = corticosteroid; PLT = platelet; SOC = standard of care; TPO-RA = thrombopoietin receptor agonist.  
After completing the open label period, participants who demonstrate a platelet response defined 
as platelet counts ≥50,000/μL or ≥30,000/μL and at least doubled from baseline at ≥50% of the 
visits without receiving rescue therapy while on treatment during the last 8 weeks of the open 
label period, will be allowed to enter the LTE. 
Participant(s) may continue in the LTE until: 
a) The participant is no longer responding (platelet counts <30,000/µL or less than 20,000/µL 
above baseline on two consecutive visits) 
b) The drug is no longer being developed by the Sponsor for ITP 
c) The program is stopped for safety reasons or 
d) The drug becomes commercially available in the participant’s country 
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Safety Measures Due to coronavirus (COVID-19) Pandemic 
Due to the COVID-19 pandemic, safety measures have been implemented to ensure continued 
supply of study medication and safety monitoring for participants. These measures are described 
in the “Guidelines to Sites for Delayed Participant Visits or Missed Visits due to travel 
restrictions and any foreseeable impacts of COVID-19.” When the COVID-19 pandemic 
resolves, the measures will be repealed back to the previous state as government rules and 
benefit/risk assessment allow. 
4.1. 
Duration of Study Participation  
For each participant, the study will last up to 60 weeks from the start of the screening period to 
the End of Study (EOS) visit. This includes screening (up to 4 weeks) through a 12 to 24-week 
blinded treatment period followed by a 28-week open label period. There is a 4-week postdose 
follow-up. 
For adult participants, the maximum duration of the LTE period will be 12 months from the date 
of the last adult participant to enter the LTE. 
For pediatric participants, the maximum duration of the LTE period will be 12 months from the 
date of the last pediatric participant to enter the LTE. 
4.1.1. 
Screening (Day -28 to Study Day-1 Predose)  
• Informed consent 
• Verify participant meets Inclusion/Exclusion criteria (use screening lab results for 
eligibility determination, with the exception of hemoglobin, which is to be rechecked 
prior to dosing on Day 1) 
• Complete ITP-PAQ or ITP-KIT, EQ-5D-5L and PGIS-Fatigue/PGIS/PGIC patient QOL 
questionnaires 
• Record concomitant medications 
• Record height (cm) 
• Record weight (kg) 
• Conduct full physical examination and medical history  
• Complete IBLS 
• Capture vital signs (body temperature, respiratory rate, blood pressure, and pulse rate) 
• Collect 12-lead single ECG 
• Collect urine sample for urinalysis 
• Collect hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency 
virus (HIV) blood samples 
• Collect QuantiFERON-Tuberculosis (TB) blood sample 
• Collect serum blood sample pregnancy test (women of childbearing potential) 
• Collect follicle-stimulating hormone (FSH) blood sample (postmenopausal woman only) 
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• Collect ABO and Rh Blood Type blood sample (historical results may be used) 
• Collect clinical laboratory blood samples: 
- 
Hematology (hemoglobin, hematocrit, red blood cells [RBCs], platelets, mean platelet 
volume, white blood cells [WBCs] with differentials [neutrophils, eosinophils, 
basophils, lymphocytes, and monocytes]) 
- 
Serum chemistry (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]); creatinine phosphokinase (CPK) and estimated glomerular 
filtration rate (eGFR) (See Appendix 10 for country-specific requirements) to be 
performed at screening only 
- 
Coagulation (prothrombin time [PT]/international normalized ratio [INR], thrombin 
time, activated partial thromboplastin time [aPTT], fibrinogen level) 
• Record AEs 
• Perform SARS-CoV-2 molecular test (if COVID-19 testing is required per local 
guidelines to be determined for each site). 
• For country-specific requirements please refer to Appendix 10. 
4.1.2. 
Blinded Treatment Period (Weeks 1 to 25)  
Day 1 Week 1: 
• Verify participant still meets Inclusion/Exclusion criteria (use screening lab results for 
eligibility determination) and randomize eligible participants to treatment 
• Complete ITP-PAQ or ITP-KIT, EQ-5D-5L, and PGIS-Fatigue/PGIS/PGIC patient 
questionnaires 
• Record concomitant medications 
• Record AEs 
• Record weight (kg) 
• Conduct abbreviated physical examination; See Appendix 10.6 for Italy-specific 
requirements 
• Complete IBLS 
• Capture vital signs (body temperature, respiratory rate, blood pressure, and pulse rate) 
• Collect 12-lead single ECG 
• Collect urine sample for urinalysis 
• Conduct urine pregnancy test (women of childbearing potential) 
• Collect clinical laboratory blood samples: 
- 
Hematology (hemoglobin, hematocrit, RBCs, platelets, mean platelet volume, WBCs 
with differentials [neutrophils, eosinophils, basophils, lymphocytes, and monocytes]) 
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- 
Serum chemistry (AST, ALT, bilirubin, ALP, albumin, creatinine, urea, total protein, 
sodium, chloride, calcium, phosphate, potassium, and glucose [random]) 
- 
Coagulation (PT/INR, thrombin time, aPTT, fibrinogen level) 
• Collect PK blood samples 
• Collect exploratory laboratory blood samples (see Appendix 10 for country-specific 
requirements): 
- 
T/B/NK counts 
- 
TPO levels 
- 
Hemolysis panel 
- 
Immunoglobulin levels 
- 
BTK occupancy (at select sites) 
- 
(Optional) vaccine-specific IgG response 
• Dispense rilzabrutinib or placebo 
• For country-specific requirements please refer to Appendix 10. 
 
Week 5: 
• Complete ITP-PAQ or ITP-KIT, EQ-5D-5L and PGIS-Fatigue/PGIS/PGIC patient 
questionnaires 
• Record concomitant medications 
• Record AEs 
• Record weight (kg) 
• Conduct abbreviated physical examination 
• Complete IBLS 
• Capture vital signs (body temperature, respiratory rate, blood pressure, and pulse rate) 
• Collect urine sample for urinalysis 
• Conduct urine pregnancy test (women of childbearing potential) 
• Collect clinical laboratory blood samples: 
- 
Hematology (hemoglobin, hematocrit, RBCs, platelets, mean platelet volume, WBCs 
with differentials [neutrophils, eosinophils, basophils, lymphocytes, and monocytes]) 
- 
Serum chemistry (AST, ALT, bilirubin, ALP, albumin, creatinine, urea, total protein, 
sodium, chloride, calcium, phosphate, potassium, and glucose [random]) 
- 
Coagulation (PT/INR, thrombin time, aPTT, fibrinogen level) 
• Collect exploratory laboratory blood samples (see Appendix 10 for country-specific 
requirements): 
- 
T/B/NK counts 
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- 
TPO levels 
- 
Hemolysis panel 
- 
Immunoglobulin levels 
- 
(Optional) vaccine-specific IgG response 
• Reconcile all study medications and dispense rilzabrutinib or placebo 
• Collect Patient Medication Diary 
• For country-specific requirements please refer to Appendix 10. 
Week 9: 
• Complete ITP-PAQ or ITP-KIT, EQ-5D-5L and PGIS-Fatigue/PGIS/PGIC patient 
questionnaires 
• Record concomitant medications 
• Record AEs 
• Record weight (kg) 
• Conduct abbreviated physical examination 
• Complete IBLS 
• Capture vital signs (body temperature, respiratory rate, blood pressure, and pulse rate) 
• Collect urine sample for urinalysis 
• Conduct urine pregnancy test (women of childbearing potential) 
• Collect clinical laboratory blood samples: 
- 
Hematology (hemoglobin, hematocrit, RBCs, platelets, mean platelet volume, WBCs 
with differentials [neutrophils, eosinophils, basophils, lymphocytes, and monocytes]) 
- 
Serum chemistry (AST, ALT, bilirubin, ALP, albumin, creatinine, urea, total protein, 
sodium, chloride, calcium, phosphate, potassium, and glucose [random]) 
- 
Coagulation (PT/INR, thrombin time, aPTT, fibrinogen level) 
• Collect exploratory laboratory blood samples (see Appendix 10 for country-specific 
requirements): 
- 
TPO levels 
- 
Hemolysis panel 
- 
(Optional) vaccine-specific IgG response 
• Reconcile all study medications and dispense rilzabrutinib or placebo 
• Collect Patient Medication Diary 
• For country-specific requirements please refer to Appendix 10. 
 
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Week 13: 
• Assess participant response to determine continuation in blinded treatment period or 
move to the open label period, if participant is moved to open label period, please 
proceed to Section 4.1.3. 
• Complete ITP-PAQ or ITP-KIT, EQ-5D-5L and PGIS-Fatigue/PGIS/PGIC patient 
questionnaires 
• Record concomitant medications 
• Record AEs 
• Record height (cm) - pediatric participants  
• Record weight (kg) 
• Conduct abbreviated physical examination 
• Complete IBLS 
• Capture vital signs (body temperature, respiratory rate, blood pressure, and pulse rate) 
• Collect urine sample for urinalysis 
• Conduct urine pregnancy test (women of childbearing potential) 
• Collect clinical laboratory blood samples: 
- 
Hematology (hemoglobin, hematocrit, RBCs, platelets, mean platelet volume, WBCs 
with differentials, [neutrophils, eosinophils, basophils, lymphocytes, and monocytes]) 
- 
Serum chemistry (AST, ALT, bilirubin, ALP, albumin, creatinine, urea, total protein, 
sodium, chloride, calcium, phosphate, potassium, and glucose [random]) 
- 
Coagulation (PT/INR, thrombin time, aPTT, fibrinogen level) 
• Collect PK blood sample - Predose only 
• Collect exploratory laboratory blood samples (see Appendix 10 for country-specific 
requirements): 
- 
T/B/NK counts 
- 
TPO levels 
- 
Hemolysis panel 
- 
Immunoglobulin levels 
- 
BTK occupancy (at select sites) - Predose only 
- 
(Optional) vaccine-specific IgG response 
• Reconcile all study medications and dispense rilzabrutinib or placebo 
• Collect Patient Medication Diary 
• For country-specific requirements please refer to Appendix 10. 
 
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Week 17 and Week 21: 
• Complete ITP-PAQ or ITP-KIT, EQ-5D-5L and PGIS-Fatigue/PGIS/PGIC patient 
questionnaires 
• Record concomitant medications 
• Record AEs 
• Record weight (kg) 
• Conduct abbreviated physical examination 
• Complete IBLS 
• Capture vital signs (body temperature, respiratory rate, blood pressure, and pulse rate) 
• Collect urine sample for urinalysis 
• Conduct urine pregnancy test (women of childbearing potential) 
• Collect clinical laboratory blood samples: 
- 
Hematology (hemoglobin, hematocrit, RBCs, platelets, mean platelet volume, WBCs 
with differentials [neutrophils, eosinophils, basophils, lymphocytes, and monocytes]) 
- 
Serum chemistry (AST, ALT, bilirubin, ALP, albumin, creatinine, urea, total protein, 
sodium, chloride, calcium, phosphate, potassium, and glucose [random]) 
- 
Coagulation (PT/INR, thrombin time, aPTT, fibrinogen level) 
• Collect exploratory laboratory blood samples (see Appendix 10 for country-specific 
requirements): 
- 
TPO levels 
- 
Hemolysis panel 
- 
(Optional) vaccine-specific IgG response 
• Reconcile all study medications and dispense rilzabrutinib or placebo 
• Collect Patient Medication Diary 
• For country-specific requirements please refer to Appendix 10. 
4.1.3. 
Open Label Period (Weeks 25 to 53)  
Week 25 (First Day of Open Label Period): 
• Complete ITP-PAQ or ITP-KIT, EQ-5D-5L and PGIS-Fatigue/PGIS/PGIC patient 
questionnaires 
• Record concomitant medications 
• Record AEs 
• Record height (cm) - pediatric participants  
• Record weight (kg) 
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• Conduct abbreviated physical examination; See Appendix 10.6 for Italy-specific 
requirements 
• Complete IBLS 
• Capture vital signs (body temperature, respiratory rate, blood pressure, and pulse rate) 
• Collect 12-lead single ECG 
• Collect urine sample for urinalysis 
• Conduct urine pregnancy test (women of childbearing potential) 
• Collect clinical laboratory blood samples: 
- 
Hematology (hemoglobin, hematocrit, RBCs, platelets, mean platelet volume, WBCs 
with differentials [neutrophils, eosinophils, basophils, lymphocytes, and monocytes]) 
- 
Serum chemistry (AST, ALT, bilirubin, ALP, albumin, creatinine, urea, total protein, 
sodium, chloride, calcium, phosphate, potassium, and glucose [random]) 
- 
Coagulation (PT/INR, thrombin time, aPTT, fibrinogen level) 
• Collect PK blood sample 
• Collect exploratory laboratory blood samples (see Appendix 10 for country-specific 
requirements): 
- 
T/B/NK counts 
- 
TPO levels 
- 
Hemolysis panel 
- 
Immunoglobulin levels 
- 
BTK occupancy (at select sites) 
- 
(Optional) vaccine-specific IgG response 
• Collect and reconcile all study medications  
• Dispense open label rilzabrutinib 
• Collect Patient Medication Diary 
• For country-specific requirements please refer to Appendix 10. 
 
Week 29: 
• Complete ITP-PAQ or ITP-KIT, EQ-5D-5L and PGIS-Fatigue/PGIS/PGIC patient 
questionnaires 
• Record concomitant medications 
• Record AEs 
• Record weight (kg) 
• Conduct abbreviated physical examination 
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• Complete IBLS 
• Capture vital signs (body temperature, respiratory rate, blood pressure, and pulse rate) 
• Collect urine sample for urinalysis 
• Conduct urine pregnancy test (women of childbearing potential) 
• Collect clinical laboratory blood samples: 
- 
Hematology (hemoglobin, hematocrit, RBCs, platelets, mean platelet volume, WBCs 
with differentials [neutrophils, eosinophils, basophils, lymphocytes, and monocytes]) 
- 
Serum chemistry (AST, ALT, bilirubin, ALP, albumin, creatinine, urea, total protein, 
sodium, chloride, calcium, phosphate, potassium, and glucose [random]) 
- 
Coagulation (PT/INR, thrombin time, aPTT, fibrinogen level) 
• Collect exploratory laboratory blood samples (see Appendix 10 for country-specific 
requirements): 
- 
T/B/NK counts 
- 
TPO levels 
- 
Hemolysis panel 
- 
Immunoglobulin levels 
- 
(Optional) vaccine-specific IgG response 
• Reconcile all study medications and dispense rilzabrutinib 
• Collect Patient Medication Diary 
• For country-specific requirements please refer to Appendix 10. 
 
Week 33: 
• Complete ITP-PAQ or ITP-KIT, EQ-5D-5L and PGIS-Fatigue/PGIS/PGIC patient 
questionnaire 
• Record concomitant medications 
• Record AEs 
• Record weight (kg) 
• Conduct abbreviated physical examination 
• Complete IBLS 
• Capture vital signs (body temperature, respiratory rate, blood pressure, and pulse rate) 
• Collect urine sample for urinalysis 
• Conduct urine pregnancy test (women of childbearing potential) 
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• Collect clinical laboratory blood samples: 
- 
Hematology (hemoglobin, hematocrit, RBCs, platelets, mean platelet volume, WBCs 
with differentials [neutrophils, eosinophils, basophils, lymphocytes, and monocytes]) 
- 
Serum chemistry (AST, ALT, bilirubin, ALP, albumin, creatinine, urea, total protein, 
sodium, chloride, calcium, phosphate, potassium, and glucose [random]) 
- 
Coagulation (PT/INR, thrombin time, aPTT, fibrinogen level) 
• Collect exploratory laboratory blood samples (see Appendix 10 for country-specific 
requirements): 
- 
T/B/NK counts 
- 
TPO levels 
- 
Hemolysis panel 
- 
Immunoglobulin levels 
- 
(Optional) vaccine-specific IgG response 
• Reconcile all study medications and dispense rilzabrutinib 
• Collect Patient Medication Diary 
• For country-specific requirements please refer to Appendix 10. 
 
Week 37: 
• Complete ITP-PAQ or ITP-KIT, EQ-5D-5L and PGIS-Fatigue/PGIS/PGIC patient 
questionnaires 
• Record concomitant medications 
• Record AEs 
• Record height (cm) - pediatric participants  
• Record weight (kg) 
• Conduct abbreviated physical examination 
• Complete IBLS 
• Capture vital signs (body temperature, respiratory rate, blood pressure, and pulse rate) 
• Collect urine sample for urinalysis 
• Conduct urine pregnancy test (women of childbearing potential) 
• Collect clinical laboratory blood samples: 
- 
Hematology (hemoglobin, hematocrit, RBCs, platelets, mean platelet volume, WBCs 
with differentials, [neutrophils, eosinophils, basophils, lymphocytes, and monocytes]) 
- 
Serum chemistry (AST, ALT, bilirubin, ALP, albumin, creatinine, urea, total protein, 
sodium, chloride, calcium, phosphate, potassium, and glucose [random]) 
- 
Coagulation (PT/INR, thrombin time, aPTT, fibrinogen level) 
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• Collect exploratory laboratory blood samples (see Appendix 10 for country-specific 
requirements): 
- 
TPO levels 
- 
Hemolysis panel 
- 
(Optional) vaccine-specific IgG response 
• Reconcile all study medications and dispense rilzabrutinib 
• Collect Patient Medication Diary 
• For country-specific requirements please refer to Appendix 10. 
 
Week 41: 
• Complete ITP-PAQ or ITP-KIT, EQ-5D-5L and PGIS-Fatigue/PGIS/PGIC patient 
questionnaires 
• Record concomitant medications 
• Record AEs 
• Record weight (kg) 
• Conduct abbreviated physical examination 
• Complete IBLS 
• Capture vital signs (body temperature, respiratory rate, blood pressure, and pulse rate) 
• Collect urine sample for urinalysis 
• Conduct urine pregnancy test (women of childbearing potential) 
• Collect clinical laboratory blood samples: 
- 
Hematology (hemoglobin, hematocrit, RBCs, platelets, mean platelet volume, WBCs 
with differentials [neutrophils, eosinophils, basophils, lymphocytes, and monocytes]) 
- 
Serum chemistry (AST, ALT, bilirubin, ALP, albumin, creatinine, urea, total protein, 
sodium, chloride, calcium, phosphate, potassium, and glucose [random]) 
- 
Coagulation (PT/INR, thrombin time, aPTT, fibrinogen level) 
• Collect exploratory laboratory blood samples (see Appendix 10 for country-specific 
requirements): 
- 
T/B/NK counts 
- 
TPO levels 
- 
Hemolysis panel 
- 
Immunoglobulin levels 
- 
(Optional) vaccine-specific IgG response 
• Reconcile all study medications and dispense rilzabrutinib 
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• Collect Patient Medication Diary 
• For country-specific requirements please refer to Appendix 10. 
 
Weeks 45 and 49: 
• Complete ITP-PAQ or ITP-KIT, EQ-5D-5L and PGIS-Fatigue/PGIS/PGIC patient 
questionnaires  
• Record concomitant medications 
• Record AEs 
• Record weight (kg) 
• Conduct abbreviated physical examination 
• Complete IBLS 
• Capture vital signs (body temperature, respiratory rate, blood pressure, and pulse rate) 
• Collect urine sample for urinalysis 
• Conduct urine pregnancy test (women of childbearing potential) 
• Collect clinical laboratory blood samples: 
- 
Hematology (hemoglobin, hematocrit, RBCs, platelets, mean platelet volume, WBCs 
with differentials [neutrophils, eosinophils, basophils, lymphocytes, and monocytes]) 
- 
Serum chemistry (AST, ALT, bilirubin, ALP, albumin, creatinine, urea, total protein, 
sodium, chloride, calcium, phosphate, potassium, and glucose [random]) 
- 
Coagulation (PT/INR, thrombin time, aPTT, fibrinogen level) 
• Collect exploratory laboratory blood samples (see Appendix 10 for country-specific 
requirements): 
- 
TPO levels 
- 
Hemolysis panel 
- 
(Optional) vaccine-specific IgG response 
• Reconcile all study medications and dispense rilzabrutinib 
• Collect Patient Medication Diary 
• For country-specific requirements please refer to Appendix 10. 
 
