An Adaptive, Open-Label, Dose-Finding, Phase 1/2 Study Investigating the Safety, Pharmacokinetics, and Clinical Activity of PRN1008, an Oral BTK Inhibitor, in Patients With Relapsed Immune Thrombocytopenia
Phase: PHASE2
Conditions: Immune Thrombocytopenia
Sponsor: Principia Biopharma, a Sanofi Company

Amended Clinical Trial Protocol 16 
 
15 May 2024 
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Page 1 of 116 
 
 
 
AMENDED CLINICAL TRIAL PROTOCOL 16  
 
Protocol Title: 
An Adaptive, Open-Label, Dose-Finding, Phase 1/2 Study Investigating 
the Safety, Pharmacokinetics, and Clinical Activity of Rilzabrutinib 
(PRN1008), an Oral BTK Inhibitor, in Patients with Relapsed Immune 
Thrombocytopenia 
Protocol No.: 
PRN1008-010 (DFI17124) 
Amendment No.: 
16 
Development Phase: 
Phase 1/2 
Investigational Product: 
Rilzabrutinib (PRN1008/SAR444671) 
Protocol Date: 
15 May 2024, Amended clinical trial protocol 16 
Sponsor: 
Principia Biopharma Inc. 
55 Corporate Drive 
Bridgewater, NJ 08807 
USA 
Sponsor's Medical 
Monitor:
 
  
 
Regulatory agency identifier number(s):  
IND: 
132668 
EU trial number: 
2023-509397-39 
NCT: 
NCT03395210 
WHO: 
Not applicable 
EUDAMED: 
Not applicable 
Other 
Not applicable 
 
CONFIDENTIALITY STATEMENT 
This document contains confidential information. It is provided for the sole use of the Principal 
Investigator, subinvestigators, staff, institutional review boards, human research ethics committees, and 
regulatory authorities. By accepting this document, you agree to maintain the information as confidential 
and to use it only for the purpose of conducting or reviewing the study protocol. 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
 
Document 
Country/ 
countries 
impacted by 
amendment 
Date, version 
Comments (all global 
versions except Version 10.1 
for Norway) 
Amended Clinical Trial Protocol 16 
All 
15 May 2024, 
Version 1 
(electronic 2.0) 
 
Amended Clinical Trial Protocol 15 
All 
19 Mar 2021, 
Version 1 
(electronic 1.0) 
 
Amended Clinical Trial Protocol 14 
All 
12 Aug 2020, 
Version 14.0 
Only submitted to United States Food 
and Drug Administration (FDA); not to 
sites or other regulatory authorities. 
Amended Clinical Trial Protocol 13.1 
All 
16 Apr 2020, 
Version 13.1 
 
Amended Clinical Trial Protocol 13 
All 
05 Mar 2020, 
Version 13.0 
Only submitted to FDA; not to sites or 
other regulatory authorities. 
Amended Clinical Trial Protocol 12 
All 
05 Dec 2019, 
Version 12.0 
 
Amended Clinical Trial Protocol 11 
All 
24 Oct 2019, 
Version 11.0 
 
Amended Clinical Trial Protocol 10.1 
Norway 
21 Jan 2020, 
version 10.1 
Norway doesn’t participate in Part B, so 
this is the last protocol version for 
Norway. 
Amended Clinical Trial Protocol 10 
All 
27 Sep 2019, 
Version 10.0 
 
Amended Clinical Trial Protocol 09 
All 
06 May 2019, 
version 9.0 
 
Amended Clinical Trial Protocol 08 
All 
24 Aug 2018, 
version 8.0 
 
Amended Clinical Trial Protocol 07 
All 
01 Dec 2017, 
version 7.0 
First version under which patients were 
enrolled 
Amended Clinical Trial Protocol 06 
All 
29 Sep 2017, 
version 6.0 
Submitted to sites, but no patients 
enrolled under this version. 
Country-specific amendments were prepared as needed during study conduct. All country-specific 
requirements were included in subsequent global amendments. 
Previous protocol versions (versions 1.0 [02 Apr 17] through 5.0 [07 Jul 17]) were not submitted 
to sites. Thus, they are not included in the document history table. 
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Amended clinical trial protocol 16 (15 May 2024) 
This amended protocol (amendment 16) is considered to be substantial based on the criteria set 
forth in Article 2(2)(13) of the Regulation of the European Parliament and the Council of the 
European Union.  
OVERALL RATIONALE FOR THE AMENDMENT 
The primary reasons for this amendment (16) to Protocol DFI17124 are to: 
• Incorporate language to comply with new EU clinical trial regulations.  
• Update overall Benefit-Risk Assessment. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Cover Page 
Removed Principal Investigator (PI) details, 
added NCT number, and updated with new 
sponsor address. 
To align with new EU CTR guidelines and 
the latest protocol template language. 
2.2 Overall Benefit-Risk 
Assessment 
In the subsection 2.2 “Overall Benefit-Risk 
Assessment”, added details of
 which include
 