Week 53 (Last Day of Open Label Period): 
• Complete ITP-PAQ or ITP-KIT, EQ-5D-5L and PGIS-Fatigue/PGIS/PGIC patient 
questionnaires 
• Record concomitant medications 
• Record AEs 
• Record height (cm) - pediatric participants  
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• Record weight (kg) 
• Conduct abbreviated physical examination; See Appendix 10.6 for Italy-specific 
requirements 
• Complete IBLS 
• Capture vital signs (body temperature, respiratory rate, blood pressure, and pulse rate) 
• Collect 12-lead single ECG 
• Collect urine sample for urinalysis 
• Conduct urine pregnancy test (women of childbearing potential) 
• Collect clinical laboratory blood samples: 
- 
Hematology (hemoglobin, hematocrit, RBCs, platelets, mean platelet volume, WBCs 
with differentials [neutrophils, eosinophils, basophils, lymphocytes, and monocytes]) 
- 
Serum chemistry (AST, ALT, bilirubin, ALP, albumin, creatinine, urea, total protein, 
sodium, chloride, calcium, phosphate, potassium, and glucose [random]) 
- 
Coagulation (PT/INR, thrombin time, aPTT, fibrinogen level) 
• Collect PK blood sample 
• Collect exploratory laboratory blood samples (see Appendix 10 for country-specific 
requirements): 
- 
T/B/NK counts 
- 
TPO levels 
- 
Hemolysis panel 
- 
Immunoglobulin levels 
- 
BTK occupancy (at select sites) 
- 
(Optional) vaccine-specific IgG response 
• Reconcile all study medications and dispense rilzabrutinib if entering Long-Term 
Extension 
• Collect Patient Medication Diary 
• For country-specific requirements please refer to Appendix 10. 
4.1.4. 
End of Study visit (Four Weeks Post Last Dose of Study Drug)  
The following assessments will be performed four weeks post last dose of study drug in the 
double blind, open label period, or LTE: 
• Complete ITP-PAQ or ITP-KIT, EQ-5D-5L and PGIS-Fatigue/PGIS/PGIC patient 
questionnaire 
• Record concomitant medications 
• Record AEs 
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• Record weight (kg) 
• Conduct full physical examination; See Appendix 10.6 for Italy-specific requirements 
• Complete IBLS 
• Capture vital signs (body temperature, respiratory rate, blood pressure, and pulse rate) 
• Collect 12-lead single ECG 
• Collect urine sample for urinalysis 
• Conduct urine pregnancy test (women of childbearing potential) 
• Collect clinical laboratory blood samples: 
- 
Hematology (hemoglobin, hematocrit, RBCs, platelets, mean platelet volume, WBCs 
with differentials [neutrophils, eosinophils, basophils, lymphocytes, and monocytes]) 
- 
Serum chemistry (AST, ALT, bilirubin, ALP, albumin, creatinine, urea, total protein, 
sodium, chloride, calcium, phosphate, potassium, and glucose [random]) 
- 
Coagulation (PT/INR, thrombin time, aPTT, fibrinogen level) 
• Collect exploratory laboratory blood samples (see Appendix 10 for country-specific 
requirements): 
- 
T/B/NK counts 
- 
TPO levels 
- 
Hemolysis panel 
- 
Immunoglobulin levels 
- 
(Optional) vaccine-specific IgG response 
• For country-specific requirements please refer to Appendix 10. 
4.1.5. 
Long-Term Extension (LTE)  
The following assessments will be performed at each visit during the LTE: 
• Complete ITP-PAQ or ITP-KIT, EQ-5D-5L and PGIS-Fatigue/PGIS/PGIC patient 
questionnaire (every 3 months only) 
• Record concomitant medications 
• Record AEs 
• Record weight (kg) 
• Conduct abbreviated physical examination; See Appendix 10.6 for Italy-specific 
requirements 
• Complete IBLS 
• Capture vital signs (body temperature, respiratory rate, blood pressure, and pulse rate) 
• Collect urine sample for urinalysis 
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• Conduct urine pregnancy test (women of childbearing potential) 
• Collect clinical laboratory blood samples: 
- 
Hematology (hemoglobin, hematocrit, RBCs, platelets, mean platelet volume, WBCs 
with differentials [neutrophils, eosinophils, basophils, lymphocytes, and monocytes]) 
- 
Serum chemistry (AST, ALT, bilirubin, ALP, albumin, creatinine, urea, total protein, 
sodium, chloride, calcium, phosphate, potassium, and glucose [random]) 
- 
Coagulation (PT/INR, thrombin time, aPTT, fibrinogen level) - only if needed to 
follow-up on bleeding related AEs 
• Collect exploratory laboratory blood samples (see Appendix 10 for country-specific 
requirements): 
- 
T/B/NK counts (every 6 months only) 
- 
TPO levels 
- 
(Optional) vaccine-specific IgG response 
• Reconcile all study medications and dispense rilzabrutinib 
• Collect Patient Medication Diary 
• For country-specific requirements please refer to Appendix 10. 
See Section 4.1.4 for the End of Study visit assessments in LTE period. 
Completion for the overall clinical study is defined as the point at which the last participant has 
completed the last visit of the study. 
4.2. 
Study Population  
Participants with refractory or relapsed ITP of >3 months duration (age 18 years and above) or 
with >6 months duration (age 12 to <18 years; see Appendix 10.2, Appendix 10.3, and 
Appendix 10.7 for country-specific age ranges). 
4.3. 
Study Assessments Overview  
See Figure 2 for a diagram of the study design and the Schedules of Assessments 
(Table 1, Table 2, and Table 3) and for description of the assessments. 
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5. 
ELIGIBILITY CRITERIA  
5.1. 
Inclusion Criteria  
Participants may be included in the study if ALL of the following criteria are met: 
1. 
Participants will be male and female with primary ITP with duration of >6 months in 
pediatric participants aged 12 to <18 years (pediatric participants aged 10 to <12 years will 
be enrolled in the EU [EEA countries] only; refer to Appendix 10.2, Appendix 10.3, and 
Appendix 10.7 for country-specific requirements) and duration of >3 months in adults 
aged ≥18 years 
2. 
Participants who had a response (achievement of platelet count ≥50,000/µL) to IVIg/anti-D 
or CSs that was not sustained and who have documented intolerance, insufficient response, 
or any contraindication to any appropriate courses of standard of care ITP therapy  
3. 
An average of 2 platelet counts at least 5 days apart of <30,000/µL during the screening 
period and no single platelet count >35,000/µL, within 14 days prior to the first dose of 
study drug 
• Pediatric participants must additionally be determined to need treatment for ITP as per 
clinical assessment by the Investigator (see Appendix 10.7 for EU [EEA countries] 
specific criteria) 
4. 
Adequate hematologic, hepatic, and renal function (absolute neutrophil count ≥1.5 × 109/L, 
AST/ALT ≤1.5 × upper limit of normal (ULN), albumin ≥3 g/dL, total bilirubin 
≤1.5 × ULN [unless the participant has documented Gilbert syndrome], estimated 
glomerular filtration rate (GFR) >50 [Cockcroft and Gault method for adult and Bedside 
Schwartz Equation for Pediatric participants]) 
5. 
Hemoglobin >9 g/dL within 1 week prior to Study Day 1 
6. 
All contraceptive use by men and women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
A) Male participants 
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 13 weeks after the last administration of study 
intervention: 
• 
Refrain from donating or cryopreserving sperm 
Plus, either: 
- 
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
OR 
- 
Must agree to use contraception/barrier as detailed below 
- 
A male condom; the participant should also be advised of the benefit for a 
female partner to use a highly effective method of contraception (as described 
in  Appendix 13 Contraceptive and barrier guidance) of the protocol as a 
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condom may break or leak when having sexual intercourse with a woman of 
childbearing potential (WOCBP) who is not currently pregnant 
B) Female participants 
A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
one of the following conditions applies: 
• Is a woman of nonchildbearing potential (WONCBP) as defined in Appendix 13 of the 
protocol. 
OR 
• Is a WOCBP and agrees to use a contraceptive method that is highly effective (with a 
failure rate of <1% per year), as described in Appendix 13 of the protocol, during the 
study intervention period (to be effective before starting the intervention) and for at 
least 4 weeks after the last administration of study intervention AND agrees not to 
donate or cryopreserve eggs (ova, oocytes) for the purpose of reproduction during this 
period. 
• A WOCBP must have a negative highly sensitive pregnancy test (serum) as required by 
local regulations) within 3 days before the first administration of study intervention  
- 
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive. 
7. 
Participants must be able to provide written informed consent or informed assent with 
corresponding informed consent obtained from the participants’ guardian and agree to the 
SoA. 
5.2. 
Exclusion Criteria  
Participants will be excluded from the study if any of the following criteria are met: 
1. Participants with secondary ITP 
2. Pregnant or lactating women 
3. Electrocardiogram (ECG) findings for participants: 
- 
Aged ≥10 and <16 years: QTcF >449 msec (males) or >457 msec (females) 
- 
Aged ≥16 and <18 years: QTcF >450 msec (males) or >460 msec (females) 
- 
Aged ≥18 years, of QTcF >450 msec (males) or >470 msec (females), poorly 
controlled atrial fibrillation (ie, symptomatic participants or a ventricular rate above 
100 beats/min on ECG), or other clinically significant abnormalities  
4. History (within 5 years of Study Day 1) or current, active malignancy requiring or likely to 
require chemotherapeutic or surgical treatment during the study, with the exception of 
non-melanoma skin cancer  
5. Transfusion with blood, blood products, plasmapheresis, or use of any other rescue 
medications with intent to increase platelet count within 14 days before Study Day 1 
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6. Change in CS and/or TPO-RA dose within 14 days prior to Study Day 1 (more than 
10% variation from current doses) 
7. Immunosuppressant drugs other than CSs within 5 times the elimination half-life of the drug 
or 14 days of Study Day 1, whichever is longer 
8. Treatment with rituximab or splenectomy within the 3 months prior to Study Day 1 
- 
Participants treated with rituximab will have normal B-cell counts prior to enrollment 
9. Ongoing need for the use of proton pump inhibitor drugs such as omeprazole and 
esomeprazole (it is acceptable to change participant to H2 receptor blocking drugs prior to 
Study Day 1) 
10. Use of known strong-to-moderate inducers or inhibitors of CYP3A within 14 days or 
5 half-lives (whichever is longer) of Study Day 1 and until the end of the active treatment 
period 
11. Planned or concomitant use of any anticoagulants and platelet aggregation inhibiting drugs 
such as aspirin (except for low dose aspirin up to 100 mg per day), nonsteroidal 
anti-inflammatory drugs, and/or thienopyridines within 14 days of Study Day 1 and until the 
end of the active treatment period 
12. Has received any investigational drug within the 30 days before receiving the first dose of 
study medication, or at least 5 times elimination half-life of the drug (whichever is longer); 
participant should not be using an investigational device at the time of dosing 
- 
Participants who previously received treatment with BTK inhibitors (except 
rilzabrutinib) within 30 days before the first dose of study drug are not eligible 
- 
Participants who previously received rilzabrutinib at any time are not eligible 
13. Current drug or alcohol abuse 
14. Refractory nausea and vomiting, malabsorption, external biliary shunt, significant bowel 
resection, or any other condition that would preclude adequate study drug absorption 
15. History of solid organ transplant 
16. Positive at Screening for HIV, HBV (surface and core antibodies unrelated to vaccination), 
or HCV (anti-HCV antibody confirmed with Hep C RNA) 
- 
Participants who are HBV surface antigen (HBsAg) positive will not be eligible 
- 
Participants who are HBsAg negative and HBV core antigen antibody (HBcAb) 
positive will be tested for HBV surface antibody (HBsAb) and HBV DNA. If HBV 
DNA is negative and HBsAb titer is ≥100 IU/L, participants may be enrolled. 
Monthly HBV DNA monitoring will be required while on treatment and for 6 months 
after the last dose of the study drug. Positive HBV DNA results will be managed 
appropriately as per local standard of care 
- 
Participants who are HBcAb positive, HBsAg negative with HBsAb titer <100 IU/L 
or negative, are not eligible 
17. Positive QuantiFERON®-TB Gold, or QuantiFERON®-TB Gold Plus (QFT Plus) at 
Screening unless all of the following 3 conditions are true (see Appendix 10 country-specific 
requirements): 
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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 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 participant may be enrolled using the local result upon approval of the 
Sponsor. 
18. History of recurring (2 or more) serious infections requiring intravenous antibiotic, antivirals, 
or antifungals therapy within the last 3 months before Study Day 1 or active serious or 
moderate infection ongoing on the day of randomization 
19. Myelodysplastic syndrome 
20. Live vaccine within 28 days prior to Study Day 1 or plan to receive one during the study 
21. Planned surgery in the time frame of the dosing period 
22. Any other clinically significant disease, condition, known allergy to any of the study 
medication, their analogues, or excipients in the various formulations of any agent (please 
see Section 6.1.1 for information on excipients), or medical history that, in the opinion of the 
Investigator or Sponsor’s medical monitor, would interfere with participant safety, study 
evaluations, and/or study procedures 
23. Positive severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) molecular test (if 
COVID-19 testing required per local guidelines to be determined for each site) 
24. The COVID-19 vaccine within 14 days prior to Study Day 1 or planned during the last 
12 weeks of blinded treatment period 
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6. 
TREATMENTS  
6.1. 
Treatments Administered  
6.1.1. 
Rilzabrutinib/Placebo  
Each rilzabrutinib tablet contains 400 mg of rilzabrutinib and is orange in color. In addition, the 
tablet contains Microcrystalline Cellulose (filler), Crospovidone (disintegrant), Sodium Stearyl 
Fumarate (lubricant) and a non-functional film coating. Each tablet is coated with a light orange 
film coat (Opadry II 85F130006) containing polyvinyl alcohol, polyethylene glycol, talc, 
titanium dioxide, and FD&C yellow #6. 
The placebo treatment is a tablet that is identical in appearance and contains the same inactive 
ingredients as that of the rilzabrutinib study medication but does not contain rilzabrutinib. In 
addition, the inactive ingredient mannitol has been added as a filler to replace rilzabrutinib. 
6.1.1.1. 
Packaging  
Rilzabrutinib drug product or placebo will be supplied to the clinical sites in bottles. Each bottle 
will contain 70 tablets or a 5-week supply of rilzabrutinib or placebo. 
6.2. 
Preparation and Administration  
6.2.1. 
Rilzabrutinib/Placebo  
No preparation of the rilzabrutinib or placebo study medication will be needed. Participants will 
use the study medication directly from the dispensed bottles. 
Study medication will be taken BID by mouth starting on Day 1. Rilzabrutinib or placebo may 
be taken with or without food. The frequency and/or severity of GI AEs may be improved if 
rilzabrutinib/placebo is taken with 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. 
6.3. 
Storage  
6.3.1. 
Rilzabrutinib/Placebo  
Rilzabrutinib or placebo tablets are supplied in 100cc bottles. The recommended storage 
condition is 2 to 25°C (IB). 
6.4. 
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 study monitor. 
The study medication should be used only by healthcare professionals who are qualified by 
training and experience in the safe use and handling of investigational drugs. 
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During the COVID-19 pandemic, drug supply can be sent to participants when the participant is 
not able to travel to the site or the site cannot host a participant visit. Site instructions for 
shipment of supplies directly to participants and procedures for conducting remote site visits 
inclusive of ensuring drug supply maintenance are described in “Guidelines to Sites for Delayed 
Participant Visits or Missed Visits due to travel restrictions and any foreseeable impacts of 
COVID-19” (Appendix 8). 
6.4.1. 
Drug Accountability  
The Investigator or his/her designated representatives will dispense study medication per the 
SoA (Table 1, 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 study medication must be maintained. The Investigational Drug Dispensing Log must be 
kept current and should contain the following information: 
• The identification (ID) of the participant to whom the study medication was dispensed 
(that is, participant ID number, and year of birth) 
• The date(s), quantity, and lot number(s) of the study medication dispensed to the 
participant 
• The ID of the person who dispensed the study medication 
All used and unused drug supplies must be returned by the participant at every visit. 
All records and used and unused drug supplies must be available for inspection by the study 
monitor at every monitoring visit. Reconciliation of all drug supplies (rilzabrutinib or placebo) 
will be performed by the study monitor.  
6.4.2. 
Destruction of Investigational Medicinal Product  
When the study is completed, any used and unused study medication (eg, empty, partially used, 
and unused containers) will be destroyed on-site or returned to the depot of destruction 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. 
Local or institutional regulations may require immediate destruction of used investigational 
medicinal product (IMP) for safety reasons. In these cases, it may be acceptable for 
investigational study center staff to destroy dispensed IMP 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 study medication from the site that has not been stored properly should not be destroyed 
until the monitor and/or Sponsor approve the destruction. 
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No destruction of unused (not dispensed) IMP takes place without Sponsor’s written 
authorization. Storage conditions must be kept until approval from the Sponsor to remove the 
product from its storage location (eg, refrigerator). Products must be kept in a dedicated 
quarantine area until destruction, with a clear sign of “quarantined” until the Sponsor’s Site 
Monitor authorizes the destruction. 
Written documentation of destruction must contain the following: 
• Identity of IMP(s) destroyed 
• Quantity of IMP(s) destroyed 
• Date of destruction 
• Method of destruction 
• Name and signature of responsible person who destroyed the IMP 
If a site does not have a destruction SOP, study drug can be returned to the depot. 
6.4.3. 
Treatment Compliance  
Accountability and participant compliance will be assessed by maintaining adequate study 
medication dispensing records and medication counts. The Investigator is responsible for 
ensuring that dosing is administered in compliance with the protocol. See Section 6.4.1 for 
instructions on Drug Accountability procedures. 
6.4.4. 
Treatment Blinding/Unblinding  
Allocation of participants to treatment groups will proceed through the use of an interactive web 
response system (IRT/IWRS) that is accessible 24 hours a day, 365 days a year.  
• The randomized intervention kit number list is generated centrally by the IRT/IWRS. 
• The randomization and intervention allocation are performed centrally by the IRT/IWRS. 
The IRT/IWRS generates the participant randomization list and allocates the intervention 
number and the corresponding intervention kits to the participants according to it. 
• A randomized participant is a participant from the screened population who has been 
allocated to a randomized intervention by the IRT/IWRS regardless of whether the 
intervention was received or not. 
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, participant number, participant year of birth, as well 
as other information (as allowed locally). The pharmacist or designee will then be provided with 
a participant randomization number and treatment assignment. Once participant 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 study 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 study will be blinded to randomization codes.  
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The treatment each participant receives will not be disclosed to the Investigator, study center 
personnel, participants, 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.  
If deemed by the Investigator to be medically necessary, the Investigator can unblind a 
participant via the IWRS after consultation with Sponsor medical monitor (See Appendix 10 for 
UK country-specific requirements). 
Sponsor PV operations/responsible third party may unblind the intervention assignment for any 
participant with a suspected unexpected serious adverse reaction (SUSAR). If the SUSAR 
requires that an expedited regulatory report be sent to one or more regulatory agencies, a copy of 
the report, identifying the participant’s intervention assignment, may be sent to Investigators in 
accordance with local regulations and/or Sponsor policy. 
At the facilities where the systemic drug concentration measurements and selected biomarkers 
are determined, the samples will be analyzed prior to data base lock leading to unblinding of 
responsible bioanalysts. Bioanalysts are excluded from the clinical trial team. One programmer 
may be unblinded to prepare the dataset for population PK analysis, and there will be strict 
procedures to maintain blind beyond the programmer. 
6.5. 
Treatment of Overdose  
An overdose (accidental or intentional) with the IMP is an event suspected by the Investigator or 
spontaneously notified by the participant and defined as a single ingestion of a dose equal to or 
greater than 1200 mg (≥3 times the indicated single dose of 400 mg) provided that it has been 
taken at once or over a 2-hour period. No specific information is available on the treatment of 
overdose of rilzabrutinib.  
In the event of an overdose, the Investigator/treating physician should: 
1. Evaluate the participant to determine, if possible, whether study intervention should be 
interrupted or whether the dose should be reduced. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
rilzabrutinib can no longer be detected systemically (at least 20 hours). 
3. Obtain a plasma sample for PK analysis within 20 hours from the date of the last dose of 
study intervention if possible.  
4. Document appropriately in the eCRF 
6.6. 
Concomitant Medications  
6.6.1. 
Prohibited Medications  
The following medications are prohibited for use during the study: 
• Concomitant use of any immunosuppressant medication, other than CS, as described in 
this protocol. Participants who need other immunosuppressant therapy during the study 
must be withdrawn. See Exclusion # 7, Section 5.2 for washout periods 
• Concomitant use of known strong-to-moderate inducers or inhibitors of cytochrome 
P450 (CYP) 3A. See Exclusion # 10, Section 5.2 for washout periods 
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• 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. Participants who are on proton pump 
inhibitors should be changed to H2 receptor blocking drugs if possible or not enroll in the 
study. Details of H2 receptor blocker administration is provided in Section 6.6.2. See 
Exclusion # 9, Section 5.2. 
• Rescue medications other than one of IVIg, high-dose CSs, platelet infusion, or anti-D 
immunoglobulin infusion intended to increase platelet counts or prevent bleeding when 
platelet counts are less than 20 × 109/L, or for bleeding or wet purpura, are not permitted 
• COVID-19 vaccine is prohibited during the last 12 weeks of the blinded treatment period. 
• Live vaccines are not permitted during the study. 
6.6.2. 
Particular Permissible Medications  
The following medications are permitted for use during the study: 
• ITP medications, an oral CS and/or a TPO-RA (authorized for the treatment of ITP) 
Note: 
- 
These medications must be maintained at stable doses from 14 days before Study 
Day 1 and until the last dose of study medication. Adjustments in the doses of 
concomitant ITP medications will be permitted for associated safety concerns only. 
- 
Administration of corticosteroids and TPO-RAs should follow corresponding updated 
package inserts/SmPCs of the marketing authorization. 
- 
Tapering is allowed during LTE period only due to achieving durable platelet 
response, and would follow the following guidelines with 2 weekly platelet counts 
between tapers: 
- 
10 mg/day every one to two weeks from an initial dose >40 mg of prednisone 
or equivalent per day 
- 
5 mg/day every one to two weeks at prednisone doses ≤40 to >20 mg or 
equivalent per day 
- 
2.5 mg/day every one to two weeks at prednisone doses ≤20 to >10 mg or 
equivalent per day 
- 
1 mg/day every one to two weeks at prednisone doses ≤10 to >5 mg or 
equivalent per day 
- 
0.5 mg/day every one to two weeks at prednisone doses ≤5 mg or equivalent 
per day down to zero. This can be achieved by alternating daily doses (eg, 
5 mg on day one and 4 mg on day two) 
- 
Dose of corticosteroid can be up titrated if platelet counts fall below 
50,000/μL on two consecutive measurements 
• IVIg or high- dose CS, platelet infusion, or anti-D immunoglobulin infusion as rescue 
medications 
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• Clinically relevant drugs that are substrates of CYP3A, including those considered to be 
sensitive CYP3A substrates. Appropriate caution should be used when co-administering 
sensitive CYP3A substrates with rilzabrutinib, including an assessment of medical 
risk-benefit for each medication. Consideration should also be given to avoidance of high 
doses, dose reduction, or replacement of sensitive CYP3A substrate drugs 
• 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. 
STUDY ASSESSMENTS AND PROCEDURES  
7.1. 
Study Recruitment Procedures  
Participants will be identified for potential recruitment by the Investigator using a recruitment 
plan agreed upon with the Sponsor, possibly including, but not limited to, a listing from a study 
center, volunteer database, newspaper/radio/internet advertisement, or mailing list. 
7.2. 
Study Enrollment Procedures  
Participants eligible for screening cannot commence enrollment study procedures until the 
informed consent process and form 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 at least 7 days apart. 
The Investigator or designee will enter data for each enrolled participant in the study electronic 
case report form (eCRF) and enter the corresponding participant ID number in the appropriate 
place on each participant’s eCRF. 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 study and complete treatment as 
specified be permitted to re-enroll in the study. 
During the COVID-19 pandemic, the Sponsor will need to assess the feasibility of implementing 
a plan for participant access to study drug and any additional measures required to monitor 
participant safety on an ongoing basis. Please notify the Sponsor and your contract research 
organization (CRO) study monitor if your site suspends participant enrollment. 
7.3. 
Temporary Discontinuation  
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs or disruption of the clinical trial due to a regional or national emergency declared 
by a governmental agency. For all temporary intervention discontinuations, duration should be 
recorded by the Investigator in the appropriate pages of the CRF or eCRF. The Investigator 
should make the best effort to resume the IMP as early as clinically and practically possible. All 
efforts should be made to follow the study procedures as per the SoAs during temporary 
disruption of study medication. 
Temporary discontinuation decided by the Investigator corresponds to a period of >2 missed 
consecutive doses of IMP. 
7.4. 
Rechallenge  
Reinitiation of the IMP will be done under close and appropriate clinical and/or laboratory 
monitoring once the Investigator will have considered according to his/her best medical IMP 
judgment that the benefit/risk balance is in favor of resuming the IMP and if the selection criteria 
for the study are still met. 
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7.5. 
Participant Exit from the Study  
7.5.1. 
Individual Participant Stopping Rules  
• Life-threatening or Common Terminology Criteria for Adverse Events (CTCAE) Grade 
4 rilzabrutinib-related TEAE except for AEs related to the disease under study or other 
underlying medical conditions 
• Serious allergic reaction to rilzabrutinib or placebo including anaphylactic reaction 
• Pregnancy 
• Any medical condition or personal circumstance that, in the opinion of the Investigator, 
exposes the participant to risk if the participant continues with rilzabrutinib or placebo or 
that prevents the participant’s adherence to the protocol 
• Human immunodeficiency virus/acquired immune deficiency syndrome (AIDS), viral 
hepatitis (B and C) infection occurring during the study 
• Violation of protocol inclusion or exclusion criteria, that in the opinion of the Sponsor, 
would significantly compromise data interpretation 
• Discontinuation of study intervention for abnormal liver tests is required by the 
Investigator when a participant meets one of the conditions outlined in Appendix 15 or in 
the presence of abnormal liver chemistries not meeting protocol-specified stopping rules 
if the Investigator believes that it is in best interest of the participant.  
No follow-up or additional procedures will be performed on participants who discontinue before 
receiving rilzabrutinib or placebo. For participants who discontinue after receiving any amount 
of rilzabrutinib or placebo, the reason for a participant’s discontinuation from the study must be 
clearly documented in the participant’s medical records and on the appropriate page of the eCRF, 
and participants will be asked to complete the ET assessments (see Table 1, Table 2 and 
Table 3). 
7.5.1.1. 
Individual Long-term Extension Participant Stopping Rules  
Participants may be withdrawn from the study if the participant is no longer responding 
according to the table below: 
 
Time in the Long-Term Extension (LTE) 
“No response” platelet counts defined as <30,000/μL or 
<20,000/μL above baseline based on: 
During the first 12 months in the LTE 
2 consecutive monthly visits 
After the first 12 months in the LTE 
1 quarterly visit 
In this case a second platelet count has to be obtained in one 
month to confirm lack of response. If the platelet count met 
the no response criteria, the participant may be terminated. 
 
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7.5.2. 
Participant Withdrawal  
All participants have the right to withdrawal of consent and discontinue participation without 
prejudice at any time during the study. Every effort should be made to comply with the protocol; 
however, participants will be withdrawn from the study entirely with no further study visits if 
any of the following situation arise: 
• Withdrawal of participant’s consent or participant’s request to discontinue from the study 
for any reason 
• The participant is unwilling or unable to comply with the protocol 
Participants who are withdrawn from the study will not be replaced. The reason for the 
participant’s withdrawal from the study should be recorded on the eCRF.  
7.5.3. 
Participant Lost to Follow-up  
At the start of the study, the Investigator should try to obtain all relevant contact details for the 
participant to facilitate contacting the participant, if necessary. In addition, each participant 
should be encouraged to attend all study visits for which the participant is scheduled. 
If a participant discontinues the study without notifying the Investigator, the Investigator must 
make every effort to contact the participant to identify the reason for the participant’s 
discontinuation and to encourage the participant to complete the applicable ET visit assessments 
(see Table 1, Table 2 and Table 3). If documented attempts to contact the participant fail, and a 
reason for the participant’s discontinuation is undiscoverable, the Investigator can declare the 
participant 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 participant. 
7.6. 
Study Stopping Rules  
Study stopping rules will include but not be limited to: 
• More than one rilzabrutinib-related death 
• Two or more life-threatening or CTCAE Grade 4 rilzabrutinib-related TEAEs except for 
AEs related to the disease under study (lack of efficacy) 
• The Sponsor elects to stop the study. 
7.7. 
Sponsor Study 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 participants 
• Participant enrollment is unsatisfactory, and the Sponsor wishes to stop the study 
• New scientific knowledge or other conditions place study participants at undue risk by 
continuing in the study 
• If the Data Safety Monitoring Board (DSMB) recommends study termination due to 
safety reasons. 
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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. 
7.8. 
Visit Overview  
During the study, participants 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, and PK 
assessment. 
Study procedures and activities will occur at each visit as specified in Table 1, Table 2 and 
Table 3. 
During the COVID-19 pandemic, remote (eg, telephone call, video call) study visits may be 
performed when a participant is not able to travel to the site or the site cannot host a participant 
visit. Procedures to be performed during remote site visits are described in “Guidelines to Sites 
for Delayed Participant Visits or Missed Visits due to travel restrictions and any foreseeable 
impacts of COVID-19” (Appendix 8). 
7.8.1. 
Screening (Day -28 to Study Day -1 Predose)  
Informed consent will be obtained at Screening before performing any study procedures. 
Participants will undergo screening assessments, including, but not limited to blood sampling, 
ECG, clinical assessment and various QOL assessments. Please refer to Table 1. 
Medical history and demographic data, including sex, age, race, body weight (kg), and 
height (cm), will be recorded. 
7.8.2. 
Baseline Study Day 1  
Participants will undergo baseline assessments shown in Table 1. The first dose of rilzabrutinib 
or placebo will be administered after all predose procedures on Day 1 have been completed. 
Participants aged 18 and older will remain in the clinic for 2 hours post-dose for a 2-hour blood 
collection. Pediatric participants will remain in the clinic for 6 hours post-dose for a 6-hour blood 
collection. 
7.8.3. 
Blinded Treatment Period (Weeks 1 to 25)  
Please refer to Table 1 for specific assessments at each visit. 
7.8.4. 
Open Label Period (Weeks 25 to 53)  
Please refer to Table 2 for specific assessments at each visit. 
7.8.5. 
4 Week Post-Dose Follow-up Period (Weeks 53 to 56 or any 4-week period 
following the End of Treatment visit)  
Please refer to Table 2 for specific assessments for the EOS Visit. 
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7.8.6. 
Early Termination Visit  
Please refer to Table 1 (if terminating during double-blind treatment) and Table 2 (Open-Label 
Period) for specific ET assessments. An attempt should be made to have the participant return for 
the ET visit as soon as possible after the last dose of rilzabrutinib or placebo. 
7.8.7. 
Long-Term Extension (LTE)  
Please refer to Table 3 for specific LTE assessments. 
7.9. 
Study Assessments  
All study assessments will be collected as outlined at the visits noted in Table 1, Table 2 and 
Table 3. 
7.9.1. 
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 assessed at Screening only for participants aged 18 and older. Height is assessed at 
Screening, Week 13, 25, 37 and 53 (last day of study drug treatment) for pediatric participants. 
Height is recorded in cm. 
7.9.2. 
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, GI, and 
pulmonary assessments. 
A licensed physician or nurse practitioner (or equivalent) will examine each participant. 
Physical examination may be performed at various unscheduled time points if deemed necessary 
by the Investigator. 
See Appendix 10.6 for Italy-specific requirements. 
7.9.3. 
Medical History  
Medical history will be recorded at Screening and include a history of all underlying medical 
conditions within the last 10 years as well as a detailed ITP history (separate disease history Case 
Report Form). 
7.9.4. 
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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7.9.5. 
Electrocardiogram (ECG) Monitoring  
Single 12-lead ECGs will be performed at Screening, Study Day 1, Week 25, Week 29, first day 
of Week 53, and at 4-weeks post-last dose. Electrocardiogram will be performed with the 
participant in a supine position. ECGs will not be performed at weekly lab visits between clinic 
visits (see Table 1 and Table 2). 
Unscheduled ECGs may be performed as deemed necessary by the Investigator. 
7.9.6. 
Clinical Laboratory Tests  
See Table 1, 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. 
The Laboratory Manual will supply complete written instructions for collection, handling, 
processing, storage, and shipping of samples. 
7.9.7. 
Pharmacokinetic Assessments  
Plasma samples will be obtained for PK characterization of rilzabrutinib as outlined in the SoA 
(see Table 1 and Table 2). If applicable, residual plasma samples could be utilized to assess PK 
of relevant metabolites of rilzabrutinib (eg, PRN834 & PRN4400). Concentrations at each time 
point will be reported. 
Pharmacokinetic samples could be used for testing analytical method performance such as 
comparability. 
Details regarding the collection, handling, processing, storage, and shipping of samples are 
provided in the Laboratory Manual. 
7.9.8. 
Bruton’s Tyrosine Kinase (BTK) Occupancy  
Blood samples will be collected at timepoints for rilzabrutinib concentration levels (BTK 
occupancy) per the SoA in Table 1 and Table 2. See Appendix 10 for country-specific 
requirements. 
Details regarding the collection, handling, processing, storage, and shipping of samples are 
provided in the Laboratory Manual. 
7.9.9. 
Vaccine IgG (optional)  
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 or 
placebo at the time of scheduled vaccination. Participants may receive vaccines for influenza, 
COVID-19, and tetanus (alone or in combination). Live attenuated vaccines are excluded. 
Participants scheduled to receive any of the aforementioned vaccines, especially a COVID-19 
vaccine, during the study periods may volunteer, after documenting informed consent, to provide 
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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. The collection of samples for the optional 
IgG assessment is applicable to both the blinded and open-label periods (See the SoA). Dates of 
vaccination, disease, brand name of vaccine product and antigenic strain should be recorded in 
the eCRF. Additional details are provided in the Laboratory Manual. See Appendix 10 for 
country-specific requirements. 
7.9.10. 
Immune Thrombocytopenia (ITP) Assessment Tools (IBLS, ITP-PAQ, 
ITP-KIT)  
Immune Thrombocytopenia Bleeding Scale (IBLS) 
The IBLS is a bleeding assessment system comprising 11 site-specific grades from 0 (none) to 2 
(marked bleeding) assessed at nine anatomical sites by history over the previous period (Hx) 
(Page LK 2007). In addition, two of these sites, skin and oral, were also assessed by physical 
examination. The ‘worst ever’ bleeding experienced at each site was graded using the same 
system. Refer to Appendix 1 for further details. 
Immune Thrombocytopenia Patient Assessment Questionnaire (ITP-PAQ) 
The ITP Patient Assessment Questionnaire™ (ITP-PAQ™) is a disease-specific instrument that 
was designed to measure the QOL of adult participants with immune thrombocytopenia. It is 
licensed for use in clinical studies through the Platelet Disorder Support Association. The 
instrument comprises 38 items completed by male respondents and 44 items completed by 
female respondents (Mathias 2007). The greater number of items for female respondents is due 
to additional questions dealing with the impact of ITP on the domains of women’s reproductive 
health, menstrual symptoms, and fertility. The shared domains are Activity, Bother, Fatigue, 
Fear, QOL, Psychological, Social activity, Symptoms and Work. The items employ a 4-week 
recall with responses recorded on 4-, 5- or 7-point Likert scales. All item scores are transformed 
to a 0 to 100 continuum where higher scores represent better QOL and are weighted equally to 
derive the scale scores. Refer to Appendix 2 for an example of the copyrighted scale. 
Treatment of ITP is intended to increase platelet counts to a hemostatic range, to decrease the 
risk of bleeding; it also seeks to ameliorate the associated reductions in health-related quality of 
life (HRQOL) (Provan 2019).  A recent survey (I-WISh) of 1507 participants from 13 countries 
showed that fatigue was one of the most frequent patient-reported symptoms at diagnosis (58%) 
and especially at survey completion (50%) (Cooper 2021). These results complete the findings 
issued from 3 focus groups (Mathias 2008) and confirmed the importance of fatigue in ITP. The 
I-WISh study recruited non-hospitalized adult ITP participants. As the participants in Study 
PRN1008-018 should be intolerant or show insufficient response to any appropriate courses of 
standard of care ITP therapy and should have low platelet counts (<30,000/µL), the Sponsor 
anticipates a high burden of fatigue in its study population. 
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KIDS’ ITP-KIT 
The ITP-KIT include a battery of three disease-specific instruments, a child self-report form 
designed to be completed by children ≥7 years, a parent proxy report form for children <7 and a 
parent impact form (Mathias 2016). The child self-report form is being used in this clinical 
study. It has a total of 26 items which are structured as Likert scales with five response options 
(never, seldom, sometimes, often, always). Respondents record their disease experience based on 
a 1-week recall. The instrument yields a total score which is the summation of the items 
converted to a 0 to 100 score with higher scores indicating better disease specific QOL. Refer 
to Appendix 3 for an example of the copyrighted scale. 
7.9.11. 
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 (Feng 2015, 
EuroQOL Group 1990). 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 4 for an example of the copyrighted scale. 
7.9.12. 
Patient Global Impression of [Fatigue] Severity (PGIS-Fatigue) Scale  
The PGIS-Fatigue is a single item generic patient response outcome (PRO) measure that asks the 
respondent to rate the severity of their disease-related fatigue over the past week. The item is 
constructed as a Likert scale on which respondents are asked to select the best response option 
describing the severity of their symptoms from None, Mild, Moderate, Severe and Very severe 
(Appendix 5). 
7.9.13. 
Patient Global Impression of Severity (PGIS) Scale  
The PGIS is a single item generic PRO measure that asks the respondent to rate the severity of 
their disease-related symptoms over the past week. The item is constructed as a Likert scale on 
which respondents are asked to select the best response option describing the severity of their 
symptoms from None, Mild, Moderate, Severe and Very severe (Appendix 5). 
7.9.14. 
Patient Global Impression of Change (PGIC) Scal  
The PGIC is a single item generic PRO measure on which the respondent assesses the degree to 
which their symptoms during the past week compared to what they experienced before initiating 
the study medication. PGIC is a commonly used method of assessing clinically important 
change. The Likert response options for this question allow for reports ranging from significant 
symptom improvement or significant symptom worsening (ie, Very much better, Moderately 
better, A little better, No change, A little worse, Moderately worse, Very much worse), 
Appendix 5. 
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7.9.15. 
Use of biological samples and data for future research  
Future research may help further the understanding of disease and the development of new 
medicines. Reuse of coded data and biological samples (leftover and additional) collected as part 
of the study will be limited to future scientific research conducted under a research plan for the 
purpose of diagnosing, preventing or treating diseases. The future research projects will be 
conducted under the Sponsor’s and/or its affiliates’ and/or, if applicable, the partner of the 
Sponsor which has licensed the study drug to the Sponsor or which is co-developing the study 
drug with the Sponsor’s control, acting alone or in collaboration with research partners such as 
universities, research institutions or industrial partners with whom the coded study data may be 
shared.  
Coded study data and biological samples will be stored and used for future research only when 
consented to by participants (see Section 12.2) and, when applicable, further information on the 
future research has been provided to the study participant, unless prohibited by local laws or 
IRBs/IECs (in such case, consent for future use of data/sample will not be included in the local 
ICF). The conditions for reuse will be adapted locally with the appropriate language in the ICF. 
In any case, a specific consent will be collected for the performance of genetic analyses on 
leftover and/or additional samples.  
 
Data protection – Processing of coded study data  
 
The study participant will be provided with all mandatory details of the data processing in the 
ICF.   
The Sponsor adopts safeguards for protecting participant confidentiality and personal data (see 
Section 13.5). 
 
Use of leftover samples and additional samples for future research 
 
Remaining leftover samples of adults and pediatric populations will be used only after the end of 
the blinded treatment period of each group, ie, end of the blinded period as defined in the study 
protocol. Additional/extra samples can be collected and used during the study conduct at a given 
timepoint (eg, at randomization visit) as defined in the study protocol. 
 
The study participant will be provided with all mandatory details of the use of the human 
biological samples (leftover and additional) in the ICF. 
 
Study participant data will be stored for up to 25 years for regulatory purposes. Biological 
samples for future use will be stored for up to 25 years after the end of the study unless local 
regulations require a different retention period. Any samples remaining at the end of retention 
period will be destroyed. If a participant requests destruction of his/her samples before the end of 
the retention period, the Investigator must notify the Sponsor (or its contract organization) in 
writing. In such case, samples will be destroyed and related coded data will be anonymized 
unless otherwise required by applicable laws.  
See Appendix 10 (Appendix 10.5) for China-specific requirements. 
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7.9.16. 
Medication errors or misuses of medicinal product  
All reports of medication error or misuse in relation to the IMP with or without an AE must be 
recorded on the corresponding page(s) of the CRF and transmitted to the Sponsor’s 
representative following standard processes.  
A medication error is an unintended failure in the drug treatment process (ie, mistake in the 
process of prescribing, storing, dispensing, preparing, or administering medicinal products in 
clinical practice) that leads to, or has the potential to lead to harm to the participant. This 
includes situations in which a participant was involved or not (eg, even if the error was 
recognized and intercepted before the participant received or used the product), and whether it 
resulted in harm to the participant or not. 
A misuse refers to situations where the medicinal product is intentionally and inappropriately 
used, ie, not in accordance with the terms of the marketing authorization or outside what is 
foreseen in the protocol, by the participant for a therapeutic purpose.   
Of note, if a medication error or misuse meets the protocol definition of an overdose, it will be 
recorded in the overdose page of the CRF. 
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8. 
ASSESSMENT OF EFFICACY  
8.1. 
Specification of the Efficacy Parameters  
Clinical assessments will include physical examination; assessment of vital signs, height, and 
weight; 12-lead ECG, collection of medical history, collection of concomitant medication 
information, assessment of bleeding with IBLS and/or other bleeding scales, QOL 
questionnaires, collection of AEs 
Laboratory assessments will include hepatitis B and C, pregnancy test, FSH, urinalysis, ABO 
and Rh, hemolysis panel (Coombs and haptoglobin), mean platelet volume, serum chemistry, 
hematology, platelet counts, PT/INR, TPO level, PK sampling, T/B/NK count, Immunoglobulin 
levels, BTK occupancy (at select sites), and optional vaccine IgG levels. 
A summary of efficacy parameters is provided in Section 3.2. A review of study assessments is 
provided in Section 7.9. See Appendix 10 for country-specific requirements. 
8.2. 
Methods and Timing for Assessing, Recording, and Analyses of Efficacy Parameters  
Methods and timing for assessing, recording, and analyzing of efficacy parameters are provided 
in Table 1, Table 2, Table 3 and Section 7.9. 
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9. 
ASSESSMENT OF SAFETY  
9.1. 
Overview  
After a comprehensive baseline evaluation, the safety of the participants will be monitored by 
assessment of vital signs, laboratory tests (hematology, urinalysis, and chemistry), disease 
assessments, 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 participant should then be followed-up until the condition resolves or becomes 
chronic or stable. 
Study stopping criteria are discussed in Section 7.6 and individual stopping criteria in 
Section 7.5. 
9.2. 
Data Safety Monitoring Board (DSMB)  
An independent DSMB will regularly review and evaluate unblinded participant safety data 
including reported 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 participant 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 Study Master File. DSMB findings that impact the safety of participants in this 
study 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 the DSMB charter.  
9.3. 
Adverse Events (AEs)  
9.3.1. 
Adverse Event Collection Period  
The AE Collection Period begins at the signing of the ICF and ends at the end of the study for 
each participant. 
During the COVID-19 pandemic, if a participant is not able to travel to the site or the site cannot 
host a participant visit AEs will be collected during phone or video calls and recorded in the 
electronic data capture (EDC) system as described in the “Guidelines to Sites for Delayed 
Participant Visits or Missed Visits due to travel restrictions and any foreseeable impacts of 
COVID-19” (Appendix 8). 
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9.3.2. 
Adverse Events  
An AE is any untoward medical occurrence in a participant or clinical investigation participant 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with the intervention. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of an IMP, 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 eCRF, 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 ITP disease activity itself. 
Unexpected progression, signs, or symptoms of the disease under study (ITP) are not AEs and 
are not to be recorded on the AE page of the eCRF unless the event meets the definition of an 
SAE or is not consistent with the typical clinical course of the participant’s disease as established 
by the participant’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. 
Definitions: 
The below guidelines should be followed when recording AEs: 
• Medical terms: Whenever possible, use recognized medical terms when recording AEs on 
the AE eCRF. Do not use colloquialisms or abbreviations. 
• Diagnosis: If known or suspected, record the diagnosis (except for eg, hypoglycemia) 
rather than component signs and symptoms on the AE eCRF 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 eCRF 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 eCRF 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 participant’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 
study, only worsening (increased frequency or intensity of the episodes or attacks) will be 
documented as an AE. If the disease is detected during the study, and if repeated episodes 
enable diagnosis of a chronic disease, the episodes will be grouped together in the eCRF, 
and the diagnosis will be clearly described. 
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• 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 eCRF. These conditions are 
considered part of the participant’s medical history and must be adequately documented 
on the appropriate page of the eCRF. Day-to-day fluctuations of pre-existing disease 
should not be recorded as an AE on the AE eCRF. 
• Disease under study (ITP): 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 eCRF unless 
the event meets the definition of an SAE or is not consistent with the typical clinical 
course of the participant’s disease as established by the participant’s medical history. 
Worsening of the disease under study or other disease-related symptoms should be 
recorded as an AE only if the event meets the definition of an SAE or is not consistent 
with the typical clinical course of the disease. 
• Laboratory abnormalities: An isolated, out-of-range laboratory result in the absence of 
any associated, clinical finding may or may not be considered an AE; the Investigator’s 
evaluation should be based on a consideration of the overall clinical context. 
• 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 (within 72 hours for ALT increased), and the 
participant 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  
9.3.3. 
Adverse Event Intensity Grading  
All clinical AEs encountered during the clinical study will be reported on the AE page of the 
eCRF. Intensity of AEs will be graded based on a modified CTCAE, Version 5.0 and reported in 
detail as indicated on the eCRF. For any AEs not found in the CTCAE, a description of intensity 
grading can be found in Appendix 12 and 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 a Grade 5 severity - rather the underlying condition will be 
recorded, and its severity graded, with death regarded as an outcome. 
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9.3.4. 
Adverse Event Relationship to Study 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 any study drug (eg, 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 study medication, or reintroduction of rilzabrutinib or placebo (if applicable) 
• Known association of the event with rilzabrutinib or placebo or with similar treatments 
• Known association of the event with the disease under study 
• Presence of risk factors in the study participant or use of concomitant medications known 
to increase the occurrence of the event 
• Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
9.3.5. 
Adverse Event Relationship to Standard of Care 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 their standard of care medication (eg, CSs or TPO-RA), 
indicating "yes" or "no" accordingly. For this study standard of care medications may only be 
reduced due to a safety concern (eg, a corresponding AE). 
9.3.6. 
Treatment Unblinding to Determine Clinical Course  
If deemed by the Investigator to be medically necessary in the event that a SUSAR occurs, to 
determine appropriate clinical treatment, the Investigator can unblind an individual participant 
via the IWRS after consultation with Sponsor medical monitor. See Appendix 10 for UK 
country-specific requirements. 
Instructions for Investigators to unblind are located in the Investigator Site File. 
9.3.7. 
Treatment and Follow-Up of Adverse Events (AEs)  
Adverse events, especially those for which the relationship to 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 eCRF. 
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9.3.8. 
Laboratory and Electrocardiogram (ECG) Abnormalities  
Laboratory test results will appear on electronically produced laboratory reports or be recorded 
on the laboratory results pages of the eCRF 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 eCRF: 
• Accompanied by clinical symptoms 
• Leading to a change in rilzabrutinib or placebo (eg, dose 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 eCRF. 
9.3.8.1. 
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, no later than 72 hours after reporting of the results and should be 
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 eCRF. 
9.3.9. 
Adverse events (AEs), Serious Adverse Events (SAEs) and Other Safety 
Reporting  
The definitions of AEs and SAEs can be found in Appendix 12. The definition of adverse event 
of special interest (AESI) is provided in Section 9.3.9.6. 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant’s legally authorized representative) that meet the definition of an AE or SAE and 
remain responsible for following up AEs, particularly those that are serious, considered related to 
the study intervention or study procedures, or that caused the participant to discontinue the study 
intervention or study (see Section 7.5). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 12. 
9.3.9.1. 
Time period and frequency for collecting AE and SAE information  
All AEs (serious or nonserious) will be collected from the signing of the ICF until the follow-up 
visit at the time points specified in the SoA (Table 1, Table 2, and Table 3). 
All AEs will be collected from the signing of the ICF at the time points specified in the SoA 
(Table 1, Table 2, and Table 3). 
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All SAEs and AESIs will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 12. The 
Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being 
available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator must promptly 
notify the Sponsor. 
9.3.9.2. 
Method of detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
9.3.9.3. 
Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. At the pre-specified study end-date, all SAEs, and other 
AEs, will be followed until resolution, stabilization, the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.5.3). Further information on follow-up 
procedures is provided in Appendix 12. 
9.3.9.4. 
Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and Investigators. 
• Serious adverse events that are considered expected will be specified in the reference 
safety information in the Investigator’s Brochure.  
• Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing an SAE, SUSAR or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. It is the responsibility of the 
Sponsor to assess whether an event meets the criteria for a SUSAR, and therefore, is 
expedited to regulatory authorities. 
• For the European Union, safety reporting to the agency is described in Appendix 10.7. 
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9.3.9.5. 
Pregnancy  
• Details of all pregnancies will be collected after the start of study intervention and until 
28 days after the last dose of study intervention. 
• If a pregnancy is reported after the first dose of the IMP, the Investigator will record 
pregnancy information on the appropriate form and submit it to the Sponsor within 
24 hours of learning of the pregnancy. 
• 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. 
• The participant/pregnant female partner will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the 
participant/pregnant female partner and the neonate, and the information will be 
forwarded to the Sponsor. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in 
Appendix 12. While the Investigator is not obligated to actively seek this information in 
former study participants/pregnant female partners, he or she may learn of an SAE 
through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study must 
discontinue study intervention or be withdrawn from the study. 
9.3.9.6. 
Adverse events of special interest  
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification (within 
24 hours) by the Investigator to the Sponsor is required. Such events may require further 
investigation in order to characterize and understand them. Adverse events of special interest 
may be added, modified. or removed during a study by protocol amendment; they include: 
• Pregnancy of a female participant entered in a study and received at least one dose of the 
IMP as well as pregnancy occurring in a female partner of a male participant entered in a 
study with IMP; 
- 
Pregnancy occurring in a female participant entered in the clinical trial or in a female 
partner of a male participant entered in the clinical trial will be qualified as an SAE 
only if it fulfills one of the seriousness criteria (see Appendix 12). 
- 
In the event of pregnancy in a female participant, IMP must be discontinued. 
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined (See Appendix 13). 
• Symptomatic overdose (serious or nonserious) with IMP 
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• Increase in ALT >3 × ULN (See Appendix 15 for follow-up instructions). If such 
laboratory values have been determined, follow-up within 72 hours of the same value and 
total bilirubin levels is required and if value is repeated (eg, ALT >3 × ULN), such value 
shall be reported as well together with the repeated total bilirubin values and any other 
laboratory values to determine the cause of the initially determined ALT increase. 
• Any Grade 4 or 5 infection where the participant is hospitalized ≥24 hours and/or 
requires emergency care and/or requires intravenous antibiotics. 
• Any occurrence of uveitis (including Vogt‐Koyanagi‐Harada disease [VKHD])  
9.3.9.7. 
Guidelines for reporting product complaints  
Any defect in the IMP must be reported as soon as possible by the Investigator to the monitoring 
team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related 
to product identification and to the potential deficiencies may need to be gathered. The 
Investigator will assess whether or not the quality issue has to be reported together with an AE or 
SAE. 
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10.
STATISTICAL METHODS
A detailed Statistical Analysis Plan (SAP) will be developed and finalized before the study 
database is locked which will supersede the statistical analysis methods described in the 
protocol; however, any major modification of the outcome measures and/or its analysis will also 
be reflected in the clinical study report (CSR). 
Descriptive summaries of variables by treatment will be provided where appropriate. Generally, 
continuous variables will be summarized using the following descriptive statistics: mean, 
standard deviation, 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. 
All statistical tests will be two-sided unless otherwise noted. 
The pediatric participants will not be tested, and descriptive statistics will be done on these 
participants. Additional statistical analyses on these pediatric participants may be provided for 
specific regulatory requests. 
10.1. Determination of Sample Size 
The adult sample size chosen for this study was selected to achieve enrollment of 129 adult 
participants (≥18 years) on rilzabrutinib and 65 adult participants on placebo. The pediatric 
sample size of up to 30 participants (20 participants on rilzabrutinib and 10 participants on 
placebo) was determined based on clinical practice and is adequate to descriptively describe the 
safety and efficacy in pediatric participants. With a sample size of 20 pediatric participants on 
rilzabrutinib the maximum width of an exact 90% CI on response rate would be 40%. 
A sample size of approximately 194 (129 versus 65 adult participants in the rilzabrutinib versus 
placebo arms, respectively) will provide 95% power to detect a 20% difference in response rates 
as defined in the primary endpoint (Section 3.2.1) between the 2 arms (25% vs 5%, in the 
rilzabrutinib versus placebo arms, respectively), using the Fisher’s Exact test with a 
0.05 two-sided significance level. 
The assumption of a 25% response rate in the rilzabrutinib group is based on the Phase 1/2 study 
PRN1008-010 Part A (DFI17124 Part A) (durable response [8 out of the last 12 weeks with 
platelet count at or above 50,000/μL in the absence of rescue medication]) and the 5% response 
rate is estimated based on the observed placebo response in previous randomized controlled trials 
of ITP medications (Bussel 2018). The participants who are not evaluable for primary efficacy 
due to dropout or missing data will be considered as non-responders. 
10.2. Objectives and Endpoints 
Please refer to Section 3. 
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10.3. Analysis Populations  
10.3.1. 
Safety Population  
All participants who are randomized and 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. Participants will be analyzed according to the treatment they actually received, not 
necessarily the treatment they were allocated to at randomization. Results for the blinded 
treatment period will be presented “as treated.” Further details will be provided in the SAP on 
how data collected during the open-label period will be analyzed. 
10.3.2. 
Intent-to-Treat (ITT) Population  
All participants who are randomized will be included in the intent-to-treat (ITT) Population. The 
ITT Population will be used for efficacy analysis. Participants 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.” 
10.3.3. 
Modified ITT (mITT) Population  
All participants who are randomized and receive at least one dose of study medication will be 
included in the mITT Population. The mITT Population may be used for sensitivity analysis. 
Participants 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.” 
10.3.4. 
Pharmacokinetic (PK) Population  
All participants who receive at least one dose of study medication in the safety population and 
have sufficient data for PK analysis will be included in the PK population. 
10.3.5. 
Disposition of the Study Participants  
The disposition of participants will be described with summaries of the number of participants 
treated and discontinued from the study, including the primary reason for premature 
discontinuation. 
10.3.6. 
Demographic and Baseline Characteristics  
Summaries of participant disposition, demographics, and baseline characteristics will be 
provided by treatment group.  
Demographic and baseline characteristics (age, sex, race, ethnicity, weight, height, and body 
mass index) will be summarized using descriptive statistics. No formal statistical analyses will be 
performed, and no inferential statistics reported. 
10.3.7. 
Exposure to Study Treatment  
The number of received doses will be summarized by treatment group. Treatment duration and 
compliance for all participants will be described. 
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10.3.8. 
Safety and Tolerability Analysis  
Safety will be assessed by the incidence, severity, and relationship of TEAEs, including 
clinically significant changes in physical examination, laboratory tests, ECG, clinical laboratory 
test results, and vital signs. AEs will be categorized as treatment-emergent after the first dose of 
rilzabrutinib has been administered. 
The nature, frequency, and severity of AEs, including AESIs, SAEs, and AEs leading to 
discontinuation will be summarized descriptively by treatment group. AEs possibly related to 
protocol allowed ITP concomitant medications, TPO- RAs and CS, will be grouped and analyzed 
separately in addition to the above. 
A by-participant TEAE data listing, including verbatim term, preferred term, and system organ 
class (SOC), treatment, relationship to the study drug and intensity (severity) will be provided. 
The number of participants experiencing AEs and number of AEs will be summarized by 
treatment group using frequency counts. 
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. 
AEs 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 study data available at the Sponsor or designee. 
Concomitant medications will be coded using the most current World Health Organization 
(WHO) drug dictionary and the version will not change through completion of study data 
available at the Sponsor or designee. 
10.3.9. 
Primary Efficacy Analysis  
The primary analysis will compare the proportion of participants in the adult ITT population who 
achieve durable platelet response defined as platelet counts at or above 50,000/μL for ≥ two-
thirds of at least 8 non-missing weekly scheduled platelet measurements during the last 12 weeks 
of the 24-week blinded treatment period in the absence of rescue medication (provided that at 
least 2 non-missing weekly scheduled platelet measurements are at or above 50,000/μL during 
the last 6 weeks of the 24-week blinded treatment period) between rilzabrutinib and placebo with 
a Cochran-Mantel-Haenszel test using the two stratification factors at a 2-sided alpha level of 
0.05 (see Appendix 10.7 for a description of the primary efficacy analysis in the EU [EEA 
countries] and UK). Participants who do not respond in the first 12 weeks and enter the 
open label period will be treated as non-responders in the primary analysis. Participants who 
discontinue the study due to a rilzabrutinib-related AE lack of efficacy or receive rescue 
medication (including an increase in allowed concomitant ITP medications dose) will be 
considered as non-responders. Sensitivity analyses will be conducted on the primary analysis.  
The primary endpoint will be analyzed for adult and pediatric participants separately. 
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Platelet counts conducted locally will be used for the primary endpoint analysis. Platelet counts 
conducted centrally at Clinic Visits will be used as a back-up for missed or non-analyzable local 
lab samples. 
10.3.10. 
Key Secondary Efficacy Analysis  
Multiplicity of the secondary analysis will be adjusted to control the overall type I error. Key 
secondary efficacy endpoints will be tested sequentially. The following five comparisons will be 
conducted between rilzabrutinib and placebo using sequential (hierarchical) testing with a fixed 
sequence as listed below, which controls the family-wise error for multiple comparisons at alpha 
level of 0.05 (two-sided): 
• Compare the number of weeks with platelet count ≥50,000/μL OR between ≥30,000/μL 
and <50,000/μL and at least double from baseline over the 24-week blinded treatment 
period (platelet counts will be censored for 4 weeks after the use of rescue therapy, if 
any) 
• Compare the number of weeks with platelet counts ≥30,000/μL and at least double from 
baseline over the 24-week blinded treatment period in the absence of rescue therapy 
• Compare time to the first platelet count ≥50,000/μL OR between ≥30,000/μL and 
<50,000/μL and at least double from baseline 
• Compare the proportion of participants requiring rescue therapy during the 24-week 
blinded treatment period  
• Compare the change from baseline on Item 10 of the ITP-PAQ (ie, physical fatigue) in 
adult participants at Week 13 
See Appendix 10.7 for EU (EEA countries) and UK-specific requirements. 
10.3.11. 
Other Efficacy Analysis  
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 analyses include the following: 
• Estimate the predictive value of platelet count for each of the three predictors separately 
or in combination: 
- 
≥30,000/μL on Study Day 8 
- 
≥20,000/μL above baseline on Study Day 8 
- 
≥50,000/μL at any time over first 8 weeks of the treatment period to achieve the 
primary endpoint 
10.3.12. 
Pharmacokinetic (PK) Analysis  
Plasma concentrations of rilzabrutinib (and metabolites, if applicable) in participants will be 
evaluated in each participant based on sampling at varied timepoints. Individual and group PK 
data will be summarized by descriptive statistics for each visit where measured. 
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Exploratory analyses will employ the use of nonlinear mixed effects (population PK) modeling 
to evaluate these data in combination with the data from other studies of rilzabrutinib. 
Exploratory analyses will also be conducted to evaluate potential relationships between PK and 
PD, safety, and efficacy endpoints. The results of these analyses may be reported outside of the 
main CSR. 
10.3.13. 
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. Full 
details will be provided in the SAP. 
10.3.14. 
Missing Data  
Details on the handling of missing data will be described in the SAP. 
10.4. Interim Analysis  
No formal interim analysis is planned for the double-blind part of the study. 
The enrollment of adult population is expected to be completed earlier than that of the pediatric 
population. Thus, an early analysis may be performed with the cutoff when the last adult 
participant has completed the blinded treatment period. As the primary analysis for the study is 
based on the adult population, the results at the early analysis will be considered as final and 
served as basis for regulatory submissions. In case of similar enrollment, the analyses on both 
adult and pediatric populations will be performed at the same time when they have completed the 
blinded treatment period and the primary analysis on efficacy will be based on the adult 
population. 
Final analysis will be performed at the completion of the study. Additional analyses (eg, Open 
Label and LTE parts) may be performed at the Sponsor’s discretion for purposes of regulatory 
filings, publications, or future planning after the early analysis without α adjustment. 
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11. 
INVESTIGATOR RESPONSIBILITIES  
By signing the separate Protocol and amended protocol agreement form, the Investigator agrees 
to do the following: 
1. 
Conduct the study 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 participants 
2. 
Comply with the E6 International Conference on Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable Food and Drug 
Administration (FDA) Codes of Federal Regulations (CFRs) 
3. 
Personally conduct or supervise the described investigation 
4. 
Inform any participants, 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 Institutional 
Review Board/Independent Ethics Committee (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 ICH Tripartite Guideline on GCP and any local 
regulations 
7. 
Have read and understood the Investigator’s Brochure, including potential risks and side 
effects of the drug 
8. 
Ensure that all associates, colleagues, and employees assisting in the conduct of the study 
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 E6 ICH 
Tripartite Guideline on GCP 
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 participants or others 
12. Not make any changes in the research without IRB/IEC approval, except where necessary 
to eliminate apparent immediate hazards to human participants 
13. Comply with all other requirements regarding the obligations of Investigators and all 
other pertinent requirements 
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12. 
DATA QUALITY ASSURANCE  
The overall procedures for quality assurance of clinical study data, including data collection and 
management, will be described in the Data Management Plan. 
Accurate and reliable data collection will be assured by verification and cross-check of the eCRF 
against the Investigator’s records by the study monitor (source document verification), and the 
maintenance of Drug Accountability (see Section 6.4.1) by the Investigator. 
Data for this study will be recorded in the study EDC eCRFs. The data will be entered by the 
study center from the source documents into the eCRF or will be loaded from other files (eg, 
safety lab data). In no case is the eCRF to be considered as source data for this study. 
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. 
12.1. Protocol Amendments and Study 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 study participants, or when the change(s) involves 
only logistical or administrative aspects of the study (eg, change in monitor(s), change of 
telephone number(s)). 
The Sponsor reserves the right to terminate the study, according to the Clinical Study 
Agreement. 
Study completion is deﬁned as the date when all participants have completed the ﬁnal study visit, 
and the study database has been locked. 
12.2. Informed Consent  
The Investigator and Sponsor must agree upon the format and content of the 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 or assent and Health 
Insurance Portability and Accountability Act (HIPAA) release (or other privacy protection 
release, as governed by local regulations) must be obtained from each participant and/or Legally 
Authorized Representative (LAR) before any study-related activities are conducted. The 
Investigator must retain all original signed and dated ICFs or assents (together with any 
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subsequent IRB/IEC -approved amended versions) in the participant’s ﬁle. A copy of the signed 
and dated ICF or assents (and any amendments) must be given to the participant and/or LAR. 
The ICF and assent documents the study-speciﬁc information the Investigator provides to the 
participant and/or LAR for the participant’s agreement to participate. Among other things, the 
Investigator or his/her designee will fully explain in layman’s terms the nature of the study, 
along with the aims, methods, anticipated beneﬁts, potential risks, and any discomfort 
participation may entail. The ICF or assent must be appropriately signed and dated before the 
participant enters the study. 
Participants and/or LARs will be informed of ﬁndings from earlier or concurrent clinical studies 
(including AEs), if it is considered that such information could potentially affect participant’s 
willingness to participate or continue in the study. Depending on the nature, severity, and 
seriousness of these AEs, the ICF or assent may be amended as deemed appropriate. The original 
and any amended signed and dated ICF(s) or assent(s) must be retained in the participant’s ﬁle at 
the study site; and a copy must be given to the participant and/or LAR. 
Participants enrolled into the pediatric portion of the trial will still be considered as part of the 
pediatric group with all the planned assessments when they turn 18 years old. They should be 
reconsented with an adult consent when they become an adult per country-specific requirements. 
For male participants, in case of pregnancy of your partner, your partner will be asked to provide 
consent for collection of the pregnancy data. 
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13. 
DATA HANDLING AND RECORD KEEPING  
13.1. Participant Confidentiality and Disclosure of Data  
The Investigator must ensure that each participant’s anonymity is maintained as described below. 
On the eCRFs or other documents submitted to the Sponsor and/or its designee, participants must 
only be identiﬁed by study, Participant 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 participants, 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 ICH and 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 participant’s original medical records for veriﬁcation of study-related 
procedures and data. Direct access includes examining, analyzing, verifying, and reproducing 
any records and reports that are needed for the evaluation of the study. The Investigator is 
obligated to inform the participant in the ICF that his/her study-related records will be reviewed, 
by the above-named representatives. 
Participants or LARs will be informed that data will be held on ﬁle, by the Sponsor, and that 
these data may be viewed by staff including the study monitor and by external auditors on behalf 
of the Sponsor and appropriate regulatory authorities. Participants or LARs will also be informed 
that a study report will be prepared and may be submitted to regulatory authorities and for 
publication. However, participants will be identiﬁed in such reports only by Participant 
Identiﬁcation Number and demographics, pertinent to restrictions of local regulations. All 
participant data will be held in strict conﬁdence, as allowed by law. 
Upon the participant’s (or LAR’s) permission, medical information may be given to the 
participant’s personal physician or other appropriate medical personnel responsible for the 
participant’s welfare. 
13.2. Electronic Case Report Forms (eCRF)  
The data collected in the source documents for this study will be entered into the study 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 study 
staff. If a participant withdraws from the study, the reason must be noted in the eCRF. If a 
participant is withdrawn from the study because of a treatment-limiting AE, 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 eCRFs and in all required reports. 
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13.3. Retention and Availability of Records  
The Investigator is required to retain the study 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 IMP If no marketing application is to be 
filed, or an application is not approved for the drug, the Investigator will retain the study 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 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 data accessible to the monitor, other authorized 
representatives of the Sponsor, and regulatory agency inspectors upon request. A ﬁle for each 
participant must be maintained that includes the signed ICF and the Investigator’s copies of all 
source documentation related to that participant. The Investigator must ensure the reliability and 
availability of source documents from which the information on the eCRF was transcribed. 
13.4. Audits and Inspections  
In accordance with ICH, GCP and the Sponsor and/or its designee audit plans, this study may be 
selected for audit. Inspection of site facilities (eg, pharmacy, drug storage areas, laboratories) and 
review of study-related records will occur to evaluate the study conduct and compliance with the 
protocol, ICH, GCP, and applicable regulatory requirements. The Investigator/ institution should 
make available for direct access all requested study-related records (ICH GCP 4.9.7) to 
appropriately qualified personnel from the Sponsor or its designees, or to health authority 
inspectors after appropriate notification. The verification of the eCRF 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 records are moved to another location, the Investigator should notify 
the Sponsor of the new location. 
13.5. Data Protection  
All personal data collected and/or processed in relation to this study will be handled in 
compliance with all applicable Privacy & Data Protection laws and regulations, including the 
GDPR (General Data Protection Regulation). The study Sponsor is responsible for ensuring 
compliance with this matter, when processing data from any individual who may be included in 
the Sponsor’s databases, including trial participants, Investigators, nurses, experts, service 
providers, Ethics Committee members, etc.  
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor takes all appropriate measures to safeguard and prevent access to this 
data by any unauthorized third party. 
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Protection of participant personal data 
Data collected must be adequate, relevant, and not excessive, in relation to the purposes for 
which they are collected. Each category of data must be properly justified and in line with the 
study objective. 
Participant race and ethnicity will be collected in this study because they might modify the drug 
response. They will not be collected in the countries where this is prohibited by local regulation. 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor or its service providers, when applicable, 
will be identifiable only by the unique identifier; participant names or any information 
which would make the participant identifiable will not be transferred to the Sponsor.  
• Participants must be informed that their personal study-related data will be used by the 
Sponsor in accordance with applicable data protection laws. The level of disclosure must 
also be explained to the participant as described in the informed consent.  
• Participants must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• The contract between Sponsor, Investigators, and study sites specifies responsibilities of 
the parties related data protection, including handling of data security breaches and 
respective communication and cooperation of the parties. Accordingly, the Investigator 
and the institution will promptly notify the Sponsor about any data security breaches and 
detail in the notification, the nature of the breach, the categories (eg, Sponsor’s personnel, 
study participants or their relatives, healthcare professionals, etc), the approximate 
number of subjects concerned, the type and approximate number of data records 
concerned and the likely consequences of the breach. The institution and/or Investigator 
will investigate the causes of the data security breach and take actions to minimize the 
effects of said breach. The institution and/or Investigator will record all information 
relating to the breach, including the results of their own investigations and investigations 
by authorities, as applicable, and will take all measures as necessary to prevent future 
data security breaches. 
• Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access. 
• Participants must be informed that their study-related data will be used for the whole 
“drug development program”, ie, for this trial as well as for the following steps necessary 
for the development of the investigational product, including to support negotiations with 
payers and publication of results. 
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Protection of personal data related to professionals involved in the study  
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to 
allow the Sponsor to manage involvement in the study and/or the related contractual or 
pre-contractual relationship. They may be communicated to any company of the Sponsor  
or to the Sponsor’s service providers, where needed. 
• Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sponsor’s Data Protection Officer (link 
available at Sanofi.com).  
• In case of refusal to the processing of personal data by or on behalf of the Sponsor, it will 
be impossible to involve the professionals in any Sponsor study. In case the professionals 
have already been involved in a Sponsor study, they will not be able to object to the 
processing of their personal data as long as they are required to be processed by 
applicable regulations. The same rule applies in case the professionals are listed on a 
regulatory agencies disqualification list. 
• Personal data can be communicated to the following recipients:  
- 
Personnel within the Sponsor or partners or service providers involved in the study  
- 
Judicial, administrative, and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity may 
also be published on public websites in the interest of scientific research transparency 
• Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering an 
adequate level of protection. Those transfers are safeguarded by the Sponsor in 
accordance with the requirement of European law including, notably:  
- 
The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers, 
- 
Sanofi’s Binding Corporate Rules for intra-group transfers.  
• Professionals have the possibility to lodge a complaint with the Sponsor’s leading 
Supervisory Authority, the “Commission Nationale de l’Informatique et des Libertés” 
(CNIL) or with any competent local regulatory authority. 
• Personal data of professionals will be retained by the Sponsor for up to 25 years unless 
further retention is required by applicable regulations. 
• In order to facilitate the maintenance of Investigators personal data, especially if they 
contribute to studies sponsored by several pharmaceuticals companies, the Sponsor 
participates in the Shared Investigator Platform (SIP) and in the TransCelerate 
Investigator Registry (IR) project 
(https://transceleratebiopharmainc.com/initiatives/investigator-registry). Therefore, 
personal data will be securely shared by the Sponsor with other pharmaceutical company 
members of the TransCelerate project. This sharing allows Investigators to keep their 
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data up to date at once across pharmaceutical companies participating in the project, with 
the right to object to the transfer of the data to the TransCelerate project.  
• Professionals have the right to request the access to and the rectification of their personal 
data, as well as their erasure (where applicable) by contacting the the Sponsor’s Data 
Protection Officer: Sanofi DPO, 46 avenue de la Grande Armée, 75017 PARIS - France 
(to contact Sanofi by email, visit https://www.sanofi.com/en/our-responsibility/sanofi-
global-privacy-policy/contact). 
13.6. 
Financial Disclosure  
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
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14. 
ETHICAL ASPECTS  
This section provides information for the Investigator on the ethics requirements for the study, 
including participant 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. 
14.1. Regulatory and ethical considerations  
• This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and the applicable amendments and Council for International 
Organizations of Medical Sciences (CIOMS) international ethical guidelines 
- 
Applicable ICH Good Clinical Practice (GCP) guidelines 
- 
The Regulation (EU) No 536/2014 of the European Parliament and the Council of 
16 April 2014 on clinical trials on medicinal products for human use, as applicable  
- 
The General Data Protection Regulation (GDPR) and any other applicable data 
protection laws 
- 
Any other applicable laws and regulations 
• The protocol, protocol amendments, ICF, Investigator’s brochure, IDFU, and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by the 
Investigator and reviewed and approved by the IRB/IEC before the study is initiated.  
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants.  
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
• The Investigator will be responsible for the following, as applicable: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC  
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, Regulation No 536/2014 of 
the European Parliament and the Council of the European Union for clinical studies, 
European Medical Device Regulation 2017/745 for clinical device research, and all 
other applicable local regulations. 
- 
Determining whether an incidental finding (as per the Sponsor’s policy) should be 
returned to a participant and, if it meets the appropriate criteria, to ensure the finding 
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is returned (an incidental finding is a previously undiagnosed medical condition that 
is discovered unintentionally and is unrelated to the aims of the study for which the 
tests are being performed). The following should be considered when determining the 
return of an incidental finding: 
• The return of such information to the study participant (and/or his/her designated 
healthcare professional, if so, designated by the participant) is consistent with all 
applicable national, state, or regional laws and regulations in the country where 
the study is being conducted, and 
• The finding reveals a substantial risk of a serious health condition or has 
concerned reproductive importance, AND has analytical validity, AND has 
clinical validity.  
• The participant in a clinical study has the right to opt out of being notified by the 
Investigator of such incidental findings. In the event that the participant has opted 
out of being notified and the finding has consequences for other individuals, eg, 
the finding relates to a communicable disease, Investigators should seek 
independent ethical advice before determining next steps. 
• In case the participant has decided to opt out, the Investigator must record in the 
site medical files that she/he does not want to know about such findings. 
As applicable, according to requirements of the Regulation No536/2014 of the European 
Parliament and the Council of the European Union, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial  that are deemed as “substantial” (ie, 
changes which are likely to have a significant impact on the safety or physical or mental integrity 
of the clinical trial participants or on the scientific value of the trial) prior to their 
implementation. 
According to the Regulation No 536/2014 of the European Parliament and the Council of the 
European Union and as specified by the applicable regulatory requirements in non-EU/EEA 
countries, the Sponsor needs to report to the concerned regulatory agency/ies serious breaches 
without undue delay but not later than 7 calendar days of becoming aware of that breach. A 
serious breach is defined as a deviation of the version of the protocol applicable at the time of the 
breach or the applicable clinical trial regulation that is likely to affect to a significant degree the 
safety and rights of a subject or the reliability and robustness of the data generated in the clinical 
trial. 
The Sponsor shall ensure that all parties involved in the conduct of the clinical trial promptly 
report any events that might meet the definition of a serious breach. 
Therefore, Investigators shall within 48h after being aware of a deviation that might meet the 
definition of a serious breach, report to the Sponsor any suspected serious breach to enable the 
Sponsor to carry out the required assessment and notify the regulatory agency/ies in the event of 
a confirmed serious breach. To that extent, the principal Investigator must have a process in 
place to ensure that the site staff or service providers engaged by the principal 
Investigator/institution are able to identify the occurrence of a (suspected) serious breach and 
that a (suspected) serious breach is promptly reported to the Sponsor through the contacts (e-mail 
address or telephone number) provided by the Sponsor. 
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14.2. Institutional Review Board Review  
This protocol and any accompanying material provided to the participant (such as participant 
information sheets or descriptions of the study 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 study.  
An approval letter or certificate (specifying the protocol number and title) from the IRB/IEC 
must be obtained before starting the study (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 CA approvals before starting the study. 
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15. 
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peripheral blood. Cytometry B Clin Cytom. 2010 Nov;78(6):372-81. 
Provan D, Arnold DM, Bussel JB, Chong BH, Cooper N, Gernsheimer T, et al. Updated 
international consensus report on the investigation and management of primary immune 
thrombocytopenia. Blood Adv. 2019 Nov 26;3(22):3780-817. 
PRN1008 Investigator’s Brochure, Principia Biopharma. 
Rip J, Van der Ploeg EK, Hendriks RW, Corneth OBJ. The role of Bruton’s Tyrosine Kinase in 
immune cell signaling and systemic autoimmunity. Crit Rev Immunol. 2018;38(1):17-62. 
Rogers KA, Ruppert AS, Bingman A, Andritsos LA, Awan FT, Blum KA, et al. Incidence and 
description of autoimmune cytopenias during treatment with ibrutinib for chronic 
lymphocytic leukemia. Leukemia 2016;30:346-50. 
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Schifferli A, Holbro A, Chitlur M, Coslovsky M, Imbach P, Donato H, et al. A comparative 
prospective observational study of children and adults with immune thrombocytopenia: 
2-year follow-up. Am J Hematol. 2018;93(6):751-9.  
Sideras P, Smith CI. Molecular and cellular aspects of X-linked agammaglobulinemia. Adv 
Immunol.1995;59:135-223. 
Simon AK, Hollander GA, McMichael A. Evolution of the immune system in humans from 
infancy to old age. Proc Biol Sci. 2015;282(1821):20143085.  
Trotter P, Hill QA. Immune thrombocytopenia: improving quality of life and patient outcomes. 
Patient Relat Outcome Meas. 2018;9:369-84. 
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16. 
APPENDICES  
Appendix 1 
ITP Disease Activity - ITP Bleeding Scale (IBLS) 
Appendix 2 
ITP Disease Activity - ITP-PAQ 
Appendix 3 
ITP Disease Activity - ITP-KIT 
Appendix 4 
General Quality of Life Evaluation: EQ-5D-5L 
Appendix 5 
Patient Global Impression of [Fatigue] Severity (PGIS-Fatigue), Patient Global 
Impression of Severity (PGIS) and Patient Global Impression of Change (PGIC) 
Appendix 6 
Strong-to-Moderate CYP3A Inhibitors and Inducers and Sensitive CYP3A 
Substrates 
Appendix 7 
Publication 
Appendix 8 
Guidelines to Sites for Delayed Participant Visits or Missed Visits due to Travel 
Restrictions and any Foreseeable Impacts of COVID-19 
Appendix 9 
Remote Study Visits for Active Participants 
Appendix 10 Country-specific Requirements 
Appendix 11 Protocol Amendment History 
Appendix 12 AEs and SAEs: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting 
Appendix 13 Contraceptive and Barrier Guidance 
Appendix 14 Patient Medication Diary 
Appendix 15 Liver Safety: Suggested Actions and Follow-up Assessments 
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Appendix 1 
ITP Disease Activity - ITP Bleeding Scale (IBLS)  
 