Added to Benefit assessment section: 
“Preliminary results of part A and Part B provide 
evidence that treatment with rilzabrutinib 400 mg 
BID induces a rapid and durable platelet 
response and continued to be well-tolerated in 
patients with ITP” 
Added to Benefit-risk section: “To date, 
preliminary analyses of efficacy and safety in 
patients with ITP support an overall favorable 
benefit-risk profile, and to continue the 
development of rilzabrutinib for patients with ITP.” 
To provide details of
, which are 
 of rilzabrutinib, as well as 
to introduce 
 
 
To align with the current version of the IB 
and provide updated safety information. 
 
4.11 Treatment of Overdose 
Added subsection 4.11 to include clear definitions 
and guidelines for treating overdose with the IMP. 
To align with new EU CTR guidelines and 
per the latest protocol template language  
4.12 Concomitant 
Medications 
Modified “per day” to “or equivalent per day” 
regarding permitted prednisone dosing. 
To account for the fact that corticosteroids 
other than prednisone could be used.  
4.12.3 Prohibited 
Added below language pertaining to prohibited 
concomitant medication: 
• 
Concomitant use of any 
immunosuppressant medication, other 
than corticosteroids, as described in 
this protocol. Participants who need 
other immunosuppressant therapy 
during the study must be withdrawn. 
See Exclusion Criterion #7 in Section 
6.1.2 and Section 6.2.2 for washout 
periods. 
To provide clarification about the 
prohibited medications and to add the 
following medications to the prohibited 
medications list: Immunosuppressants, 
anti-CD20 medications, new start or 
increase in doses of TPO-RA, and live 
vaccines. 
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Section # and Name 
Description of Change 
Brief Rationale 
• 
Rituximab or other anti-CD20 
medications, vincristine or 
immunosuppressants other than 
corticosteroids, and new starts or 
increases in doses of eltrombopag, 
romiplostim, or avatrombopag are not 
permitted as rescue therapy while the 
patient is receiving treatment with 
rilzabrutinib.  
• 
Live vaccines are not permitted during 
the study. See Section 6.1.2 and 6.2.2. 
for Exclusion Criteria #20 
8. List of Study 
Assessments 
Added a new subsection 8.4 to include language 
pertaining to "Use of biological samples and data 
for future research". 
To allow the use of leftover biological 
samples and data for future research and 
to align with new EU CTR guidelines. 
9.2 Packaging 
Changed to “Rilzabrutinib 100 mg and 300 mg 
tablets, 35 count per bottle and 400 mg tablets, 
70 count per bottle are packaged in white high-
density polyethylene (HDPE) bottles with 
child-resistant induction-sealed caps.” 
To be consistent with the recently updated 
Pharmacist’s Manual v6.0 
9.5 Destruction of 
Investigational 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.” 
Added “If a site does not have a destruction SOP, 
study drug can be returned to the depot.” 
To be consistent with recently updated 
Pharmacist’s Manual v6.0 
 
11.7.2 SAE Reporting 
Added reference to safety reporting for the EU 
with direction to Section 16.8.1 
Updated to “SAE Reporting Information 
mailto: 
ssf.1008010sae@sanofi.com” 
To align with new EU CTR guidelines 
11.9 Adverse Event of 
Special Interest 
Added this section to include that
 pregnancy, drug overdose,
 are considered adverse events of special 
interest  (AESIs) 
To provide a definition of AESIs 
11.10 Medication Errors, or 
Misuses of Medicinal 
Product 
Added section with details on the handling of 
medication errors and misuse of medicinal 
product 
To align with new EU CTR guidelines 
13. Regulatory, Ethical, and 
Study Oversight 
Considerations 
Section title was updated from “Ethical Aspects” 
to cover regulatory and study oversight 
considerations as well. 
Added section 13.2 on data protection. Updated 
sections 13.1 and 13.4 to include new language 
on regulatory and ethical considerations and 
IRB/IEC review 
Updated language to align with the EU-
CTR and as per the latest protocol 
template language . 
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Section # and Name 
Description of Change 
Brief Rationale 
14.1 Investigator’s 
File/Retention of Records 
Updated with new guidelines on the Investigator’s 
retention of records and documents 
To align with the EU-CTR on the required 
retention period of 25 years for all records 
and documents pertaining to the conduct 
of this study 
14.8 Publication of Data 
and Protection of Trade 
Secrets 
Added language with further details on the 
Investigator and Sponsor’s responsibilities when 
publishing data 
To expand on proper practices for the 
protection of trade secrets and guide 
investigators on the publication of data 
16.5 Appendix 5 
Added following assessments: ECG (12-lead, 
single), hemolysis panel, mean platelet volume 
and immunoglobulins 
 