 
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Appendix 2 
ITP Disease Activity - ITP-PAQ  
 
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Appendix 3 
ITP Disease Activity - ITP-KIT  
 
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Appendix 4 
General Quality of Life Evaluation: EQ-5D-5L  
 
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Appendix 5 
Patient Global Impression of [Fatigue] Severity (PGIS-Fatigue), 
Patient Global Impression of Severity (PGIS), and Patient Global 
Impression of Change (PGIC)  
 
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Appendix 6 
Strong-to-Moderate CYP3A Inhibitors and Inducers and Sensitive 
CYP3A Substrates  
 
 
Strong 
Moderate 
CYP3A Inducers 
Apalutamide, carbamazepine, enzalutamide, 
mitotane, phenytoin, rifampin, St. John’s wort 
Bosentan, efavirenz, etravirine, phenobarbital, 
primidone 
CYP3A Inhibitors 
Boceprevir, clarithromycin, cobicistat, 
danoprevir/ritonavir, elvitegravir/ritonavir, 
grapefruit, starfruit, and products containing these 
fruits (such as juice and marmalades), idelalisib, 
indinavir/ritonavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, nefazodone, nelfinavir, 
paritaprevir/ritonavir and ombitasvir and/or 
dasabuvir, posaconazole, ritonavir, 
saquinavir/ritonavir, telaprevir, telithromycin, 
tipranavir/ritonavir, troleandomycin, voriconazole 
Aprepitant, ciprofloxacin, conivaptan, crizotinib, 
cyclosporine, dronedarone, erythromycin, 
fluconazole, fluvoxamine, imatinib, tofisopam, 
verapamil 
Source: Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers, U.S. Food and Drug Administration. This list is 
not intended to be exhaustive and may be out of date. For updated information, please refer to https://www.fda.gov/drugs/drug-interactions-
labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers or product labeling. 
 
Sensitive CYP3A Substrates 
Alfentanil, aprepitant, avanafil, budesonide, buspirone, conivaptan, darifenacin, darunavir, dasatinib, dronedarone, 
ebastine, eletriptan, eplerenone, everolimus, felodipine, ibrutinib, indinavir, lomitapide, lovastatin, lurasidone, 
maraviroc, midazolam, naloxegol, nisoldipine, quetiapine, saquinavir, sildenafil, simvastatin, sirolimus, tacrolimus, 
ticagrelor, tolvaptan, tipranavir, triazolam, vardenafil 
Source: Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers, U.S. Food and Drug Administration. This list is 
not intended to be exhaustive and may be out of date. For updated information, please refer to https://www.fda.gov/drugs/drug-interactions-
labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers or product labeling. 
 
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Appendix 7 
Publication  
Ownership of the Results-Publication Policy 
Sponsor assumes full responsibility relating to this function and retains exclusive property rights 
over the results of the study, which Sponsor may use as it deems fit. 
If the study has multiple centers, the first publication must include complete results from data 
analyzed by Sponsor from multiple centers. The Investigator commits himself not to publish or 
communicate data collected in only one center or part of a center before the publication of the 
complete results of the study unless prior written agreement from the other Investigators and 
Sponsor has been obtained. 
A copy of any intended publication or communication related to the study or related to the results 
obtained during or after the study shall be submitted to Sponsor at least 90 days before the 
forecasted date of distribution or submission for publication. The authoring Investigator shall 
take Sponsor’s comments into due consideration and hereby agrees to incorporate any changes in 
any such publication or communication that Sponsor may reasonably require to protect 
Sponsor’s proprietary rights and interests. Should the authoring Investigator decide to not 
incorporate changes reasonably required by Sponsor, the authoring Investigator shall provide the 
reasons in writing to Sponsor. 
In the case where Sponsor is in the process of filing a patent application on the results of the 
study, Sponsor may delay its authorization for publication or communication of the results of the 
study until the date of international registration of the patent. 
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Appendix 8 
Guidelines to Sites for Delayed Participant Visits or Missed Visits 
due to travel restrictions and any foreseeable impacts of COVID-19  
Sponsor 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. Refer to Appendix 10.7 for EU [EEA countries] specific guidance. 
The safety data to date and the unique mechanism of action of rilzabrutinib continues to support 
a favorable risk-benefit profile for immune thrombocytopenia participants experiencing active 
disease manifestations. 
Sponsor intends to continue to enroll participants, provide IMP to randomized participants, and 
to perform protocol assessments as possible during the pandemic while following the recent 
guidance issued from US 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 20 March 2020 
entitled “Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) 
Pandemic” for the management of studies and participant 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, Sponsor is committed to provide measures that assure 
continued drug supply and safety monitoring for participants. We are working in collaboration 
with sites and their respective Independent Ethics Committees (IECs) 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 participants 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’s Brochure for further information on the potential risks and benefits of 
treatment with rilzabrutinib. 
Since rilzabrutinib is an oral medication, maintaining drug supply for participants during these 
restrictive times is feasible, especially as the drug can be administered at home and we at 
Principia Biopharma Inc. are committed to making drug supply to participants a top priority. 
This is important because participants with immune thrombocytopenia (ITP) require 
uninterrupted treatment to maintain platelet response. Recommendations from the Centers for 
Disease Control and Prevention and 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 
participant’s benefit/risk profile for inclusion and continuation in the study on a case-by-case 
basis. 
We are committed to keeping you informed in writing if there are any new significant safety 
findings that emerge affecting a participant’s willingness to participate or pose additional risk. 
For sites affected by restrictions due to COVID-19, Sponsor will implement the following 
changes in research plans in order to eliminate apparent immediate hazards to research 
participants in study PRN1008-018 (EFC17093): 
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Remote study visits for active participants 
It is expected that if your site is not affected and the participant may travel to the site for a 
regular scheduled protocol visit, that the visit occurs per schedule. It is important to discuss all 
upcoming visits in the next month with all participants in order to provide sufficient time to plan 
for the visit. 
In the circumstance that the participant may not travel to the site, or the site is quarantined and 
cannot host a participant visit - please follow the guidelines below for allowing continued supply 
of rilzabrutinib (study drug). 
In-clinic study visits as outlined in the protocol SoA, may be changed to a remote visit (eg, 
telephone call, video call) for visits 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 site 
monitor of any concerns so we can address any specific needs at your site as well as understand 
your internet and source documentation access. Refer to - Remote Study Visits for Active 
Patients on how to perform and document these remote visits. 
Enrollment 
Please notify Sponsor and your CRO study monitor of your Institution policy during the 
pandemic and any temporary suspension prior to enrolling new participants. We need to ensure 
participant safety can be adequately monitored, access to study drug is feasible and a plan is in 
place for that participant to address how this will be implemented. 
Local nurse service, home-health visits 
Sponsor provides the option for participants to use a home-health care nurse. A nurse will be 
able to visit your home to collect necessary vital signs and blood draws. This will only be for 
sites that are permitted to use this service. 
Quality of Life (QOL) Questionnaires: 
Sponsor and the CRO are making all QOL Questionnaires available electronically for this study. 
The ITP-PAQ, Kids’ ITP Tools (ITP-KIT), and EuroQOL-5 Dimension 5 Level (EQ-5D-5L) 
will all be available through our authorized vendor via the web or an application on the 
participant’s own device. These will be submitted for approval with the original submission to 
the Institutional Review Board (IRC)/IEC. 
Urine Pregnancy Testing (UPT) for Women of Childbearing Potential 
It is important to confirm pregnancy status for women of childbearing potential. Please send 
3 urine pregnancy tests to the subject with each shipment of IMP. If the UPT has a package 
insert with instructions on collection, include this in the shipment. During the follow up phone 
call with the participant, have the participant collect the urine sample and conduct the pregnancy 
test. During the follow-up call, confirm pregnancy status (negative or positive) and document the 
result in the source notes. The participant may confirm the result by showing the test over the 
video with site staff documenting the status was visualized (positive or negative) or provide a 
photo of the test to site staff. A positive test result will need to be reconfirmed with a second test. 
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Investigational Medicinal Product (IMP) shipments direct to research participants 
Where participants are self-isolating or in quarantine, arrangements for a nominated person to 
collect and deliver product may be implemented with the participant’s documented verbal 
consent. Sites are requested to obtain and document a participant’s verbal consent to provide 
contact details for IP shipping and transport purposes. See Appendix 10.2 for Germany specific 
details concerning direct to participant shipment of IMP.  
Options for IP transport: 
• No change from current practice in protocol: Participant can pick up dispensed study 
medication when attending a site visit, using the normal practice for bringing study 
medication home. 
• By direct from site/hospital to participant using PCI’s World Courier Account or 
authorized vendor, insulated shipper and temperature monitor, study medication may be 
delivered from the site to the participant’s home. Detailed instructions on this process are 
in the study Pharmacy Manual. 
If you are not able to use PCI’s World Courier Account or authorized vendor for shipping 
supplies and delivery to send study medication to the participant, you will need to provide the 
information to Sponsor 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. Sponsor 
will need to approve the material and courier prior to shipment to the participant. Upon approval 
by Sponsor in writing, the site may arrange the shipment with the local courier. 
Protocol deviations: 
Where the change to remote visits is being implemented due to COVID-19 to protect the safety 
and well-being of participants, 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-specific assessments). Please continue to document in your source documents all 
protocol deviations and inform your local site clinical research associate (CRA) monitor. Notify 
your IRB/IEC as required locally. 
Remote site monitoring visits, if applicable (where allowed by local regulations): 
As you know, the Sponsor is required to monitor the safety and risk-benefit 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. To meet our Sponsor oversight 
obligations while CRA monitors are not allowed on-site, we ask that you provide source 
documents with all personal information REDACTED for your site CRA 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. 
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Appendix 9 
Remote Study Visits for Active Participants  
1. Remote visit procedures to be performed: 
a. Inform the participant that the study clinic visit will be changed to a remote visit. 
b. Remind the participants of their online options to complete the QOL questionnaires.  
i. In the event the participant is unable to complete them online, email or mail the 
QOL Questionnaires to the participant. The participant 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. 
c. Schedule a home-health care nurse to visit the participant and collect the required lab 
samples. 
i. Schedule a local lab visit to collect at a minimum the platelet count. Obtain the 
lab name and information when scheduling the test. If the platelet count cannot 
be obtained because a lab is not available, please notify your local contract 
research associate as this is both an efficacy and safety assessment. 
d. Collect the following critical study data via the phone call or video call. Document the 
conversation of the 5 items below. 
i. New or changes in AEs/SAEs 
ii. New or changes in concomitant medications 
iii. New or changes in immune thrombocytopenia concomitant medications 
iv. Confirm IMP compliance 
v. Platelet count (done, yes/no, result and units) 
2. Documentation: 
a. Source documents: Continue to observe good documentation practice and record all 
details of the remote study visit, including: 
i. Participant Study Identification  
ii. Date and method of remote visit 
iii. Site staff who performed remote visit 
iv. All remote data collected 
b. Electronic Case Report Forms: Enter all data collected within 5 days of the remote 
visit. Any data not collected should be entered as ‘Not done’ in the applicable eCRF. 
c. If the participant is not able to complete the QOL electronically, after the participant 
completes the paper questionnaire, the participant 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 participant verbal 
answer. This telephone report will reside with the source data and entered into the 
electronic data capture system. The data will then later be verified against the original 
supplied by the participant. This deviation in the process will be noted by the Study 
Coordinator and documented. 
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Appendix 10 Country-Specific Requirements  
Appendix 10.1 UK country-specific requirements 
• Synopsis and Section 5.2, Exclusion criteria, criterion 17: For participants in the UK, a 
positive QuantiFERON®-TB Gold Plus at Screening will result in exclusion. The 
3 conditions to allow inclusion with a positive test do not apply to participants in the UK. 
• Section 6.4.4, Treatment blinding/unblinding: For participants in the UK, the Investigator 
can unblind a participant via the IWRS if deemed medically necessary without previous 
consultation with the Sponsor medical monitor, but the Sponsor medical monitor should 
be notified. 
Appendix 10.2 Germany country-specific requirements 
• Inclusion criterion #1: Participants to be enrolled in Germany will be men and women 
with primary ITP with duration of >3 months who are ≥18 years of age. 
• Table 1, Schedule of Assessments, Blinded Treatment Period; Table 2, Schedule of 
Assessments, Open Label period; Table 3, Schedule of assessments, Long-term 
Extension: Participants in Germany must be tested for SARS-CoV-2 infection within 
1 week prior to or up to 2 days after each monthly in clinic 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 test may no longer be required (with approval from the ethics 
committee) if the local regulations change with control of the SARS-CoV-2 pandemic.  
• Direct to participant shipment is only allowed until 31 December 2023, as long as the 
ordinance "Ordinance to ensure the supply of medically necessary products to the 
population in the event of an epidemic caused by the SARS-CoV-2 Coronavirus 
(Ordinance to Ensure the Supply of Medicines)” is in place in Germany. 
Appendix 10.3 Austria, Turkey, and Ukraine country-specific requirements 
• Inclusion criterion #1: Participants to be enrolled in Austria, Turkey, and Ukraine will be 
men and women with primary ITP with duration of >3 months who are ≥18 years of age. 
Appendix 10.4 Canada country-specific requirements 
• Synopsis and Section 5.2, Exclusion criteria, criterion 17: For participants in Canada, a 
positive QuantiFERON®-TB Gold Plus at Screening will result in exclusion. The 
3 conditions to allow inclusion with a positive test do not apply to participants in Canada. 
Appendix 10.5 China country-specific requirements 
• Synopsis and Section 3.2.4 Exploratory Endpoints: the following exploratory endpoints 
are not applicable to participants in China 
- 
BTK occupancy 
- 
Changes from baseline in TPO levels, T-lymphocytes/ B-lymphocytes/natural killers 
(T/B/NK) counts, immunoglobulin (IgG, IgG1, IgG4, IgM, IgE) levels 
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- 
(Optional) Vaccine-specific IgG response during treatment 
• Synopsis Schedule of Assessments, Section 4.1.2 Blinded Treatment Period (Weeks 1 to 
25), Section 4.1.3 Open Label Period (Weeks 25 to 53), Section 4.1.4 End of Study visit 
(Four Weeks post last dose of study drug), Section 4.1.5 Long-Term Extension, 
Section 7.9.8 Bruton’s Tyrosine Kinase (BTK) Occupancy, and Section 8.1 Specification 
of the Efficacy Parameters: Exploratory biomarker samples (including BTK occupancy, 
TPO levels, T/B/NK counts, immunoglobulin levels, hemolysis panel, and optional 
vaccine-specific IgG response) will not be collected for participants in China. Therefore, 
exploratory biomarker sampling and assessment are not applicable to participants in 
China.  
• Future use of biological samples is not applicable for participants in China. All residual 
mandatory samples collected from participants in China have to be destroyed upon CSR 
completion at the latest. 
Appendix 10.6 Italy country-specific requirements 
• For the pediatric population, Tanner staging should be performed at W1, W25, W53, 
EOS/ET, and every 1 year during the LTE period until the end of the trial or until the 
participant reaches Tanner stage V (whichever comes first). Self-reported Tanner staging 
or records from pediatric assessments in standard of care settings are considered 
acceptable. 
• Details regarding risk mitigation measures for exceeding blood sample volumes are 
provided in the Laboratory Manual. 
Appendix 10.7 EU (EEA countries) and UK-specific requirements 
Synopsis, Section 3.1 Objectives, Section 3.1.1 Efficacy Objectives, Section 3.2 Endpoints, 
Section 10.3.9 Primary Efficacy Analysis; In the UK and countries within the EU (EEA 
countries): 
• The primary endpoint in the blinded treatment period is the proportion of participants 
able to achieve platelet counts at or above 50,000/μL for at least 8 out of the last 
12 weeks of the 24-week blinded treatment period in the absence of rescue therapy. 
• The primary efficacy analysis is as follows: The primary analysis will compare the 
proportion of participants in the adult ITT population who achieve durable platelet 
response defined as platelet counts at or above 50,000/μL for ≥8 out of the 12 scheduled 
observations in the last 12 weeks of the 24-week blinded treatment period in the absence 
of rescue medication between rilzabrutinib and placebo with a Cochran-Mantel-Haenszel 
test using the two stratification factors at a 2-sided alpha level of 0.05. Participants who 
do not respond in the first 12 weeks and enter the open label period will be treated as 
non-responders in the primary analysis. Participants who discontinue the study due to a 
rilzabrutinib-related AE, lack of efficacy or receive rescue medication (including an 
increase in allowed concomitant ITP medications dose) will be considered as 
non-responders. Sensitivity analyses will be conducted on the primary analysis. 
• In the blinded treatment period, the following is a key secondary objective: To evaluate 
the change from baseline in IBLS. 
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• In the blinded treatment period, the following is a key secondary efficacy endpoint (the 
last endpoint in the multiplicity control): Change from baseline in IBLS assessment at 
Week 25 
• Key secondary efficacy analysis: Compare the change from baseline in IBLS assessment 
at Week 25 
EU (EEA countries) only 
Throughout the protocol, the allowed age range for pediatric participants is ≥10 to <18 years, 
where permitted by local regulation. 
Synopsis and Section 5.1, Inclusion criterion 1: 
Participants will be male and female with primary ITP with duration of >6 months in pediatric 
participants aged ≥10 to <18 years (where allowed by local regulation) and duration of  
>3 months in adults ≥18 years. 
Synopsis and Section 5.1, Inclusion criterion 3: 
An average of 2 platelet counts at least 5 days apart of <30,000/µL during the screening period 
and no single platelet count >35,000/µL, within 14 days prior to the first dose of study drug.  
• Pediatric participants who are 10 to < 12 years must have body weight ≥30 kg and must 
additionally be determined to need treatment for ITP as per clinical assessment by the 
Investigator.  
Safety reporting to the agency 
In the European Union, the Sponsor will comply with safety reporting requirements and 
procedures as described in the European Clinical Trials Regulation (EU) No 536/2014. All 
SUSARs to IMP will be reported to the EudraVigilance database within the required regulatory 
timelines. 
Contingency measures for the COVID-19 pandemic: 
For European countries contingency measures are currently only applicable for the 
COVID- 19 pandemic, not in other unspecified pandemics or emergencies. 
The following contingencies may be implemented for the duration of the emergency 
(after Sponsor agreement is obtained). 
Study intervention 
The following contingencies may be implemented to make clinical supplies available to the 
participant for the duration of the emergency. 
• The DTP supply of rilzabrutinib from the PI/site/Sponsor where allowed by local 
regulations and agreed upon by the participant. See Appendix 10.2 for Germany-specific 
requirements. 
If a participant has to stop rilzabrutinib due the COVID-19 pandemic, reinitiation of the study 
intervention can only occur once the Investigator has determined, according to his/her best 
judgement, that 1) rilzabrutinib did not contribute to the occurrence of the concerned AE and 2) 
the selection criteria for the study are still met (refer to Section 5). Reinitiation of the study 
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intervention will be done under close and appropriate clinical/and or laboratory monitoring and 
following the instructions provided in Section 7.4. 
Study assessments and procedures 
During the emergency, if the site will be unable to adequately follow protocol mandated 
procedures, alternative treatment outside the clinical trial should be proposed and screening 
and/or enrollment may be temporarily delayed. Attempts should be made to perform all 
assessments in accordance with the approved protocol to the extent possible. In case this is not 
possible due to a temporary disruption caused by an emergency, focus should be given to 
assessments necessary to ensure the safety of participants and those important to preserving the 
main scientific value of the study. 
Procedures to be considered in the event of a regional or national emergency declared by 
a governmental agency: 
• If on-site visits are not possible, remote visits (eg, with home nurses, home health vendor, 
etc) may be planned for the collection of possible safety and/or efficacy data including 
1) collection of samples for screening and clinical safety analyses, 2) ECG and vital signs 
assessments, and 3) AEs. See Table 1, Table 2, and Table 3 for examples of laboratory 
samples that may be collected at home. 
• The Sponsor will continue safety reporting. Investigators will continue to collect AE 
information from participants through alternative means such as via phone calls or 
telemedicine if the participant is unable to visit the site. If on-site visits are not possible, 
visit windows may be extended for assessment of safety and/or efficacy data that cannot 
be obtained remotely. 
• Use of local clinic or laboratory locations may be allowed when central labs cannot be 
performed due to a government declared national emergency. If the central lab 
assessment is related to a study endpoint and the sample cannot be shipped to the central 
laboratory, then analysis should be performed locally. Sponsor must have access to the 
normal ranges and certification information of any additional laboratory assessments used 
to support the evaluation of results. 
• Contingencies implemented due to an emergency will be documented. 
• Monitoring and quality assurance activities may need to be temporarily adjusted with the 
rights and safety of the participants in mind and according to local requirements. Once 
the situation is normalized, increased on-site monitoring may be necessary for a period of 
time to ensure any impact from adjusted monitoring is rectified. 
• Remote source data verification (rSDV) should only be used if suitable data protection, 
including data security and the protection of personal data – is ensured with consideration 
given to pseudonymization of data. One of the following three methods for rSDV may be 
used as appropriate and in compliance with local regulations:  
- 
Sharing pseudonymized copies of trial related source documents with the monitor; 
this may be done electronically where manageable by the site staff; 
- 
Direct, suitably controlled remote access to trial participants’ electronic medical 
records; 
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- 
Video review of medical records with clinical site team support, without sending any 
copy to the monitor and without the monitor recording images during the review. 
• Participant source data collected remotely are likely to require re-monitoring, in 
particular if it was based on pseudonymized documents, which cannot be considered as 
source documents, and considering that remote monitoring is expected to only have 
focused on the most critical information. Source documents/source data to be made 
available under the rSDV include but not limited to documents/data related to primary 
endpoints, SAEs, important medical events, or the reasons for exclusion of a subject from 
the trial. 
• To share pseudonymized trial related source documents via secure platform, site staff 
should create copies of the requested trial participant’s records, redact (ie, pseudonymize 
and mask any unnecessary personal information unrelated to the trial) the copies, and 
identify them with the trial participant identification code in the trial. 
Statistical analyses 
Analyses and methods required to evaluate the impact on efficacy (eg, missing data) and safety 
will be detailed in the SAP. 
Informed consent 
Contingency procedures may be implemented for the duration of the emergency. The participant 
or their legally authorized representative should be verbally informed prior to initiating any 
changes that are to be implemented for the duration of the emergency (eg, study visit 
delays/treatment extension, use of local labs). If re-consent is necessary for the implementation 
of new urgent changes in trial conduct, alternative ways of obtaining reconsent should be 
considered such as contacting the trial participants by phone or video call and obtaining oral 
consent. If available per local regulation, a validated electronic system may be used per usual 
practice. 
Trial participants should be informed in a timely manner by the Investigator of any changes to 
the trial conduct, eg, cancelled visits, change in laboratory testing or delivery of IMP. Any 
change in study conduct initiated by the Investigator due to an emergency situation should be 
reported to the Sponsor. The Sponsor will report these changes to the competent authorities and 
ethics committees. 
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Appendix 11 Protocol Amendment History  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Appendix 11.1 Clinical trial protocol version 1.1 (06 August 2020) 
OVERALL RATIONALE FOR THE AMENDMENT 
This protocol is being amended to provide correction. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 5.1, Inclusion Criteria 
Removed inclusion criterion #6, 
adolescent weight requirement. 
Correction. 
Appendix 11.2 Clinical study protocol version 1.2 Germany (28 October 2020) 
OVERALL RATIONALE FOR THE AMENDMENT 
This protocol is being amended from protocol version 1.1 to incorporate Germany specific 
requirements. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis, Inclusion criteria 
(Criterion 1); Section 5.1, Inclusion 
criteria (Criterion 1) 
Added a bullet statement under this 
criterion stating the following: “The 
following countries will only enroll 
patients ≥18 years of age: Germany 
Country-specific requirement. 
Table 1, Schedule of assessments - 
blinded treatment period 
Table 2, Schedule of assessments - 
open label period 
Table 3, Schedule of assessments - 
Long-Term Extension 
Footnote added to each table (footnote 
“r” for Table 1, footnote “l” for Table 2, 
and footnote “f” for Table 3 specifying 
that patients in Germany must be tested 
for SARS-CoV-2 infection within 1 week 
prior to or up to 2 days after each 
monthly in clinic visit. 
Addition of country-specific 
requirements for Germany. 
Section 2.5, Study design rationale; 
Appendix 8, Guidelines to Sites for 
Delayed Participant Visits or Missed 
Visits due to travel restrictions and 
any foreseeable impacts of 
COVID-19 
Text added that remote monitoring is not 
available in Germany. 
Addition of country-specific 
requirements for Germany. 
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Appendix 11.3 Clinical study protocol version 1.2 Canada (03 November 2020) 
OVERALL RATIONALE FOR THE AMENDMENT 
This protocol is being amended from protocol version 1.1 to incorporate Canada specific 
requirements. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis, Individual patient stopping 
rules 
Added the information regarding serious 
allergic reaction to rilzabrutinib or placebo 
to list of individual patient stopping rules 
Correction to match protocol 
Section 7.3.1. 
Synopsis, Individual patient stopping 
rules; Section 7.3.1, Individual 
patient stopping rules 
Added the information regarding 
HIV/AIDs, viral hepatitis (B and C) 
infection. 
Added to align across rilzabrutinib 
immune thrombocytopenia (ITP) clinical 
studies.  
Appendices, Appendix 8, Guidelines 
to sites for delayed patient visits or 
missed visits due to travel restrictions 
or any foreseeable impacts of 
COVID-19. 
Added section regarding urine pregnancy 
testing for women of childbearing 
potential. 
To clarify how to collect pregnancy test 
results if remote visits are needed for 
COVID-19. 
Appendix 11.4 Clinical study protocol version 1.3 Canada (06 November 2020) 
OVERALL RATIONALE FOR THE AMENDMENT 
This protocol is being amended from protocol version 1.2 Canada to incorporate Canada specific 
requirements. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Table 2, Schedule of assessments - 
open label period 
Removed row for Hep B& C, and HIV 
assessment. 
Correction; not applicable to this 
open-label period. 
Appendix 11.5 Clinical study protocol version 1.2 United Kingdom (09 November 2020) 
OVERALL RATIONALE FOR THE AMENDMENT 
This protocol is being amended from protocol version 1.1 to incorporate United Kingdom 
specific requirements. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis, Exclusion Criteria 
(Criterion 17); Section 5.2, Exclusion 
criteria (Criterion 17) 
Exclusion criterion #17: added the 
information that for patients in the UK 
with a positive QuantiFERON®-TB Gold 
Plus (QFT Plus) at Screening is 
exclusionary 
Addition of country-specific requirements 
for UK. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 4.1.4, End of study visit (four 
weeks post last dose of study drug) 
Updated section title; updated first 
sentence in section for consistency with 
section title. 
Clarification. 
Section 4.1.5, Long-term Extension 
(LTE) 
Moved text defining completion for the 
overall clinical study to this section. 
Clarification. 
Section 6.4.4, Treatment 
blinding/unblinding 
Revised the text regarding the unblinding 
deemed by the Investigator to be 
medically necessary with notification to 
the Sponsor 
Addition of country-specific requirements 
for UK. 
Appendix 11.6 Clinical study protocol version 1.2 Austria (03 December 2020) 
OVERALL RATIONALE FOR THE AMENDMENT 
This protocol is being amended from protocol version 1.1 to incorporate Austria specific 
requirements. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis, Inclusion criteria 
(Criterion 1); Section 5.1, Inclusion 
criteria (Criterion 1) 
Added a bullet statement under this 
criterion stating the following: “The 
following countries will only enroll 
patients ≥18 years of age: Austria” 
Country-specific requirement. 
Appendix 11.7 Clinical study protocol version 1.2 France (04 December 2020) 
OVERALL RATIONALE FOR THE AMENDMENT 
This protocol is being amended from protocol version 1.1 to incorporate France specific 
requirements. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 6.2.1, Rilzabrutinib/placebo  
Added sentence to state that frequency 
and/or severity of GI AEs may be 
improved if rilzabrutinib/placebo is taken 
with food. 
Clarification to align with Investigator’s 
Brochure. 
Section 6.5.2 Particular Permissible 
Medications 
Parenthetical statement added to first 
bullet as follows: a TPO-RA (authorized 
for the treatment of ITP). 
Clarification. 
 
Second sub-bullet added to first bullet as 
follows: Administration of corticosteroids 
and TPO-RAs should follow 
corresponding updated package 
inserts/SmPCs of the marketing 
authorization. 
Clarification of guidance for 
investigators. 
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Appendix 11.8 Clinical study protocol version 1.2 Norway (15 December 2020) 
OVERALL RATIONALE FOR THE AMENDMENT 
This protocol is being amended from protocol version 1.1 to incorporate Norway specific 
requirements. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis, Inclusion criteria 
(Criterion 6); Section 5.1, Inclusion 
criteria (Criterion 6) 
Added clarification of reproductive 
potential as follows: fertile, following 
menarche and until becoming 
post-menopausal unless permanently 
sterile. 
Clarification. 
Appendix 11.9 Clinical study protocol version 1.3 France (02 January 2021) 
OVERALL RATIONALE FOR THE AMENDMENT 
This protocol is being amended from protocol version 1.2 France to incorporate France specific 
requirements. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis, Inclusion criteria 
(Criterion 2); Section 5.1, Inclusion 
criteria (Criterion 2) 
Added “or any contra-indication” to any 
appropriate courses of standard of care 
ITP therapy. 
Clarification. 
Appendix 11.10 Clinical study protocol version 1.2 Turkey (06 January 2021) 
OVERALL RATIONALE FOR THE AMENDMENT 
This protocol is being amended from protocol version 1.1 to incorporate Turkey specific 
requirements.   
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis, Inclusion criteria 
(Criterion 1); Section 5.1, Inclusion 
criteria (Criterion 1) 
Added a bullet statement under this 
criterion stating the following: “The 
following countries will only enroll 
patients ≥18 years of age: Turkey” 
Country-specific requirement. 
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Appendix 11.11 Clinical study protocol version 1.2 Ukraine (21 January 2021) 
OVERALL RATIONALE FOR THE AMENDMENT 
This protocol is being amended from protocol version 1.1 to incorporate Ukraine specific 
requirements. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis, Inclusion criteria 
(Criterion 1); Section 5.1, Inclusion 
criteria (Criterion 1) 
Added a bullet statement under this 
criterion stating the following: “The 
following countries will only enroll 
patients ≥18 years of age: Ukraine” 
Country-specific requirement. 
Appendix 11.12 Clinical study protocol version 2.0 (19 February 2021) 
This amended clinical trial protocol (version 2.0) is considered to be substantial based on the 
criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the 
Council of the European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
This protocol is being amended to incorporate feedback from health authorities as well as other 
clarifications deemed necessary by the Sponsor. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page 
Updated protocol version and date; added 
company logo. 
Administrative. 
Approval of the protocol 
Removed signature page. 
For consistency with current Sanofi 
protocol template and processes. 
Protocol approval is conducted via 
electronic signature. 
Investigator’s agreement 
Removed signature page. 
For consistency with current Sanofi 
protocol template and processes. A 
separate signature page will be 
available. 
Protocol amendment summary of 
changes 
Inserted table to include the history related to the 
initial Clinical Study Protocol and the Amended 
Clinical Study Protocol.  
Inserted for the current Amended Clinical Study 
Protocol text related to the overall rationale and 
protocol amendment summary of changes table. 
New section per Sanofi protocol 
template and process. 
Synopsis, Objectives, Endpoints; 
Section 3.1, Objectives; Section 
3.2, Endpoints 
Added “Other Secondary Objectives” heading to 
clarify that safety objectives, pharmacokinetic 
objectives, and quality of life objectives are 
secondary objectives; and to distinguish them 
from the key secondary endpoints. 
Clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
Synopsis, Individual patient 
stopping rules 
In the list of stopping rules added as a second 
bullet the information regarding serious allergic 
reaction to rilzabrutinib or placebo. 
Correction to match protocol 
Section 7.3.1. 
Synopsis, Individual patient 
stopping rules; Section 7.3.1, 
Individual patient stopping rules 
Added as a fifth bullet the information regarding 
HIV/AIDs, viral hepatitis (B and C) infection. 
Added to align across rilzabrutinib 
immune thrombocytopenia (ITP) 
clinical studies. 
Synopsis, Inclusion criteria 
(Criterion 1); Section 5.1, 
Inclusion criteria (Criterion 1) 
Added a bullet statement under this criterion 
stating the following: “The following countries will 
only enroll patients ≥18 years of age: Austria, 
Germany, Turkey, Ukraine,” with reference to 
Appendix 10. 
Country-specific requirement. 
Synopsis, Inclusion criteria 
(Criterion 2); Section 5.1, 
Inclusion criteria (Criterion 2) 
Added “or any contra-indication” to any 
appropriate courses of standard of care ITP 
therapy. 
Clarification. 
Synopsis, Inclusion criteria 
(Criterion 6); Section 5.1, 
Inclusion criteria (Criterion 6) 
Added clarification of reproductive potential as 
follows: fertile, following menarche and until 
becoming post-menopausal unless permanently 
sterile. 
Clarification. 
Synopsis, Exclusion criteria 
(Criterion 7); Section 5.2, 
Exclusion criteria (Criterion 7) 
Revised text as follows: “Immunosuppressant 
drugs other than CSs within 5 times the 
elimination half-life of the drug or 14 days of 
Study Day 1, whichever is longer.” 
Updated per Food and Drug 
administration feedback to ensure 
appropriate duration of wash-out 
period. 
Synopsis, Exclusion criteria 
(Criterion 16); Table 1 Schedule of 
assessments - blinded treatment 
period (footnote “g”); Section 5.2, 
Exclusion criteria (Criterion 16) 
Exclusion criterion #16, second bullet revised as 
follows: “If HBV DNA is negative and HBsAB 
titer is ≥100 IU/L, patients may be enrolled.” New 
footnote “g” added to Table 1. The units were 
also corrected from 100 IU/mL to IU/L. 
Added to emphasize that 
hepatitis B virus DNA has to be 
negative. 
Synopsis, Exclusion Criteria 
(Criterion 17); Section 5.2, 
Exclusion criteria (Criterion 17) 
Exclusion criterion #17: added the information 
that for patients in the UK with a positive 
QuantiFERON®-TB Gold Plus (QFT Plus) at 
Screening is exclusionary; reference to 
Appendix 10 for country-specific requirements 
added.  
Addition of country-specific 
requirements for UK. 
Synopsis, Randomization 
procedure 
Revised text to specify that randomization will be 
carried out separately for the two age groups and 
added details. 
Different randomization procedures 
are now used for the two age 
groups; therefore, randomization is 
done separately for each group.  
Synopsis, Primary efficacy 
analysis, Key secondary efficacy 
analysis; Section 10.3.2, 
Intent-to-treat (ITT) population 
Revised text to specify that efficacy analyses will 
be performed using the ITT population. 
Health authority request; ITT 
includes all randomized patients 
and preserves the rigor of 
randomization.  
Table 1, Schedule of assessments 
- blinded treatment period 
Removed previous footnote “b” regarding AEs 
after Screening and before baseline, and 
renumbered footnotes. 
Correction; The footnote is not 
applicable. 
 
Replaced “PRN1008” with “rilzabrutinib or 
placebo” in footnotes “o” and “p.” 
Correction. 
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Section # and Name 
Description of Change 
Brief Rationale 
Table 1, Schedule of assessments 
- blinded treatment period; 
Section 4.1.1, Screening (Day -28 
to Study Day -1 Predose) 
Added “estimated glomerular filtration rate 
(eGFR)” to serum chemistry performed at 
screening in footnote “k” in Table 1; added 
creatinine phosphokinase (CPK) and estimated 
glomerular filtration rate (eGFR) to the bullet for 
serum chemistry in Section 4.1.1. 
Correction; previously missing. 
Table 2, Schedule of assessments 
- open label period 
Removed row for Hep B& C, and HIV 
assessment. 
Correction; not applicable to this 
open-label period. 
 
Added PK sample to ET/unscheduled visit. 
Correction; previously missing. 
 
Added a new footnote “a” regarding 
measurement of height, and renumbered 
footnotes. 
Clarification and consistency with 
Table 1. 
 
Revised footnote “e” to remove text regarding 
serum pregnancy test at screening. 
Correction; not applicable to this 
open-label period. 
 
Revised footnote “f” to remove text regarding 
creatinine phosphokinase (CPK) at screening. 
Correction; not applicable to this 
open-label period. 
Table 1, Schedule of assessments 
- blinded treatment period 
Table 2, Schedule of assessments 
- open label period 
Table 3, Schedule of assessments 
- long-term extension 
Footnote added to each table (footnote “r” for 
Table 1, footnote “m” for Table 2, and footnote “f” 
for Table 3 specifying that patients in Germany 
must be tested for SARS-CoV-2 infection within 
1 week prior to or up to 2 days after each 
monthly in clinic visit along; further details 
provided in Appendix 10. 
Addition of country-specific 
requirements for Germany. 
Section 2.1, Overview of immune 
thrombocytopenia (ITP); 
Section 15, References 
Second paragraph: Added sentence regarding 
clinical response rate of second line treatment 
with TPO-RAs, and added reference 
(Ghanima 2019). 
Additional information provided.  
Section 2.5, Study design 
rationale 
Updated second paragraph with additional 
details regarding platelet counts. 
Additional information provided. 
Section 2.5, Study design 
rationale; Appendix 8, Guidelines 
to Sites for Delayed Participant 
Visits or Missed Visits due to 
travel restrictions and any 
foreseeable impacts of COVID-19; 
Appendix 9, Remote study visits 
for active patients (where allowed 
by local regulations) 
Text added that remote monitoring is not 
available in Germany with reference to 
Appendix 10. 
Addition of country-specific 
requirements for Germany. 
Section 4.1.1, Screening (Day -28 
to Study Day -1 predose) (Second 
bullet); Section 4.1.2, Blinded 
Treatment Period (Weeks 1 to 24) 
(First bullet) 
Added text clarifying that screening lab results 
will be verified for eligibility determination, with 
the exception of hemoglobin, which is to be 
rechecked prior to dosing. 
Clarification. 
Section 4.1.3, Open label period 
(Weeks 25 to 53) 
Removed height assessment from Week 29. 
Correction, to match the procedures 
as listed in Table 2. 
 
Added “and dispense rilzabrutinib if entering 
Long Term Extension” to last bullet for Week 53. 
Clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 4.1.4, End of study visit 
(four weeks post last dose of 
study drug) 
Updated section title; updated first sentence in 
section for consistency with section title. 
Clarification. 
Section 4.1.5, Long-term 
extension (LTE) 
Moved text defining completion for the overall 
clinical study to this section. 
Clarification. 
Section 6.2.1, 
Rilzabrutinib/placebo 
Added sentence to state that frequency and/or 
severity of GI AEs may be improved if 
rilzabrutinib/placebo is taken with food. 
Clarification to align with 
Investigator’s Brochure. 
Section 6.4.4, Treatment 
blinding/unblinding 
To the text regarding the unblinding deemed by 
the Investigator to be medically necessary, 
added a reference to Appendix 10 for UK 
country-specific requirements. 
Addition of country-specific 
requirements for UK. 
Section 6.5.1, Prohibited 
medications 
Added text specifying that patients in Germany 
who need other immunosuppressant therapy 
during the study must be withdrawn, with a 
reference to Appendix 10. 
Addition of country-specific 
requirements for Germany. 
Section 6.5.2, Particular 
permissible medications 
Parenthetical statement added to first bullet as 
follows: a TPO-RA (authorized for the treatment 
of ITP). 
Clarification. 
 
Second sub-bullet added to first bullet as follows: 
Administration of corticosteroids and TPO-RAs 
should follow corresponding updated package 
inserts/SmPCs of the marketing authorization. 
Clarification of guidance for 
investigators. 
 
Second bullet: Revised text to state “IVIg or 
high-dose CS, platelet infusion, or anti-D 
immunoglobulin infusion as rescue 
medication.” 
Correction to align across the 
protocol sections. 
Section 7.6.6, Early Termination 
visit 
Added a statement regarding having patients 
return for the ET visit as soon as possible after 
the last dose of rilzabrutinib or placebo. 
Clarification. 
Section 7.7.3, Medical history 
Added text specifying that medical history will 
include a history of all underlying medical 
conditions within the last 10 years as well as 
detailed ITP history. 
Clarification. 
Section 9.4, Pregnancy 
Added information regarding reporting pregnancy 
AEs/SAEs, including complication or elective 
termination, abnormal pregnancy outcomes. and 
post-study pregnancy related SAEs. 
Clarification. 
Section 10, Statistical methods 
Updated text regarding SAP in first paragraph. 
Clarification. 
Section 10.3.3, Modified ITT 
(mITT) Population 
The mITT population will not be used for primary 
efficacy analyses. Thus, the second sentence in 
this section was revised to state the following: 
“The mITT population may be used for sensitivity 
analyses.” 
Health authority request; the ITT 
population will be used for primary 
efficacy analyses. 
Section 11, Investigator 
Responsibilities 
Updated to specify that investigators will sign the 
separate protocol and amended protocol 
agreement form. 
Template update. 
Section 14.1, Local 
regulations/Declaration of Helsinki 
Updated section with new template language. 
Template update. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 16, Appendices, 
Appendix 8, Guidelines to sites for 
delayed patient visits or missed 
visits due to travel restrictions or 
any foreseeable impacts of 
COVID-19. 
Added section regarding urine pregnancy testing 
for women of childbearing potential. 
To clarify how to collect pregnancy 
test results if remote visits are 
needed for COVID-19. 
Appendix 10, Country-specific 
requirements 
Appendix 10 added per Sanofi template to 
include country-specific requirements for UK, 
Germany, Austria, Turkey, and Ukraine. 
Template update; incorporation of 
country-specific requirements into 
appendix. 
Appendix 11, Protocol 
Amendment History 
Appendix 11 added per Sanofi template. 
Template update. 
Throughout document 
Replaced “PRN1008” with “rilzabrutinib” as 
applicable. Sanofi protocol number (EFC17093) 
add to protocol as applicable. 
Administrative update. 
In addition, other minor editorial changes (eg, grammatical, stylistic, and minor typographical 
error corrections) were implemented throughout the protocol. 
Appendix 11.13 Amended Clinical Trial Protocol 02 (21 July 2021) 
This amended clinical trial protocol 02 (Amendment 02) is considered to be substantial based on 
the criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the 
Council of the European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The primary reasons for this amendment to Protocol PRN1008-018 are： 
• To incorporate feedback from health authorities as well as other clarifications deemed 
necessary by the Sponsor. 
• To implement new clinical safety results and measures based on updated Investigator’s 
Brochure (IB). 
• To add the exploratory endpoint in order to evaluate the impact of the IMP on vaccine 
responses. 
• To add other exploratory efficacy endpoints to enable comparison between studies and 
projects. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page and throughout the 
protocol 
Document formatting revisions were made. 
The header and footnote were updated. 
Compound number, Sponsor name and 
regulatory information were updated on the 
title page. 
Administrative changes to comply 
with Sanofi standard. 
Synopsis: Investigational Plan, 
Section 4 Study Design 
Stratification by age during randomization was 
removed. 
Correction as age is not a 
stratification factor for this study. 
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Section # and Name 
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Brief Rationale 
Synopsis: Investigational Plan, Table 
1: Schedule of Assessments - 
Blinded Treatment Period, 
footnote b, Section 4 Study Design 
The definitions of responder and 
non-responder were revised to: 
“At the end of 12 weeks of treatment, patients 
will be assessed for achieving a platelet 
response defined as platelet count of 
≥50,000/μL OR a platelet count between 
≥30,000/μL and <50,000/μL and at least 
doubled from baseline at any time during the 
first 12 weeks and in the absence of 
rescue medication in the 4 weeks prior to 
the latest elevated platelet count that 
meets platelet response criteria. Baseline is 
defined as the average of all the patient’s 
Predose platelet counts (Screening and Study 
Day 1). 
• 
Participants who respond will continue 
the blinded treatment period for a total of 
24 weeks before entering the open label 
Period. 
• 
Participants who do not respond 
(including patients who receive rescue 
medication after Week 8) will be allowed 
to discontinue from the study or may 
enter the 28-week open label period at 
the end of Week 12, receiving treatment 
with 400 mg BID of rilzabrutinib. Initial 
study medication assignment will remain 
blinded. 
… 
After completing the Open Label Period, 
patients who demonstrate a platelet response 
defined as platelet counts ≥50,000/μL or 
≥30,000/μL and at least doubled from 
baseline at ≥50% of the visits without 
receiving rescue therapy during the last 
8weeks of the open label period, will be 
allowed to enter the LTE.”  
Clarification 
Synopsis: Planned number of 
participants, Sample size, and 
Section 10.1 Determination of 
Sample Size 
The planned number of adult participants was 
updated to “approximately 194”. 
The Sample Size in Synopsis and 
Section 10.1 were revised to: 
“The adult sample size chosen for this study 
was selected to achieve enrollment of 
129 adult patients (≥18 years) on rilzabrutinib 
and 65 adult patients on placebo.”… 
“The primary efficacy endpoint…A sample 
size of 194 (129 versus 65 adult patients in 
the rilzabrutinib versus placebo arms, 
respectively) will provide 86% power to detect 
a 20% difference in response rates between 
the 2 arms (25% vs 5%, in the rilzabrutinib 
Sample size recalculated based 
on increasing the study power 
from 80% to 8 6% to detect a 
20% difference in response rates 
between the 2 study arms. 
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Brief Rationale 
versus placebo arms, respectively), using the 
Fisher’s Exact test with a 0.01 two-sided 
significance level.” 
Synopsis: Inclusion criteria #1, and 
Section 5.1 Inclusion criteria #1 
Revised to: 
Participants will be male and female with 
primary ITP with duration of >6 months in 
ages 12 to <18 years (If not permitted per 
the country-specific  requirements, see 
Appendix 10 country-specific 
requirements) and duration of >3 months in 
ages 18 years and above. 
Grammar and stylistic change 
Synopsis: Inclusion criteria #3, and 
Section 5.1 Inclusion criteria #3 
“Participants from 12 to <18 years of age must 
additionally be determined to need treatment 
for ITP as per clinical assessment by the 
Investigator” was added as a note to clarify 
this criterion for pediatric patients.  
Changes made according to the 
opinion of the EMA Pediatric 
Committee to ensure a thorough 
individualized assessment of 
each potential adolescent 
patient’s need for treatment under 
the proposed protocol. 
Synopsis: Inclusion criteria #4, and 
Section 5.1 Inclusion criteria #4 
This criterion was updated to: 
 “Adequate hematologic, hepatic, and renal 
function (absolute neutrophil count  
≥1.5 X 109/L, AST/ALT ≤1.5 x upper limit of 
normal (ULN), albumin ≥3 g/dL, total bilirubin 
≤1.5 x ULN, [unless the patient has 
documented Gilbert syndrome], estimated 
glomerular filtration rate (GFR) >50 (Cockcroft 
and Gault method)” 
Clarification 
Synopsis: Inclusion criteria #5, 
Section 4.1.2 Blinded Treatment 
Period (Weeks 1 to 24), and 
Section 5.1 Inclusion criteria #5 
This criterion was updated as: 
“Hemoglobin >9 g/dL within 1 week prior to 
Study Day 1”. 
Therefore, the following was removed from 
Section 4.1.2 for Day 1 Week 1: “with the 
exception of hemoglobin which is to be 
rechecked prior to dosing”. 
Allow flexibility to get hemoglobin 
test results within 1 week prior to 
Study Day 1. 
Synopsis: Inclusion criteria #6, 
Section 5.1 Inclusion criteria #6, and 
Appendix 13 Contraceptive and 
Barrier Guidance 
Inclusion criterion regarding contraceptive use 
by men and women was revised. Male 
contraception requirements were added. 
Appendix 13 was added as part of standard 
appendices in Sanofi protocol template. 
Updated contraceptive language 
and appendix as per Sanofi 
standard. 
Synopsis: Exclusion criteria #10, 
Section 5.2 Exclusion criteria #10 
Revised to:  
“Use of known strong-to-moderate inducers or 
inhibitors of CYP3A within 14 days or 
5 half-lives (whichever is longer) of Study Day 
1 and until the end of the active treatment 
period” 
Correction to ensure no 
pharmacokinetic impact on 
rilzabrutinib by time-dependent 
CYP3A inhibitors and CYP3A 
inducers. 
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Section # and Name 
Description of Change 
Brief Rationale 
Synopsis: Exclusion criteria #17, 
Section 5.2 Exclusion criteria #17, 
and Appendix 10 Country-specific 
requirements 
Revised to: 
Positive QuantiFERON®-TB Gold, or 
QuantiFERON®-TB Gold Plus (QFT Plus) at 
Screening unless all of the following 
3 conditions are true (see 
Appendix 10 country specific 
requirements). 
Appendix 10.4 Canada country-specific 
requirements added with the following text: 
“• Synopsis and Section 5.2, Exclusion 
criteria, criterion 17: For patients in 
Canada, a positive QuantiFERON®-TB 
Gold Plus at Screening will result in 
exclusion. The 3 conditions to allow 
inclusion with a positive test do not apply 
to patients in Canada.” 
Stylistic change and addition of 
country-specific requirements for 
Canada. 
Synopsis: Exclusion criteria #18, 
Section 5.2 Exclusion criteria #18 
Revised to: 
“History of recurring (2 or more) serious 
infections requiring intravenous antibiotic, 
antivirals or antifungals therapy within the 
last 3 months before Study Day 1 or active 
serious or moderate infection ongoing on the 
day of randomization” 
To exclude patients with history of 
recurring (2 or more) serious viral 
and fungal infections requiring 
intravenous antivirals or 
antifungals therapy within the last 
3 months before Study Day 1. 
Synopsis: Exclusion criteria #23, 
#24, Section 5.2 Exclusion criteria 
#23, #24  
Added the following exclusion criteria: 
23. Positive COVID-19 molecular test (if 
COVID-19 testing required per local 
guidelines to be determined for each site) 
24. COVID-19 vaccine within 14 days prior 
to Study Day 1 or planned during the last 
12 weeks of blinded treatment period 
COVID-19 testing, and COVID-19 
vaccination requirement added to 
ensure patients safety during the 
study and as per local health 
authority recommendations. In 
addition, recent reports suggest 
exacerbation of immune 
thrombocytopenia following 
COVID-19 vaccination among 
patients with ITP (Kuter 2021). 
Administration of COVID-19 
vaccination during the last 
12 weeks of the blinded treatment 
period is prohibited because it 
may confound the primary 
endpoint results. 
Table 1: Schedule of Assessments - 
Blinded Treatment Period 
Added “SARS-CoV-2 test” at Screening in 
Table 1 and corresponding footnote v. 
“v. COVID-19 molecular test (if COVID-19 
testing is required per local guidelines to 
be determined for each site).” 
Section 6.6.1 Prohibited Medications 
Added: 
 “COVID-19 vaccine is prohibited during 
the last 12 weeks of the blinded treatment 
period” 
Synopsis: Exploratory Endpoints, 
and Section 3.2.4 Exploratory 
Endpoints 
Added the following 3 exploratory endpoints: 
• 
Percentage of weeks with platelet 
count ≥50,000/μL OR between 
≥30,000/μL and <50,000/μL and at 
least doubled from baseline over the 
24-week blinded treatment period in 
the absence of rescue therapy 
• 
Proportion of participants with 
complete response (defined as 
platelet count ≥100,000/μL on 
2 consecutive visits at least 5 days 
Added exploratory efficacy to 
enable comparison between 
studies and projects. 
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apart and no bleeding or rescue ITP 
therapy use on and through these two 
visits. 
• 
Proportion of participants with 
platelet count ≥50,000/μL on 
2 consecutive visits at least 
5 days apart and no rescue ITP 
therapy use on and through these 
two visits. 
Synopsis: Exploratory Endpoints, 
and Section 3.2.4 Exploratory 
Endpoints 
The following exploratory endpoint: “(Optional) 
Vaccine-specific IgG response during 
treatment” was added. 
 
Changes made to address the 
purpose of adding the exploratory 
endpoint in order to evaluate the 
impact of the IMP on vaccine 
responses, and for consistency 
with this added exploratory 
endpoint, changes were made 
through the protocol. 
Synopsis: Table 1: Schedule of 
Assessments - Blinded Treatment 
Period, Table 2: Schedule of 
Assessments - Open Label Period, 
Table 3: Schedule of Assessments - 
Long-Term Extension 
“(Optional) sample for vaccine-specific IgG” 
was added in Table 1. Table 2 and Table 3. 
Footnotes “s”, “n” and “i” were added to Table 
1, 2 and 3, respectively, to clarify the 
requirements regarding the optional sample 
for vaccine-specific IgG: 
“Optional collection of 2 blood samples for 
vaccine-specific IgG in rum (see 
Section 7.7.9 for a list of routine 
vaccines). 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”. 
 
Section 4.1.2 Blinded Treatment 
Period (Weeks 1 to 24), 
Section 4.1.3 Open Label Period 
(Weeks 25 to 53), Section 4.1.4 End 
of Study visit (Four Weeks post last 
dose of study drug), Section 4.1.5 
Long-Term Extension (LTE) 
Added “(Optional) vaccine-specific IgG 
response” as one of the collected exploratory 
laboratory blood samples. 
 
Section 7.7.9 Vaccine IgG (optional)  
Section 7.7.9 was developed for optional 
Vaccine IgG collection and requirements. 
 
Section 8.1 Specification of the 
Efficacy Parameters 
Added “optional vaccine IgG levels” as one of 
the planned laboratory assessments in 
Section 8.1. 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Synopsis: Exploratory Endpoints, 
and Section 3.2.4 Exploratory 
Endpoints 
Refer to Appendix 10 Country-specific 
requirements for China-specific endpoints 
after the exploratory endpoints listing.  
Changes made to comply with 
Sanofi standards and to clarify 
country-specific requirements for 
participants in China. 
Synopsis: Table 1: Schedule of 
Assessments - Blinded Treatment 
Period, Table 2: Schedule of 
Assessments - Open Label Period, 
Table 3: Schedule of 
Assessments - Long-Term Extension 
Footnotes “r”, “m”, and “h” were added for in 
Table 1, Table 2 and Table 3, respectively, 
referring to Appendix 10 for country-specific 
requirements.  
 
Section 4.1.2 Blinded Treatment 
Period (Weeks 1 to 24), 
Section 4.1.3 Open Label Period 
(Weeks 25 to 53), Section 4.1.4 End 
of Study visit (Four Weeks post last 
dose of study drug), Section 4.1.5 
Long-Term Extension (LTE) 
For each bullet point “Collect exploratory 
laboratory blood samples” reference to 
Appendix 10 country-specific 
requirements) has been added. 
 
Section 7.7.8 Bruton’s Tyrosine 
Kinase (BTK) Occupancy, 
Section 7.7.9 Vaccine IgG (optional), 
Section 8.1 Specification of the 
Efficacy Parameters 
Refer to Appendix 10 country-specific 
requirements as these 3 sections contains 
assessments that are not applicable for 
participants in China. 
 
Appendix 10.5 China country-specific 
requirements 
This entire section was added to outline 
country specific requirements for participants 
from China, such as exploratory biomarker 
samples and optional blood samples for 
vaccine-specific IgG response will not be 
collected for participants in China; exploratory 
endpoints regarding BTK occupancy, 
biomarker levels, and (optional) 
vaccine-specific IgG response are not 
applicable to participants in China, and 
specific requirement was mentioned for 
biological samples handling and disposal. 
 
Synopsis: Pharmacokinetics and 
Section 10.3.12 Pharmacokinetic 
Analysis (PK) 
Added “metabolites, if applicable” as part of 
the analytes in plasma samples.  
To allow PK assessment of 
relevant metabolites of 
rilzabrutinib. 
Section 7.7.7 Pharmacokinetic 
Assessments 
Added the following text: 
“Plasma samples will be obtained for PK 
characterization of rilzabrutinib as outlined 
in the SoA (see Table 1, Table 2 and 
Table 3). If applicable, residual plasma 
samples could be utilized to assess PK of 
relevant metabolites of rilzabrutinib (eg, 
PRN834 & PRN4400). Concentrations at 
each time point will be reported. 
Pharmacokinetic samples could be used 
for testing analytical method performance 
such as comparability.” 
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Section # and Name 
Description of Change 
Brief Rationale 
Synopsis: Table 1: Schedule of 
Assessments - Blinded Treatment 
Period 
Added footnote “t” to “inform consent” at 
Screening. 
“t. Participants enrolled into the 
adolescent portion of the trial will still be 
considered as part of the adolescent group 
with all the planned assessments when 
they turn 18 years old, unless specified, 
and they should be re-consented with an 
adult consent.” 
Clarification 
Synopsis: Table 1: Schedule of 
Assessments - Blinded Treatment 
Period, Section 4 Study Design 
Added following text to both Table 1 footnote 
“w” and Section 4: 
“During the blinded treatment period 
(Week 13 to Week 24): Participants who 
discontinue from the blinded treatment 
period due to safety or other reasons and 
choose to join the open label period will 
undergo the Week 25 assessments at their 
next scheduled visit.” 
Added the following text in Section 4: 
“Participants who discontinue the blinded 
treatment period and choose not to join 
the open label period, should attend an ET 
visit as shown in the SoA (Table 1) for 
collection of data at the time of study 
discontinuation and for follow-up and any 
further evaluations that need to be 
completed.” 
To clarify the study design and 
visits/assessments to be 
performed for patients who 
discontinue from the blinded 
treatment period. 
Synopsis: Table 1: Schedule of 
assessments - Blinded Treatment 
Period, Table 2: Schedule of 
assessments - Open Label Period 
Added footnote “u” and ”s” in Table 1 and 
Table 2, respectively, to clarify hematology 
samples collected at weekly lab visits are only 
for platelet count collection. 
“This is only for collecting platelet count 
and can be conducted on-site or at home 
during a nurse visit.” 
Footnote “o” and “p” in Table 1, and footnote 
“j” and “k” in Table 2 were revised to clarify 
time window information for PK and BTK 
occupancy sampling. 
Clarification and include time 
window for PK sampling time 
points 
Synopsis: Table 1: Schedule of 
Assessments - Blinded Treatment 
Period, Table 2: Schedule of 
Assessments - Open Label Period, 
Table 3: Schedule of Assessments - 
Long-Term Extension 
Added a row for “paper diary” to be collected 
at the same time of the rilzabrutinib 
dispensation. 
Implement paper diary to 
document IMP administration 
information. 
Synopsis: Table 3: Schedule of 
Assessments - Long-Term Extension 
QOL questionnaires footnote “g” was revised 
to include ITP-KIT for adolescent patients and 
PGIC assessments for adult patients. 
Correction 
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Synopsis: Table 1: Schedule of 
Assessments - Blinded Treatment 
Period, Table 2: Schedule of 
Assessments - Open Label Period, 
Table 3: Schedule of Assessments - 
Long-Term Extension, and 
Appendix 10.2 Germany 
country-specific requirements 
The previous footnotes “r”, “m” and “f” were 
removed from the Table 1, 2 and 3, 
respectively. 
Added footnote “r” to refer to Appendix 10.2 
Country-specific requirements in Table 1 and 
added a row for “SARS-CoV-2 test” with new 
footnotes “m” and “h” referring to 
Appendix 10 for country-specific requirements 
for Germany in Table 2 and Table 3. 
The following specific requirements was 
revised in Appendix 10.2 Germany 
country- specific requirements: 
“Participants in Germany must be tested… 
The test may no longer be required (with 
approval from the ethics committee) if the 
local regulations change with control of the 
SARS-CoV-2 pandemic”. 
Update SARS-CoV-2 test 
language according to Germany 
regulations, and the SoA 
(Table 1, Table 2 and Table 3) 
were rearranged to better present 
this specific assessment. 
Synopsis: Table 2: Schedule of 
Assessments - Open Label Period 
In column title, “SD169” and “SD365” were 
corrected to “First” day of WK25 and 
WK53, respectively.  
Footnotes “o”, “p” and “q” were added: 
“o. Week 25/SD169 visit is the last visit of 
the blinded treatment period and also 
serve as the start of the open label period. 
p. For patients who will enter the open 
label period directly after 12 weeks of 
blinded treatment, they will attend the 
Week 13/SD85 visit which corresponds to 
the Week 25/SD169 visit (Table 2), this 
would be their last visit of the blinded 
treatment period and also the start of the 
open label period. They will follow the 
open label period SoA from Week 29 
(Table 2) starting at their next scheduled 
visit. 
q. For patients who will enter the open 
label period directly after 12 weeks of 
blinded treatment, the last day (EOT visit) 
in open label period will occur on 
Week 41/SD281.” 
Correction and clarification 
Synopsis: Table 2: Schedule of 
Assessments - Open Label Period, 
and Section 4.1.3 Open Label Period 
(Weeks 25 to 53) 
In synopsis Table 2: 
“ECG (12-lead, single), PK sample, and BTK 
Occupancy (at selected sites)” were ticked at 
Week 41.  
Footnote “r” was added clarifying the fact that 
these assessments will be performed “only 
for patients who will join the open label 
part at Week 13”. 
Updated Section 4.1.3, “ECG (12-lead, 
single), PK sample, and BTK Occupancy (at 
selected sites)” were added into Week 41 
assessments. 
Update to add ECG, PK and BTK 
occupancy assessments at 
Week 41 for patients that will join 
the open label period at Week 13. 
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Section # and Name 
Description of Change 
Brief Rationale 
Synopsis: Table 3: Schedule of 
Assessments - Long-Term 
Extension, and Section 4.1.5 
Long-Term Extension (LTE) 
In synopsis Table 3: 
“ECG (12-lead, single)”, “hemolysis panel”, 
and “immunoglobulin levels” were added and 
ticked at End of Study visit.  
Updated Section 4.1.5, refer to 
Section 4.1.4 for the end of study visit 
assessments in the LTE. 
Update to align the end of study 
visit assessments in open-label 
period and LTE. 
Section 2.4 Clinical Experience 
Updated clinical experiences as per new data 
included in the latest IB with the data cut-off 
date of 22 April 2021. 
Update and consistency 
Section 2.4.1 Safety  
Updated clinical safety results as per new 
data included in the latest IB with the data 
cut-off date of 22 April 2021. 
To implement new clinical safety 
results based on updated IB and 
to develop sections regarding 
benefit and risk assessments as 
per Sanofi standard. 
Section 2.7 Overall Risk-Benefit 
Assessment, Section 2.7.1 Risk 
assessment, Section 2.7.2 Benefit 
assessment, and Section 2.7.3 
Overall benefit: risk conclusion 
Section 2.7 Overall Risk-Benefit Assessment 
was revised. Three subsections 
“Section 2.7.1 Risk assessment, Section 2.7.2 
Benefit assessment, and Section 2.7.3 Overall 
benefit: risk conclusion” were developed 
under Section 2.7 to implement new findings 
in the updated IB. 
Synopsis: Table 3: Schedule of 
Assessments - Long-Term Extension 
Added footnote “a” for concomitant medication 
to indicate the taper of corticosteroid (CS) 
and/or thrombopoietin receptor agonist 
(TPO- RA) is permitted.  
Updated text to address 
corticosteroid taper in LTE. 
Section 4 Study Design 
Added text: 
“In the LTE part, reductions in the doses 
or withdrawal of concomitant ITP 
medications (an oral CS and/or a TPO-RA) 
will also be permitted if the participant 
achieves platelet count of  
≥50,000/μL in three scheduled visits (over 
12 weeks). Retreatment with the same 
medication(s) and doses of ITP 
concomitant medication(s) used at 
baseline (an oral CS and/or a TPO-RA), 
changing the dose or initiation of new ITP 
medications (an oral CS and/or a TPO-RA) 
will also be allowed. Tapering of 
concomitant CS should be performed in 
accordance with the schedule in 
Section 6.6.2.” 
Section 6.6.2 Particular Permissible 
Medications 
The corticosteroid tapering rules added 
Section 4 Study Design: Figure 1: 
Study Design Flow Chart 
Updated study schema to better present the 
study design. 
Correction and consistency 
Section 4.1.2 Blinded Treatment 
Period (Weeks 1 to 24), and 
Section 4.1.3 Open Label Period 
(Weeks 25 to 53) 
“PK blood sample” was rearranged as a 
separate bullet from the exploratory laboratory 
blood samples. 
Correction 
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Description of Change 
Brief Rationale 
Section 6.4.2 Destruction of 
Investigational Product 
Revised as “When the study is completed, 
any used and unused study medication (eg, 
empty, partially used, and unused containers) 
will be destroyed on-site or returned to the 
depot of destruction as requested.” 
Clarified to match Sanofi standard 
process of IMP destruction. 
Section 6.5 Treatment of Overdose 
Section 6.5 Treatment of Overdose was 
developed. Overdose of rilzabrutinib is 
defined, and the information of handling and 
reporting of rilzabrutinib overdose was 
implemented. 
To implement definition and 
handling procedures of 
rilzabrutinib overdose to align with 
other rilzabrutinib protocols. 
Section 6.6.1 Prohibited Medications, 
and Appendix 10.2 
Revised text specifying that all patients who 
need other immunosuppressant therapy 
during the study must be withdrawn. 
In Appendix 10.2, the country-specific 
language related to Section 6.6.1 was 
therefore removed. 
Correction and consistency 
Section 7.7.10 Immune 
Thrombocytopenia (ITP) Assessment 
Tools (IBLS, ITP-PAQ, ITP KIT) and 
throughout the protocol 
Section 7.7.10 was updated to introduce the 
ITP Bleeding Scale (IBLS). 
Throughout the protocol, “ITP-BAT” was 
corrected as “ITP Bleeding Scale” or “IBLS”. 
Correction as previously the IBLS 
was referred to as ITP-BAT by 
mistake. 
Section 9.3.9 Adverse events (AEs), 
Serious Adverse Events (SAEs) and 
Other Safety Reporting, Appendix 12 
AEs and SAEs: Definitions and 
Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
The entire Section 9.3.9 was updated and 
replaced with Sanofi standard process 
regarding AE, SAE, and other safety 
reporting. New subsections were developed, 
the definition of adverse event of special 
interest (AESI) was introduced.  
Appendix 12 was added as part of standard 
appendices in Sanofi protocol template. 
Updated section per Sanofi 
protocol template and process. 
The definition of AESI was added 
to align across rilzabrutinib 
clinical development program.  
Section 10.3.4 Pharmacokinetic (PK) 
population 
 
The definition of pharmacokinetic population 
was updated to “All patients who receive at 
least one dose of study medication in the 
safety population and have sufficient data 
for PK analysis.” 
Correction 
Section 10.3.8 Safety and Tolerability 
Analysis 
Included AESIs in the planned safety 
statistical analysis. 
Consistency 
Appendix 1 
ITP Disease Activity - ITP Bleeding 
Scale (IBLS) 
Appendix 2 ITP Disease Activity - 
ITP-PAQ 
Appendix 3 ITP Disease Activity - 
ITP-KIT 
Appendix 4 General Quality of Life 
Evaluation: EQ-5D-5L 
Appendix 5 Patient Global 
Impression of Severity (PGIS) and 
Patient Global Impression of Change 
(PGIC) 
Updated questionnaires with watermarks and 
copyright information (where applicable). 
Updated questionnaires that 
comply with Sanofi standard. 
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Section # and Name 
Description of Change 
Brief Rationale 
Appendix 6 Strong-to-Moderate 
CYP3A Inhibitors and Inducers and 
Sensitive CYP3A Substrates 
The table of Strong-to-Moderate CYP3A 
Substrates, Inhibitors and Inducers and 
Sensitive CYP3A Substrates were updated.  
Updated the 
Appendix 6 according to updated 
information from US Food and 
Drug Administration websites. 
Appendix 11: Protocol Amendment 
History 
This entire section was updated with the 
protocol amendment01 summary of changes 
table.  
Changes made to comply with 
Sanofi standards. 
In addition, other minor editorial changes (eg, grammatical, stylistic, references, and minor 
typographical error corrections) were implemented throughout the protocol. 
Appendix 11.14 Amended Clinical Trial Protocol 03 (11 August 2022) 
The primary reasons for this amendment to Amended Clinical Trial Protocol 02: 
• To modify the primary endpoint and objective to specify participants having platelet 
counts at or above 50,000/µL for ≥ two-thirds of at least 8 non-missing weekly scheduled 
platelet measurements during the last 12 weeks of the 24-week blinded treatment period 
in the absence of rescue therapy, provided that at least 2 non-missing weekly scheduled 
platelet measurements are at or above 50,000/μL during the last 6 weeks of the 24-week 
blinded treatment period. This change does not apply to the EU (EEA countries) and the 
UK.  
• To require conducting platelet count testing at local laboratories. 
• To provide guidelines for temporary discontinuation of study medication. 
• To move the IBLS assessment from the Secondary to the Exploratory endpoints (not 
applicable for the EU [EEA countries] and UK). 
• To introduce a fatigue assessment using Item 10 of the ITP-PAQ, as a Key Secondary 
endpoint. 
• To provide new instructions for the long-term extension duration and study visit 
schedule. 
• To add efficacy objectives and endpoints to the open label and long-term extension 
periods.  
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Cover page 
Sponsor address revised from “220 E Grand Avenue 
South San Francisco CA 94080, USA” to “55 Corporate 
Drive Bridgewater, NJ 08807” 
To provide the new 
address of Principia 
Biopharma Inc.  
Protocol Amendment Summary of 
Changes: Document History; 
Appendix 11: Protocol Amendment 
History 
Expanded the table to include previous country-specific 
protocol amendments and added the relevant changes 
to the protocol history in Appendix 11. 
To comply with the Sanofi 
template 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1 Synopsis: Duration of 
Study Participation, Investigational 
Plan: Study Design; Section 4.1: 
Duration of study participation  
Changed the duration of participation for participants 
who enter the long-term extension (LTE) to indicate that 
they will continue to receive treatment until the time 
expected for the last participant who enters the LTE to 
complete 12 months.   
 
Duration of long-term 
extension changed to allow 
participants who respond to 
the study medication to 
continue on treatment, and 
to evaluate the long-term 
safety and efficacy of 
treatment with rilzabrutinib     
Section 1 Synopsis: Number of 
Study Sites 
Revised the number of study sites from approximately 
125 sites to approximately 150 sites worldwide. 
Number of sites increased 
due to an increase in study 
sample size in the adult 
population and inclusion of 
new countries (China and 
Japan) and to help achieve 
the enrollment goals 
Section 1 Synopsis: Objectives, 
Primary Efficacy Objective Blinded 
Treatment Period); Endpoints, 
Primary Efficacy Endpoint; 
Section 3.1.1 Efficacy Objectives, 
Primary Efficacy Objective; 
Section 3.2.1 Primary Efficacy 
Endpoint 
 
The primary objective and endpoint for the blinded 
treatment period was revised to specify that the 
assessment will be based on the durability of platelet 
response defined as the proportion of participants able 
to achieve platelet counts at or above 50,000/μL for 
≥ two-thirds of at least 8 non-missing weekly scheduled 
platelet measurements during the last 12 weeks of the 
24-week blinded treatment period in the absence of 
rescue therapy provided that at least 2 non-missing 
weekly scheduled platelet measurements are at or 
above 50,000/μL during the last 6 weeks of the 24-week 
blinded treatment period.  
See Appendix 10.7 for efficacy EU (EEA countries) and 
UK-specific requirements. 
 
 
Correction to better define 
the primary objective 
(durable platelet response) 
and the criteria for meeting 
the primary efficacy 
objective/endpoint and to 
reflect the feedback from 
FDA pertaining to the 
definition of platelet durable 
response. Considering the 
EMA feedback, the durable 
platelet response will be 
defined based on the 
previous definition of the 
primary endpoint 
(proportion of adult 
participants able to achieve 
platelet counts at or above 
50,000/μL for at least 8 out 
of the last 12 weeks of the 
24-week blinded treatment 
period in the absence of 
rescue therapy) will be 
applicable to EU (EEA 
countries) and UK only, 
See Appendix 10.7. 
Section 1 Synopsis: Objectives, 
Key Secondary Efficacy Objectives 
(Blinded Treatment Period); 
Section 3.1.1 Efficacy Objectives, 
Key Secondary Efficacy Objectives 
(Blinded Treatment Period) 
Added the following key secondary efficacy objective 
evaluated during the blinded treatment period: “To 
evaluate the effect of rilzabrutinib versus placebo on the 
change from baseline on Item 10 of the ITP-PAQ (ie, 
physical fatigue) in adult participants (≥18 years) at 
Week 13” 
Deleted: “To evaluate the effect of rilzabrutinib versus 
placebo on the change from baseline in Idiopathic 
Thrombocytopenic Purpura Bleeding Scale (IBLS) 
assessment”. This revision is not applicable to EU (EEA 
countries) and the UK as per RA (EMA) feedback (See 
Appendix 10.7). 
To position Item 10 of the 
ITP-PAQ instrument within 
the key secondary 
objectives. Included 
“rilzabrutinib versus 
placebo”, to be clear about 
the comparison.  
To re-position the change 
in IBLS to be an 
exploratory endpoint except 
in the EU (EEA countries) 
and the UK as per RA 
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Section # and Name 
Description of Change 
Brief Rationale 
The second key secondary efficacy objective in the 
blinded treatment was revised to: To evaluate the effect 
of rilzabrutinib versus placebo on the number of weeks 
with platelet counts ≥30,000/μL and at least doubled 
from baseline over the 24-week blinded treatment 
period in the absence of rescue therapy.  
(EMA) feedback (See 
Appendix 10.7). 
To be consistent with the 
endpoint below. 
 
 
 
 
Section 1 Synopsis: Endpoints, Key 
Secondary Efficacy Endpoints 
(Blinded Treatment Period); Key 
Secondary Efficacy Analyses 
Section 3.2.2 Key Secondary 
Efficacy Endpoints; 
Section 10.3.10 Key Secondary 
Efficacy Analysis 
Revised the Key Secondary Efficacy endpoints for the 
blinded treatment period as follows: 
• 
Inserted an endpoint assessing change from 
baseline on Item 10 of the ITP-PAQ (ie, 
physical fatigue) in adult participants  
(≥18 years) at Week 13 
• 
Deleted the endpoint evaluating the change 
from baseline in IBLS assessment at  
Week 25 
The second, key secondary efficacy endpoint in the 
blinded treatment was revised to: Number of weeks with 
platelet counts ≥30,000/μL and at least doubled from 
baseline over the 24-week blinded treatment period in 
the absence of rescue therapy.  
Fatigue endpoint added to 
key secondary endpoints. 
IBLS assessment moved to 
exploratory endpoints 
except for EU (EEA 
countries) and the UK as 
per RA (EMA) feedback; 
see Appendix 10.7. 
Correction to the endpoint 
to include responders with 
platelet count ≥30,000 /μL 
and at least doubled from 
baseline. The platelet count 
<50,000 /μL was removed 
because it excludes 
patients with platelet 
response of ≥50,000 /μL 
from the analysis. 
Section 1 Synopsis: Endpoints; 
Section 3 Objectives and Endpoints 
Added new subsections to specify exploratory 
endpoints that will be evaluated during the open label 
period and long-term extension to distinguish them from 
those assessed during the blinded treatment period.  
To clarify the exploratory 
endpoints that will be 
evaluated during the open 
label and long-term 
extension periods. 
Section 1 Synopsis: Objectives, 
Other Secondary Objectives; 
Endpoints, Other Secondary 
Endpoints; Section 3.1.2 Other 
Secondary Objectives; Section 
3.2.3 Other Secondary Endpoints  
Added the following other secondary efficacy objective 
and endpoint, respectively: 
• 
To evaluate the stability of platelet response 
of rilzabrutinib. 
• 
Stability of response defined as the proportion 
of participants able to achieve stable platelet 
response, which is defined as no 2 scheduled 
visits, at least 4 weeks apart, with a platelet 
count less than 50,000/μL, without an 
intervening visit with a platelet count 
≥50,000/μL, within a period of 24 weeks 
following initial achievement of the platelet 
response (initial platelet response defined as 
platelet count ≥ 50,000/μL within 12 weeks of 
initiation of treatment with rilzabrutinib during 
the study).   
To include a long-term 
efficacy endpoint that can 
be evaluated at the blinded 
treatment period, open 
label period and the 
long-term extension. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1 Synopsis: Inclusion 
criteria #3; 
Section 5.1: Inclusion criteria #3 
IC #1 revised to: 
Patients will be male and female with primary ITP with 
duration of >6 months in pediatric participants aged 
12 to <18 years (pediatric participants aged 10 to  
<12 years will be enrolled in the EU [EEA countries] 
only; refer to Appendix 10.2, Appendix 10.3 and 
Appendix 10.7 for country-specific requirements) and 
duration of  >3 months in adults aged ≥18 years. 
Revision to indicate specific 
age criteria for the EU 
(EEA countries) 
 
IC #3 revised to:  
An average of 2 platelet counts at least 5 days apart of 
<30,000/µL during the screening period, and no single 
platelet count >35,000/µL within 14 days prior to the 
first dose of study drug 
• 
Pediatric participants must additionally be 
determined to need treatment for ITP as per 
clinical assessment by the Investigator (see 
Appendix 10.7 for EU [EEA countries] specific 
criteria) 
In accordance to EMA 
feedback, country-specific 
requirement (body weight 
limit) was included to 
ensure that the exposure to 
the IMP among pediatric 
participants 10 to >12 years 
old is comparable to 
pediatric participants 
≥ 12 years old.   
Section 1 Synopsis: Endpoints, 
Exploratory Endpoints (Blinded 
Treatment Period); 
Section 3.2.4 Exploratory Endpoints 
Revised the Exploratory endpoints in the blinded 
treatment period as follows: 
Inserted: “Change from baseline in Idiopathic 
Thrombocytopenic Purpura Bleeding Scale (IBLS) 
assessment at Week 13 and Week 25” 
Specified that the change in all ITP-PAQ domains will 
be assessed from baseline to Week 25 and from  
Week 13 to Week 25. In addition, specified that the 
change in all but Item 10 (Fatigue Scale) will be 
assessed from baseline to Week 13 as an exploratory 
endpoint. 
IBLS assessment moved to 
exploratory endpoints 
except for EU (EEA 
countries) and the UK as 
per RA (EMA) feedback; 
see Appendix 10.7. 
Assessment of fatigue 
moved from exploratory to 
key secondary endpoints. 
Section 1 Synopsis: Endpoints, 
Exploratory Endpoints (Blinded 
Treatment Period); 
Section 3.2.4.1 Blinded Treatment 
Period; 
Section 7.9 Study Assessments; 
Appendix 5: Patient Global 
Impression of [Fatigue] Severity 
(PGIS-Fatigue), Patient Global 
Impression of Severity (PGIS), and 
Patient Global Impression of 
Change (PGIC) 
Added an exploratory endpoint assessing 
“disease-related fatigue using the PGIS-Fatigue scale”. 
Added a subsection 7.9.12 with a description of the 
PGIS-Fatigue and the questionnaire to Appendix 5.  
To add an assessment that 
focuses on fatigue severity.  
Section 1 Synopsis: Study Design; 
Section 4: Study Design 
Added the following paragraph: Randomization will be 
carried out separately for the two age groups. For the 
adult group, stratified permuted block randomization will 
be implemented; for the pediatric group, dynamic 
randomization algorithm (minimization) will be 
implemented. The factors used for stratification (for 
adult participants) or balance (for pediatric participants) 
are splenectomy status (yes/no), and by severity of 
thrombocytopenia (Inclusion Criteria 3 platelet counts 
<15,000/μL or ≥15,000/μL). 
Clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1 Synopsis: Sample Size;  
Section 10.1 Determination of 
Sample Size 
Revised text: 
A sample size of approximately 194 (129 versus  
65 adult participants in the rilzabrutinib versus placebo 
arms, respectively) will provide 86% power to detect a 
20% difference in response rates as defined in the 
primary endpoint (Section 3.2.1) between the 2 arms 
(25% vs 5%, in the rilzabrutinib versus placebo arms, 
respectively), using the Fisher’s Exact test with a 
0.01 two-sided significance level. 
Added paragraph to Section 10.1: 
The assumption of a 25% response rate in the 
rilzabrutinib group is based on the 
Phase 2 Study PRN1008-010 Part A (DFI17124 Part A) 
(durable response [8 out of the last 12 weeks with 
platelet count at or above 50,000/μL in the absence of 
rescue medication]) and the 5% response rate is 
estimated based on the observed placebo response in 
previous randomized controlled trials of ITP medications 
(Bussel 2018). The participants who are not evaluable 
for primary efficacy due to dropout or missing data will 
be considered as non-responders.  
To clarify the assumptions 
and rationale of the study 
sample size calculation. 
Section 1 Synopsis: Primary 
Efficacy Analysis,  
Section 10.3.9: Primary Efficacy 
Analysis 
Revised text:  
The primary analysis will compare the proportion of 
participants in the adult ITT population who achieve 
durable platelet response defined as platelet counts at 
or above 50,000/μL for ≥ two-thirds of at least 
8 non- missing weekly scheduled platelet 
measurements during the last 12 weeks of the 24-week 
blinded treatment period in the absence of rescue 
medication (provided that at 2 non-missing weekly 
scheduled platelet measurements are at or above 
50,000/μL during the last 6 weeks of the 24-week 
blinded treatment period) between rilzabrutinib and 
placebo with a Cochran-Mantel-Haenszel test using the 
two stratification factors at a 2-sided alpha level of 0.01. 
Participants who do not respond in the first 12 weeks 
and enter the open label period will be treated as 
non-responders in the primary analysis. 
Added:  
“The primary endpoint will be analyzed for adult and 
pediatric participants separately. 
Platelet counts conducted locally will be used for the 
primary endpoint analysis. Platelet counts conducted 
centrally at Clinic Visits will be used as a back-up for 
missed or non-analyzable local lab samples.” 
Consistency with primary 
endpoint modification. 
Clarify that platelet count 
assessments for the 
primary endpoint should be 
conducted at the local 
laboratories.  
Section 1 Synopsis: Other statistical 
considerations; 
Section 10 Statistical methods; 
Section 10.4 Interim Analysis 
New section added to further clarify the separate 
analyses for adult and pediatric participants due to 
different enrollment expectations, and to clarify that 
additional analyses may be performed at the Sponsor’s 
discretion for purposes of regulatory filings, 
publications, or future planning after the early analysis. 
Clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1 Synopsis: Table 1, 
Table 2, and Table 3;  
Section 4.1 Duration of Study 
Participation  
The term “Paper Diary” has been revised to “Patient 
Medication Diary” and the collection of this diary newly 
specified in Section 4.1. 
To align with correct 
naming of the document. 
Section 1 Synopsis: Table 1, and 
Footnote a 
Added the following text to footnote a: “The screening 
period can be up to -31 days of Study Day 1.” 
Clarification 
Section 1 Synopsis: Table 1, 
Footnote d 
Added: Medical history should include vaccine history. 
Clarification 
Section 1 Synopsis: Table 1, 
Footnote l; Table 2: Footnote g 
Text added to footnote: 
Local laboratories will be used for platelet analysis 
required at ALL visits (ie, Clinic Visits and Weekly Lab 
Visits in between Clinic Visits). 
The central laboratory will be used for the analyses 
required at Clinic Visits including hematology, 
differential, and reticulocytes. The results of 
hematology, differential and reticulocytes obtained at 
local laboratories will be used only if the central lab 
results of Clinic Visits are missing due to any reason. 
Central platelet counts assessed at Clinic Visits will be 
used if local platelet results are missing for any reason.  
Hematology footnote 
modified to clarify that 
platelet counts should be 
conducted at the local 
laboratories. 
Section 1 Synopsis: Table 1, 
Footnote o 
Revised this footnote to exclude the Week 25 
assessment (included with Table 2), and deleted the 
last sentence:  
“At Week 53 and ET, random timepoint samples will be 
collected and the time of sample and time of the last 
dose of rilzabrutinib or placebo will be captured.” 
Clarification to align with 
SoA 
Section 1 Synopsis: Table 1, 
Footnote p 
Deleted the Week 25 assessment (included in 
Table 2) and removed below text from footnote p: 
“At Week 53 a random timepoint sample will be 
collected and the time of draw and time of the last dose 
of rilzabrutinib or placebo will be captured.” 
Clarification to align with 
SoA 
Section 1 Synopsis: Table 1, 
Footnote q 
Added: The PGIC will be collected starting after Day 1. 
The PGIC asks the 
participant to describe 
disease-related symptoms 
since starting the study 
medication. 
Section 1 Synopsis: Table 1 
Footnote u, Table 2 Footnote r 
Revised: 
Table 1 Footnote u to: “This visit is for platelet count 
assessment and can be conducted on-site or remotely. 
After the end of treatment (EOT) visit, weekly platelet 
count assessment is not required; however, it is up to 
the Investigator to decide whether to conduct weekly 
platelet assessments using unscheduled visits, if 
deemed necessary for participant safety.”  
Clarification  
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Section # and Name 
Description of Change 
Brief Rationale 
Table 2 Footnote r (previously footnote s) to: “This visit 
is for platelet count assessment and can be conducted 
on-site or remotely. Lab visits will occur weekly from 
Week 25 to Week 53. The Investigator can request that 
the participant visits the clinic for additional platelet 
monitoring during unscheduled visits if needed. After 
the end of treatment (EOT) visit, weekly platelet count 
assessment is not required; however, it is up to the 
Investigator to decide whether to conduct weekly 
platelet assessments using unscheduled visits, if 
deemed necessary for participant safety.” 
Section 1 Synopsis: Table 1 
Added annotation and corresponding footnote x to 
indicate the end of study visit for participants who 
discontinue treatment during the blinded treatment 
period.  
“All participants who discontinue treatment during the 
blinded or open-label period need to have an ET visit as 
specified in Table 1 and an End of Study visit (4 weeks 
after last IMP intake) as specified in the End of Study 
visit in Table 2 (See End of Study Table 2).” 
Clarification of end of study 
visit for early termination 
during blinded treatment 
period  
Section 1 Synopsis: Table 2 
Deleted ECG, PK and BTK assessments at Week 41 
and the ECG assessment at Week 29.  
To decrease the study 
burden as assessments at 
these visits are not needed. 
Section 1 Synopsis: Table 2, 
Footnote c 
Added the following text to footnote c:  
“Adult participants are also required to complete ECG at 
Week 25.” 
Clarification 
Section 1 Synopsis: Table 2, 
Footnote j 
Revised footnote j to: 
“At Week 25 visit, PK samples for participants aged  
18 years or older will be collected Predose (within  
1.5 hours predose) and 2 hours postdose (±15 mins). 
At the Week 25 visit, PK samples for pediatric 
participants (see Appendix 10.7 for EU [EEA countries] 
age ranges) will be taken Predose (within 1.5 hours 
predose) and postdose at the following timepoints:  
0.5 hours (±5 mins), 2 hours (±5 mins) and 4 hours 
(±15 mins), 6 hours (±15 mins). At these visits, 
participants will wait to take their morning dose until 
they complete the blood draw of pre-dose sample. At 
Week 53 and ET visits, a random timepoint PK samples 
will be collected and the time of sample and time of the 
last dose of rilzabrutinib will be captured.” 
Clarification to align with 
SoA 
Section 1 Synopsis: Table 2, 
Footnote k 
Revised footnote k to: 
“At Week 25 visit, BTK occupancy samples for 
participants aged 18 years or older will be collected 
Predose (within 1.5 hours predose) and 2 hours 
postdose (±15 mins). At Week 25 visit, BTK Occupancy 
samples for pediatric participants (see Appendix 10.7 
for EU [EEA countries] age ranges) will be taken 
Predose (within 1.5 hours predose) and postdose at the 
following timepoints: 0.5 hours (±5 mins), 2 hours  
(±5 mins) and 4 hours (±15 mins), 6◦hours (±15 mins). 
At these visits, participants will wait to take their 
Clarification to align with 
SoA 
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Section # and Name 
Description of Change 
Brief Rationale 
morning dose until they complete the blood draw of 
pre-dose sample. At Week 53, a random timepoint BTK 
occupancy sample will be collected and the time of 
sample and time of the last dose of rilzabrutinib will be 
captured” 
Section 1 Synopsis: Table 2, 
Footnote p 
Added the below text to footnote p:  
“for a total of 28 weeks” 
Clarification 
Section 1 Synopsis: Table 2, 
Footnote q 
Revised footnote q to: 
“For participants who will enter the open label period 
directly after 12 weeks of blinded treatment, they will 
follow the open-label extension SoA (Week 25 to 
Week  53) which means that they will be treated on the 
open-label part for a total of 28 weeks. After Week 53, 
the participants will follow the SoA according to their 
eligibility for the LTE period.” 
To clarify the 
end-of-treatment visit for 
participants entering the 
open-label extension. 
Section 1 Synopsis: Table 2 
Footnote “r” in Amended Clinical Trial Protocol 02 was 
deleted.   The previous footnote “s” is now footnote “r”. 
No longer needed 
Section 1 Synopsis: Table 2, 
Footnote s 
Revised footnote “r” (previously footnote “s”):  
“This visit is for platelet count assessment and can be 
conducted on-site or remotely. Lab visits will occur 
weekly from Week 25 to Week 53. The Investigator can 
request that the participant visits the clinic for additional 
platelet monitoring during unscheduled visits if 
needed. ” 
Clarification  
Section 1 Synopsis: Table 3; 
Section 4.1.5. Long-Term Extension 
(LTE) 
Revised the clinic visit schedule for participants in the 
long-term extension.  
Column header of Table 3 revised to: 
“Clinic Visits Every 28 Days for the first year of LTE 
then every 3 months thereafter”. Deleted “visits every 
28 days for 12 months” from the main header. 
Clarification of frequency of 
clinic visits for participants 
in the long-term extension 
Section 1 Synopsis: Table 3 
Deleted the PK assessment at the ET/Unscheduled visit 
Added check marks and annotation “m” to specify 
physical exam and ECG assessments, collection of 
medication diary and performance of SARS-CoV-2 test 
at the ET visit, and a footnote “m” to indicate that the 
assessment is for the ET visit only. 
Added an ECG assessment at the Week 53 visit and a 
footnote ‘n’ to indicate that assessments performed at 
the Open Lapel period Week 53 visit will be used at the 
starting visit (Week 53) of the LTE. 
Assessment not needed 
 
 
Assessment needed 
 
 
Clarification 
Section 1 Synopsis: Table 3 
Added annotation c, e, f, m and n and corresponding 
footnotes in the table and annotations of other footnotes 
changed accordingly.  
Clarification and 
consistency with other 
schedules of assessments 
Section 2.4 Clinical Experience 
Deleted details of studies in patients. 
Refer reader to the 
Investigator’s Brochure 
instead  
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Section # and Name 
Description of Change 
Brief Rationale 
Section 2.4.3 Pharmacokinetics and 
Pharmacodynamics 
Revised text for the first 2 paragraphs:  
“Rilzabrutinib is rapidly cleared from the plasma, with a 
terminal half-life of approximately 4 hours, maximum 
concentration time of approximately 2 hours after 
ingestion, and a volume of distribution of 149 L after 
intravenous administration. No significant accumulation 
was observed after multiple dosing. Approximately 3% 
of rilzabrutinib is excreted unchanged in the urine.  
Rilzabrutinib is available in a tablet formulation for 
investigation in-patient populations in clinical studies. 
Food delays the time of observed maximum plasma 
concentration (Tmax) by 1.5 h and decreases AUC and 
Cmax of rilzabrutinib by 20% and 30%, respectively, 
which is not considered to be clinically relevant. 
Rilzabrutinib showed approximately linear increases in 
exposure between doses of 150 mg and 600 mg.” 
Updated clinical 
pharmacology reference 
data 
Section 2.4.4 Drug-Drug Interaction 
Potential 
Text revised to:  
“Rilzabrutinib is a substrate of the CYP3A isoenzyme. In 
clinical drug-drug interaction studies, the CYP3A 
inhibitor ritonavir increased plasma rilzabrutinib 
concentrations (PRN1008-014) and the CYP3A inducer 
rifampin decreased plasma rilzabrutinib concentration 
(PRN1008-024); therefore, concomitant use of strong 
and moderate CYP3A inhibitors or inducers should be 
avoided. Rilzabrutinib is also a substrate of P-gp from 
in-vitro studies. However, the P-gp inhibitor quinidine 
didn’t change plasma concentrations of rilzabrutinib 
(PRN1008-024); thus, rilzabrutinib could be 
administered with P-gp inhibitors clinically.” 
Updated clinical 
pharmacology reference 
data 
Section 2.6 Dose Rationale 
Paragraph added to provide a dosing rationale for 
pediatric participants 10 to <18 years of age. 
Provide a rationale for the 
selected dosing in this 
population. 
Section 2.7.1 Risk Assessment 
Table 4 
Revised mitigation strategy text for infection to: 
“Documented vaccinations per local guidelines are 
required. Serum immunoglobulin levels will be 
monitored throughout the study. Participants who 
received live vaccine within 28 days before first dose 
will be excluded. Live vaccines are not allowed during 
treatment. Participants with evidence suggestive of 
active TB are excluded. Participants with history of 
serious infections requiring intravenous therapy with the 
potential for recurrence are excluded.” 
Changed the duration in 
which participants may 
receive a live vaccine prior 
to first dose from 12 weeks 
to 28 days. 
Section 4 Study Design 
 
Figure 1 inserted, which describes the decision process 
for assessing response in participants who have 
completed 12 weeks in the study. 
Insertion of a visual aid to 
show the decision process 
for assessing response  
Section 4.1.1 Screening (Day -28 to 
Study Day -1 Predose) 
Added the below text to screening visit: 
“Perform SARS-CoV-2 molecular test (if 
COVID- 19 testing is required per local guidelines to be 
determined for each site).” 
To add COVID-19 testing 
requirements per local 
guidelines. 
Section 4.1 Duration of Study 
Participation 
Collection of Patient Medication Diary added to the 
following Visits: Week 5 to Week 53 and the LTE visits. 
Consistency with schedules 
of assessments 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.4.4 Treatment 
Blinding/Unblinding 
Added the following bullets after “Allocation of 
participants to treatment groups will proceed through 
the use of an interactive web response system 
(IRT/IWRS) that is accessible 24 hours a day, 365 days 
a year.”:  
• 
The randomized intervention kit number list is 
generated centrally by the IRT/IWRS. 
• 
The randomization and intervention allocation 
are performed centrally by the IRT/IWRS. The 
IRT/IWRS generates the participant 
randomization list and allocates the 
intervention number and the corresponding 
intervention kits to the participants according 
to it. 
• 
A randomized participant is a participant from 
the screened population who has been 
allocated to a randomized intervention by the 
IRT/IWRS regardless of whether the 
intervention was received or not. 
Added a paragraph to specify who may unblind the data 
in the case of a reported SUSAR. 
Added a paragraph to document that the blind will be 
broken prior to database lock (DBL) and access 
provided to designated individual(s) to allow initiation of 
PK analyses prior to DBL.  
Sponsor template and 
standard operating 
procedure requirements 
Section 6.6.1 Prohibited 
Medications 
Added “live vaccines” to the list of prohibited 
medications. 
Live vaccines are not 
permitted during the study. 
Section 7.3 Temporary 
Discontinuation; 
Section 7.4 Rechallenge 
Two new subsections added (7.3 and 7.4) and 
numbering of subsections in Section 7 updated 
accordingly. These new subsections describe when 
temporary discontinuation of IMP may be considered, 
how to manage it, reinitiate it and what defines it. 
Added to permit temporary 
discontinuation of IMP 
under certain 
circumstances. 
Section 7.5.1 Individual Participant 
Stopping Rules 
Added a new stopping rule related to abnormal liver 
tests: “Discontinuation of study intervention for 
abnormal liver tests is required by the Investigator when 
a participant meets one of the conditions outlined 
in Appendix 15 or in the presence of abnormal liver 
chemistries not meeting protocol-specified stopping 
rules if the Investigator believes that it is in best interest 
of the participant.” 
To comply with Sanofi 
protocol requirements. 
Section 7.5.1.1 Individual 
Long-Term Extension Participant 
Stopping Rule 
Section 7.5.1.1 is added for participants who may 
withdraw from the study if no longer responding in the 
LTE.  
Clarification 
Section 7.9.9 Vaccine IgG 
(optional) 
The following vaccinations were removed from the list of 
those allowed during the study: measles (alone or in 
combination), or shingles (varicella zoster virus). 
These are live vaccines 
and are therefore not 
permitted during the study. 
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Section # and Name 
Description of Change 
Brief Rationale 
Clarified the optional collection of vaccine-specific IgG 
samples applies to participants who have received at 
least 6 weeks of rilzabrutinib or placebo at the time of 
scheduled vaccination and is applicable to the blinded 
treatment and open label periods and long-term 
extension.  
Clarified who the optional 
collection of IgG samples is 
intended for. 
Section 7.9.10 Immune 
Thrombocytopenia (ITP) 
Assessment Tools (IBLS, ITP-PAQ, 
ITP-KIT) 
Added a paragraph describing intention of ITP 
treatments and real-world evidence of the burden of 
fatigue in patients with ITP. 
To provide a rationale for 
promoting fatigue 
assessment from an 
exploratory to a key 
secondary efficacy 
endpoint. 
Section 7.9.15 Use of biological 
samples and data for future 
research 
New section added comprising Sanofi template 
standard language that explains Sponsor’s intent to 
store biological samples for research purposes from 
consenting participants. 
Clarification and 
consistency with template 
requirements 
Section 7.9.16 Overdose, 
medication errors, misuses or 
abuses of medicinal product 
New section added to provide definition and instruction 
for reporting of overdoses, medication errors, misuses 
or abuses of medicinal product. 
EU CTR requirement 
Section 9.3.9 Adverse Events 
(AEs), Serious Adverse Events 
(SAEs) and Other Safety Reporting 
Revised instructions for AE reporting:  
“The Investigator and any qualified designees are 
responsible for detecting, documenting, and recording 
events reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative) that meet 
the definition of an AE or SAE and remain responsible 
for following up AEs, particularly those that are serious, 
considered related to the study intervention or study 
procedures, or that caused the participant to 
discontinue the study intervention or study 
(see Section 7.5). 
Clarification and 
consistency with template 
requirements 
Section 9.3.9.5 Pregnancy 
Specified that only pregnancies reported after the first 
dose of the IMP, will be recorded by the Investigator 
and submitted to the Sponsor within 24 hours of 
learning of the pregnancy. 
Revised the timeframe of collection of details of all 
pregnancies from 7 days to 28 days after the last dose 
of study intervention:  
“Details of all pregnancies will be collected after the 
start of study intervention and until 28 days after the last 
dose of study intervention.” 
Added the below text: 
“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.” 
Clarification to align with 
the SoA and Sanofi 
template requirements. 
Section 9.3.9.6 Adverse Events of 
Special Interest 
The “symptomatic overdose with IMP” qualifier was 
updated to include both serious and nonserious 
overdoses. 
Specified the immediate notification timeframe to be 
within 24 hours. 
Clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
The following text was revised: Pregnancy of a female  
participant entered in a study and received at least one  
dose of the IMP as well as pregnancy occurring in a  
female partner of a male participant entered in a study  
with IMP. 
Section 12.2 Informed Consent 
 
 
 
 
 
Appendix 10: Country-Specific 
Requirements 
Added: Participants enrolled into the pediatric portion of  
Clarification 
the trial will still be considered as part of the pediatric 
group with all the planned assessments when they turn 
18 years old. They should be re-consented with an adult 
consent when they become an adult per 
country-specific requirements. 
Added Appendix 10.6 Italy country-specific  
Country-specific 
requirements:  
requirement 
“For pediatric participants (10 to <18 years old) enrolled  
Added to describe primary 
in Italy, eGFR will be calculated using the Bedside  
and secondary endpoints 
Schwartz Equation.”  
specific to the region and to 
Added Appendix 10.7 to 1) describe primary and key  
specify new agreement 
secondary endpoints specific to the EU (EEA countries)  
with RA (EMA) to include 
and the UK, 2) allow inclusion of children ≥10 to  
pediatric participants ≥10 
<18 years of age (EU [EEA] countries only) and  
to <18 years (previously 
3 specify a body weight lower limit for pediatric  
adolescents ≥12 years to 
participants.  
<18 years). 
Appendix 11: Protocol Amendment 
This entire section was updated with the country 
Changes made to comply 
History 
specific protocol amendments summary of changes 
with Sanofi standards. 
tables. 
Appendix 11: Protocol Amendment 
This entire section was updated with the Amended 
Changes made to comply 
History 
Clinical Trial Protocol 02 summary of changes table. 
with Sanofi standards. 
Appendix 12.3 Recording and 
Assessment of Intensity definitions modified to reflect 
Consistency with grading 
follow-up of AE and/or SAE 
NCI-CTCAE grading system. 
definitions in Section 9.3.3 
Appendix 14: Patient Medication 
“Blank Patient Medication Diary” added to the 
Added for reference. 
Diary 
appendices. 
Appendix 15: Liver Safety: 
Liver safety follow-up guidelines added. 
Added to provide guidance 
Suggested Actions and Follow-up 
on actions and follow-up 
Assessments 
assessments for ALT 
increase. 
Throughout  
1) The term “patient” was revised to “participant”. 
2) The term “caplet” was replaced with “tablet”. 
3) In most instances the term adolescent was replaced 
with pediatric. The term adolescent was retained in the 
protocol title. 
1) To reflect common  
terminology in the template, 
2) To correct naming of the 
formulation and 3) To 
reflect that participants 10 
to <12 years may be 
enrolled in the EU (EEA 
countries). 
In addition, other minor editorial changes (eg, grammatical, stylistic, references, and minor 
typographical error corrections) were implemented throughout the protocol. 
 
 
 
 
 
 
 
 
 
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Amended Clinical Trial Protocol 04 (24 July 2023) 
This amended clinical trial protocol 04 (Amendment 04) is considered to be substantial based on the 
criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the 
Council of the European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The primary reasons for this amendment are to: 
•   Update the 2-sided significance level from 0.01 to 0.05 for the hypothesis testing of the  
 
primary efficacy end point. 
•   Clarify distinct durations of participation in the long-term extension (LTE) for the adult  
 
and pediatric populations. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page, Protocol Amendment 
Amendment number has been revised to “04”. 
Administrative change to 
Summary of Changes, and 
comply with Sanofi standard 
headers throughout 
format. 
Protocol Amendment Summary of 
Expanded the table to include previous 
To comply with the Sanofi 
Changes: Document History; 
country-specific protocol amendments and added the 
template. 
Appendix 11: Protocol 
relevant changes to the protocol amendment history 
Amendment History 
in Appendix 11. 
Section 1 Synopsis: Sample size  
and Primary Efficacy Analysis;  
Section 10.1: Determination of  
Sample Size; Section 10.3.9:  
Primary Efficacy Analysis; 
Section 16 Appendix 10.7: EU 
(EEA Countries) and UK-specific 
Requirements 
Section 1 Synopsis: Sample size, 
and Section 10.1 Determination of 
Sample Size 
Updated the 2-sided significance level from 0.01 to 
0.05 for the hypothesis testing (ie, 
Cochran-Mantel-Haenszel test) of the primary 
efficacy end point. 
 
 
 
 
Updated the study power from 86% to 95% to reflect  
the update of the 2-sided significance level from 0.01  
to 0.05. 
 
 
In the following sentence “up to” has been added 
before “30 participants”: 
“The pediatric sample size of up to 30 participants (20 
participants on rilzabrutinib and 10 participants on 
placebo) was determined based on clinical practice and 
is adequate to descriptively describe the safety and 
efficacy in pediatric participants.” 
To align with health authority 
common standard, in response to 
the feedback received from 
health authority. 
Revised to reflect the impact of 
changing the 2-sided 
significance level from 0.01 to 
0.05 on the study power. 
To clarify that 30 participants is 
the maximum number of 
pediatric participants planned to 
be enrolled. 
 
 
 
 
 
 
 
 
 
 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1 Synopsis: Duration of  
Study Participation; Section 4.1:  
Duration of Study Participation 
 
 
 
 
 
 
Section 1 Synopsis: Table 1 
(Schedule of 
assessments-Blinded 
Treatment 
Period), footnote d, Table 2 
(Schedule of assessments-Open 
Label Period), footnote b, and 
Table 3 (Schedule of 
assessments-Long-Term  
Extension Period), footnote b;  
Sections 4.1.2: Blinded Treatment  
Period (Weeks 1 to 25); Section 
4.1.3: Open Label Period (Weeks 
25 to 53); Section 4.1.4: End of 
Study Visit (Four Weeks post last 
dose of study drug); Section 
4.1.5: Long-Term Extension 
(LTE); Section 7.9.2: Physical 
Examination 
Revised text to specify that: 
For adult participants, the maximum duration of the  
long-term extension (LTE) period will be 12 months  
from the date of the last adult participant to enter the  
LTE. 
For pediatric participants, the maximum duration of the 
LTE period will be 12 months from the date of the last 
pediatric participant to enter the LTE. 
 
Added cross references to Section 16 Appendix 10.6, 
Italy-specific requirement for details concerning 
Tanner staging in pediatric participants. 
To clarify the duration of  
participation in the LTE  
separately for adults and  
pediatrics. Due to low 
enrollment rate of pediatric  
population compared to adults,  
last participant in (LPI) of  
pediatrics expected to occur  
much later than LPI of adults.  
Health authority requirement to  
assess pubertal status in  
pediatric participants. 
Section 1 Synopsis: Table 1 - 
Added cross reference in footnote b to Figure 1, 
To clarify how to calculate 
Schedule of Assessments- 
Decision tree for assessing response at Week 13 for 
platelet count at baseline. 
Blinded Treatment Period 
details on calculating baseline platelet count. 
Section 1 Synopsis: 
Investigational plan; Section 4 
Study Design 
 
 
 
 
 
Section 4 Study Design 
Updated the following text on calculating baseline  
To clarify how to calculate 
platelet count: “The baseline value of platelet count is  
platelet count at baseline. 
defined as the average of all the participant’s Predose 
platelet counts (Screening and Study Day 1).” 
 
Added a footnote for Figure 1 on calculating baseline 
platelet count as below: 
“The baseline value of platelet count is defined as the 
average of all the participant’s Predose platelet 
counts (Screening and Study Day 1). 
In case of availability of 3 platelet counts, the baseline  
platelet count will be the average of the 2 qualifying  
platelet counts during Screening and within 14 days  
before the first dose and the platelet count at Week 1  
(Study Day 1). 
In case the second qualifying platelet count is collected 
at the Study Day 1 prior to the first dose, the baseline 
platelet count will be the average of the 
2 qualifying platelet counts.” 
 
 
 
 
 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1 Synopsis: Inclusion 
criteria #3 
Section 5.1: Inclusion Criteria # 3 
Section 16 Appendix 10: 
Country -Specific Requirements, 
10.7 EU (EEA countries) and 
UK-specific requirements 
 
Section 1 Synopsis: Exclusion 
criteria #22 
Section 5.2: Exclusion 
Criteria # 22 
For the following sentence, the comma is removed 
after "screening period" and a comma is added 
before the word "within": 
“An average of 2 platelet counts at least 5 days apart of 
<30,000/µL during the screening period and no single 
platelet count >35,000/µL, within 14 days prior to the 
first dose of study drug” 
 
The following text has been added: “known allergy to 
any of the study medication, their analogues, or 
excipients in the various formulations of any agent 
(please see Section 6.1.1 for information on 
excipients)” 
To clarify that both the  
qualifying platelet counts as  
well as the criterion of “no  
single platelet 
count >35,000/µL” should be  
evaluated within 14 days prior  
to the first dose of the study  
drug. 
To exclude participants with  
history of known allergy to any  
of the study medication, their  
analogues, or excipients. 
Section 2.5: Study Design 
Deletion of the sentence related to remote site 
To align with Germany health 
Rationale 
monitoring not available in Germany. 
authority requirements. 
Sections 4.1.2: Blinded Treatment  
Period (Weeks 1 to 25); Section 
4.1.3: Open Label Period (Weeks 
25 to 53); Section 4.1.4: End of 
Study Visit (Four Weeks post last 
dose of study drug); 
Section 4.1.5: Long Term  
Extension (LTE); Section 
Mean platelet volume has been added to hematology 
and the word “random" is added for glucose test. 
For consistency with the rest of 
the protocol. 
Section 6.1.1: 
The following text has been added to the section 
To provide additional 
Rilzabrutinib/Placebo 
describing the study intervention: 
information on excipients. 
“Each tablet is coated with a light orange film coat  
(Opadry II 85F130006) containing polyvinyl alcohol,  
polyethylene glycol, talc, titanium dioxide, and FD&C  
yellow #6.” 
Section 9.3.9.5: Pregnancy 
 
 
 
 
 
Section 9.3.9.6: Adverse Events of 
Special Interest 
Section 12.2: Informed Consent 
 
 
 
 
 
Section 16 Appendix 8: 
Guidelines to Sites for Delayed  
Participant Visits or Missed Visits  
due to travel restrictions and any  
foreseeable impacts of COVID-19 
In the following sentences the word “will/should” has 
been replaced with “must”: 
“Any female participant who becomes pregnant while 
participating in the study must discontinue study 
intervention or be withdrawn from the study.” 
 
“In the event of pregnancy in a female participant, 
IMP must be discontinued” 
The following statement has been added to the  
section about signing a specific informed consent 
form (ICF) for female partners: “for male participants, in 
case of pregnancy of your partner, your partner will be 
asked to provide consent for collection of the 
pregnancy data.” 
Cross-references referring to Appendix 10.2 and 
Appendix 10.7 have been added. 
 
 
Deletion of the sentence related to remote site 
monitoring not available in Germany. 
To ensure participant’s safety  
and to comply with regulatory  
guidance. 
To provide information on 
signing a specific ICF for the 
partners of the male 
participants. 
As per addition of text in 
Appendix 10.2 and 
Appendix 10.7. 
To align with Germany health 
authority requirements. 
 
 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 16 Appendix 10:  
Country-Specific Requirements, 
10.2 Germany country-specific 
requirements. 
 
 
 
 
 
 
 
 
 
Section 16 Appendix 10:  
Country-Specific Requirements, 
10.6 Italy country-specific 
requirement 
Deletion of the text: “Section 2.5, Study design rationale; 
Appendix 8, Remote site monitoring: During the 
coronavirus (COVID-19) pandemic, remote site 
monitoring is not available in Germany” 
 
Added the following text: 
“Direct to participant shipment is only allowed until 
31 December 2023, as long as the ordinance  
"Ordinance to ensure the supply of medically 
necessary products to the population in the event of an 
epidemic caused by the SARS-CoV-2 Coronavirus 
(Ordinance to Ensure the Supply of Medicines)” is in 
place in Germany.” 
Added the following text: “For the pediatric  
population, Tanner staging should be performed at  
W1, W25, W53, end of study (EOS)/early termination 
(ET), and every 1 year during the LTE period until the  
end of the trial or until the participant reaches Tanner  
stage V (whichever comes first). Self-reported Tanner  
staging or records from pediatric assessments in 
standard-of-care settings are considered acceptable.” 
 
Included the following statement: 
“Details regarding risk mitigation measures for  
exceeding blood sample volumes are provided in the 
Laboratory Manual.” 
To align with Germany health 
authority requirements. 
Health authority requirement to 
assess pubertal status in 
adolescent participants. 
To provide information on risk 
mitigation measures for 
exceeding blood sample 
volumes 
Section 16 Appendix 10:  
Country-Specific Requirements, 
10.7 EU (EEA countries) and 
UK-specific requirements 
Deleted the word “adult”  
Correction and consistency 
 
Sub-section: EU (EEA countries) only, added  
To provide additional 
contingency measures for the COVID-19 pandemic.  
information on contingency 
measures and data  
management during the  
pandemic. 
Section 16 Appendix 11: Protocol 
Added the summary of changes from the prior 
To comply with the Sanofi 
Amendment History 
amendment. 
template. 
Section 16 Appendix 12.1  
Definition of AE, Events meeting 
the AE definition 
Added the following to the lists of events meeting an  
adverse event (AE) criterion: “Signs, symptoms, or  
the clinical sequelae of any medication errors, misuse  
and abuse with the investigational medicinal product  
(IMP). An abuse corresponds to the persistent or 
sporadic, intentional excessive use of a medicinal  
product, which is accompanied by harmful physical or  
psychological effects, ie, intentional non-therapeutic  
use of a medicinal product by a participant for a  
perceived reward or desired non-therapeutic effect  
including, but not limited to, “getting high” (euphoria).” 
To comply with the Sanofi 
template. 
 
In addition, other minor editorial changes (eg, grammatical, stylistic, abbreviations, references, 
and minor typographical error corrections) were implemented throughout the protocol. 
 
 
 
 
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Appendix 12 AE and SAEs: Definitions and procedures for Recording 
evaluating, Follow-up, and Reporting 
Appendix 12.1 Definition of AE 
AE definition 
•
An AE is any untoward medical occurrence in a patient or clinical study participant,
temporally associated with the use of study intervention, whether or not considered
related to the study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally
associated with the use of study intervention.
Definition of unsolicited and solicited AE 
•
An unsolicited AE is an AE that was not solicited using a participant diary and that is
communicated by a participant/LAR who has signed the informed consent. Unsolicited
AEs include serious and non-serious AEs.
•
Potential unsolicited AEs may be medically attended (ie, symptoms or illnesses requiring
a hospitalisation, or emergency room visit, or visit to/by a health care provider). The
participants/LAR will be instructed to contact the site as soon as possible to report
medically attended event(s), as well as any events that, though not medically attended,
are of participant’s/LAR’s concern. Detailed information about reported unsolicited AEs
will be collected by qualified site personnel and documented in the participant’s records.
•
Unsolicited AEs that are not medically attended nor perceived as a concern by
participants/LARs will be collected during interview with the participants/LARs and by
review of available medical records at the next visit.
•
Solicited AEs are predefined local and systemic events for which the participant is
specifically questioned, and which are noted by the participants in their diary.
Events meeting the AE definition 
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or
other safety assessments (eg, ECG, radiological scans, vital signs measurements),
including those that worsen from baseline, considered clinically significant in the medical
and scientific judgment of the Investigator (ie, not related to progression of underlying
disease), eg:
-
Symptomatic and/or
-
Requiring either corrective treatment or consultation, and/or
-
Leading to IMP discontinuation or modification of dosing, and/or
-
Fulfilling a seriousness criterion, and/or
-
Defined as an AESI

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•
Exacerbation of a chronic or intermittent pre-existing condition including either an
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study
intervention or a concomitant medication.
•
Signs, symptoms, or the clinical sequelae of any medication errors, misuse, and abuse
with the IMP. An abuse corresponds to the persistent or sporadic, intentional excessive
use of a medicinal product, which is accompanied by harmful physical or psychological
effects, ie, intentional non-therapeutic use of a medicinal product by a participant for a
perceived reward or desired non-therapeutic effect including, but not limited to, “getting
high” (euphoria).
•
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be
reported as an AE or SAE. Such instances will be captured in the efficacy assessments.
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy
will be reported as AE or SAE if they fulfill the definition of an AE or SAE.
•
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, “lack of
efficacy” or “failure of expected pharmacological action” also constitutes an AE or SAE.
Events NOT meeting the AE definition 
•
Any clinically significant abnormal laboratory findings or other abnormal safety
assessments which are associated with the underlying disease, unless judged by the
Investigator to be more severe than expected for the participant’s condition.
•
The disease/disorder being studied or expected progression, signs, or symptoms of the
disease/disorder being studied, unless more severe than expected for the participant’s
condition.
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or
detected at the start of the study that do not worsen.

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Appendix 12.2 Definition of SAE 
An SAE is defined as any adverse event that, at any dose: 
a) Results in death
b) Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which
the participant was at risk of death at the time of the event. It does not refer to an
event, which hypothetically might have caused death, if it were more severe.
c) Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been admitted (usually
involving at least an overnight stay) at the hospital or emergency ward for
observation and/or treatment that would not have been appropriate in the physician’s
office or outpatient setting. Complications that occur during hospitalization are AEs. If
a complication prolongs hospitalization or fulfills any other serious criteria, the event is
serious. When in doubt as to whether “hospitalization” occurred or was
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen
from baseline is not considered an AE.
d) Results in persistent or significant disability/incapacity
- The term disability means a substantial disruption of a person’s ability to
conduct normal life functions.
- This definition is not intended to include experiences of relatively minor
medical significance such as uncomplicated headache, nausea, vomiting,
diarrhea, influenza, and accidental trauma (eg, sprained ankle) which may
interfere with or prevent everyday life functions but do not constitute a
substantial disruption.
e) Is a congenital anomaly/birth defect
f)
Other situations:
- Medical or scientific judgment should be exercised by the Investigator in
deciding whether SAE reporting is appropriate in other situations such as
significant medical events that may jeopardize the participant or may require
medical or surgical intervention to prevent one of the other outcomes listed in
the above definition. These events should usually be considered serious.
-
Note: The following list of medically important events is intended to serve as
a guideline for determining which condition has to be considered as a
medically important event. The list is not intended to be exhaustive:
-
Intensive treatment in an emergency room or at home for:
- Allergic bronchospasm
- Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone
marrow aplasia, myelodysplasia, pancytopenia, etc)
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- Convulsions (seizures, epilepsy, epileptic fit, absence, etc).
-
Development of drug dependence or drug abuse
-
ALT >3 × ULN + total bilirubin >2 × ULN or asymptomatic ALT
increase >10 × ULN
-
Suicide attempt or any event suggestive of suicidality
-
Syncope, loss of consciousness (except if documented as a consequence of
blood sampling)
-
Bullous cutaneous eruptions
Appendix 12.3 Recording and follow-up of AE and/or SAE 
AE and SAE recording 
Assessment of intensity 
The NCI-CTCAE Version 5.0 will be used to assess the severity of AEs/SAEs. 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 
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. 
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•
When an AE/SAE occurs, it is the responsibility of the Investigator to review all
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports)
related to the event.
•
The Investigator will then record all relevant AE/SAE information.
•
It is not acceptable for the Investigator to send photocopies of the participant’s medical
records to the Sponsor’s representative in lieu of completion of the required form.
•
There may be instances when copies of medical records for certain cases are requested by
the Sponsor’s representative. In this case, all participant identifiers, with the exception of
the participant number, will be redacted on the copies of the medical records before
submission to the Sponsor’s representative.
•
The Investigator will attempt to establish a diagnosis of the event based on signs,
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the
individual signs/symptoms) will be documented as the AE/SAE.

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Death will not be recorded as a Grade 5 severity - rather the underlying condition will be 
recorded, and its severity graded, with death regarded as an outcome. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described in 
the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
Follow-up of AEs and SAEs 
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The Investigator is obligated to assess the relationship between study intervention and
each occurrence of each AE/SAE.
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or
arguments to suggest a causal relationship, rather than that a relationship cannot be ruled
out.
•
The Investigator will use clinical judgment to determine the relationship.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk
factors, as well as the temporal relationship of the event to study intervention
administration will be considered and investigated.
•
The Investigator will also consult the Investigator’s Brochure (IB) and/or Product
Information, for marketed products, in his/her assessment.
•
For each AE/SAE, the Investigator must document in the medical notes that he/she has
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred, and the Investigator has minimal
information to include in the initial report to the Sponsor. However, it is very important
that the Investigator always make an assessment of causality for every event before
the initial transmission of the SAE data to the Sponsor.
•
The Investigator may change his/her opinion of causality in light of follow-up
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is one of the criteria used when determining regulatory
reporting requirements.
•
The Investigator is obligated to perform or arrange for the conduct of supplemental
measurements and/or evaluations as medically indicated or as requested by the Sponsor’s
representative to elucidate the nature and/or causality of the AE or SAE as fully as
possible. This may include additional laboratory tests or investigations, histopathological
examinations, or consultation with other health care professionals.
•
If a participant dies during participation in the study or during a recognized follow-up
period, the Investigator will provide the Sponsor with a copy of any post-mortem findings
including histopathology.
•
New or updated information will be recorded in the originally submitted documents.
•
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of
receipt of the information.

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Appendix 12.4 Reporting of SAEs 
SAE reporting to the Sponsor via an electronic data collection tool 
SAE reporting to the Sponsor via paper data collection tool 
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The primary mechanism for reporting an SAE to the Sponsor’s representative will be the
electronic data collection tool.
•
If the electronic system is unavailable, then the site will use the paper SAE data
collection tool (see next section) to report the event within 24 hours.
•
The site will enter the SAE data into the electronic system as soon as it becomes
available.
•
After the study is completed at a given site, the electronic data collection tool will be
taken off-line to prevent the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data
on a previously reported SAE after the electronic data collection tool has been taken
off-line, then the site can report this information on a paper SAE form (see next section)
or to the Sponsor’s representative by telephone.
•
Contacts for SAE reporting can be found in the Investigator Study File.
•
Facsimile transmission of the SAE paper data collection tool is the preferred method to
transmit this information to the Sponsor’s representative.
•
In rare circumstances and in the absence of facsimile equipment, notification by
telephone is acceptable with a copy of the SAE data collection tool sent by overnight
mail or courier service.
•
Initial notification via telephone does not replace the need for the Investigator to
complete and sign the SAE data collection tool within the designated reporting time
frames.
•
Contacts for SAE reporting can be found in the Investigator Study File.

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Appendix 13   Contraceptive and Barrier Guidance
Appendix 13.1 Definitions 
A woman is considered WOCBP (fertile) from the time of menarche until becoming 
postmenopausal (see below) unless permanently sterile (see below). 
Females on HRT and whose menopausal status is in doubt will be required to use one of the 
non-estrogen hormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of  
postmenopausal status before study enrollment. 
Permanent sterilization methods include: 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
If fertility is unclear (eg, amenorrhea in athletes) and a menstrual cycle cannot be confirmed 
before first administration of study intervention, additional evaluation should be considered. 
Women in the following categories are considered WONCBP: 
1. Any female with permanent infertility due to one of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
-
For individuals with permanent infertility due to an alternate medical cause other
than the above, (eg, Mullerian agenesis, androgen insensitivity, gonadal
dysgenesis), Investigator discretion should be applied to determining study entry.
2. Postmenopausal female
A postmenopausal state is defined as the period of time after a woman has experienced no 
menses for 12 consecutive months without an alternative medical cause. 
-
A high FSH level in the postmenopausal range may be used to confirm a
postmenopausal state in women not using hormonal contraception or HRT.
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A postmenopausal state is defined as the period of time after a woman has experienced
no menses for 12 consecutive months without an alternative medical cause.
•
A high FSH level in the postmenopausal range must be used to confirm a postmenopausal
state in women not using hormonal contraception or hormonal replacement therapy
(HRT).
•
Documented hysterectomy
•
Documented bilateral salpingectomy
•
Documented bilateral oophorectomy
•
For individuals with permanent infertility due to an alternate medical cause other than the
above, (eg, Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), investigator
discretion should be applied to determining study entry eligibility.

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Females on HRT and whose menopausal status is in doubt must discontinue HRT
to allow confirmation of postmenopausal status before study enrollment.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
Appendix 13.2 Contraception guidance 
Participants should be given advice about donation and cryopreservation of germ cells prior to the 
start of the study intervention, in line with the fact that study intervention may affect ova up to 4 
weeks and sperm up to 13 weeks (see inclusion criteria). 
If locally required, acceptable contraceptive methods are limited to those which inhibit ovulation as 
the primary mode of action. 
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CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly effective methodsb that have low user dependency Failure rate of <1% per year when used 
consistently and correctly. 
•
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc
•
Intrauterine device (IUD)
•
Intrauterine hormone-releasing system (IUS)c
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or due to a medical cause)
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual
partner of the woman of childbearing potential and the absence of sperm has been confirmed. If
not, an additional highly effective method of contraception should be used.
Note: documentation of azoospermia for a male participant can come from the site personnel’s review 
of the participant’s medical records, medical examination, or medical history interview. 
Highly effective methodsb that are user dependent Failure rate of <1% per year when used 
consistently and correctly.  
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition 
of ovulationc 
•
oral
•
intravaginal
•
transdermal
•
injectable
Progestogen-only hormone contraception associated with inhibition of ovulationc
•
Oral
•
injectable
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant. 

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a   Contraceptive use by men or women should be consistent with local regulations regarding the use of 
 
contraceptive methods for those participating in clinical studies. 
b   Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
 
when used consistently and correctly. 
c   Male condoms must be used in addition to hormonal contraception. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception for 
this study. Male condom and female condom should not be used together (due to risk of failure from friction). 
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Appendix 14   Patient Medication Diary
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Appendix 15   Liver AND OTHER Safety: Suggested Actions and Follow-up 
Assessments
Neutropenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting adverse events in Section 9.3 is met. 
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*If unable to retest in 72 hours, use original lab results to decide on further reporting/monitoring/discontinuation. 
** Unless a protocol-defined criterion for permanent discontinuation is met 
*** See box below 
Note: 
•  
“Baseline” refers to ALT sampled at baseline visit; or if baseline value unavailable, to the latest ALT sampled before the baseline 
visit. The algorithm does not apply to the instances of increase in ALT during screening. 
•    See Section 9.3 or guidance on safety reporting. 
 
 
 
 
 
 
 
 
 
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Appendix 16 Collection, storage and future use of data and human biological 
samples
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Compliance with Member State applicable rules for the collection, storage, and future use
of human biological samples (Article 7.1h)
o
This appendix is provided separately.
•
Compliance with Member State applicable rules for the collection, storage, and future use
of (personal) data (article 7 (1 d) of EU Regulation 536/2014)
o
This appendix is provided separately.

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