Modified footnote 4 to include “Needed on 
Day 169 Visit/rollover/C1D1_LTE.” 
Added footnotes 9-13 elaborating on the 
hemolysis panel, mean platelet volume, immature 
platelet fraction, immunoglobulins, BTK 
occupancy, and QOL questionnaires 
To align assessments in D169 Appendix 5 
with the assessments under Day 
169/C1D1_LTE in Appendix 6 
 
To clarify the circumstances requiring uses 
of specific assessments, and the types of 
assessments used 
16.6 Appendix 6 
Added footnote 12, “QOL questionnaire includes 
 and ITP-PAQ”  
To clarify what QOL questionnaires were 
used as assessments 
16.7 Appendix 7 
Added figures for 
management algorithm 
To guide investigators on the evaluation 
and reporting of these adverse events. 
 
16.8 Appendix 8 
Added EU-specific sub-section 
To clarify safety reporting guidelines 
specific to the European Union 
16.9 Appendix 9 
Added section on the collection, storage, and 
future use of data and human biological samples 
To direct investigators to where they can 
find further information on compliance with 
Member State applicable rules for use of 
data and biological samples 
Throughout the document 
Changed the abbreviation of the ITP Bleeding 
Scale from “ITP-BAT” to “IBLS” 
Correction of the ITP Bleeding Scale 
abbreviation. 
In addition, other minor editorial changes (eg, grammatical, stylistic, consistency, and minor 
typographical error corrections) were implemented throughout the protocol. 
 
 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 16 ..........................................................................1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................................................2 
TABLE OF CONTENTS .................................................................................................................6 
PRN1008-010 STUDY SYNOPSIS ..............................................................................................11 
GLOSSARY OF ABBREVIATIONS AND TERMS ...................................................................27 
1 
BACKGROUND ...............................................................................................................29 
1.1 
Scientific Rationale for Treatment of ITP with Rilzabrutinib .........................29 
1.2 
Summary of Rilzabrutinib Clinical Experience ...............................................29 
1.3 
Clinical Pharmacokinetics and Pharmacodynamics of Rilzabrutinib ..............30 
2 
DOSE RATIONALE AND STUDY DESIGN .................................................................31 
2.1 
Rationale for the Study Design ........................................................................31 
2.1.1 
Rationale for Doses Used and Duration of Study Part A.................................31 
2.1.2 
Rationale for Doses Used and Duration of Study Part B .................................32 
2.2 
Overall Benefit-Risk Assessment ....................................................................32 
3 
OBJECTIVES AND OUTCOME MEASURES OF THE STUDY ..................................36 
3.1 
Objectives of the Study: Part A .......................................................................36 
3.1.1 
Safety Objective ...............................................................................................36 
3.1.2 
Efficacy Objectives ..........................................................................................36 
3.1.3 
Pharmacokinetics Objective.............................................................................36 
3.1.4 
Exploratory Objectives ....................................................................................36 
3.2 
Objectives of the Study: Part B ........................................................................36 
3.2.1 
Safety Objective ...............................................................................................36 
3.2.2 
Efficacy Objectives ..........................................................................................36 
3.2.3 
Pharmacokinetics Objective.............................................................................37 
3.2.4 
Exploratory Objectives ....................................................................................37 
3.3 
Outcome Measures of the Study: Part A..........................................................37 
3.3.1 
Primary Safety Endpoints ................................................................................37 
3.3.2 
Primary Efficacy Endpoint ..............................................................................37 
3.4 
Outcome Measures of the Study: Part B ..........................................................37 
3.4.1 
Primary Safety Endpoints ................................................................................37 
3.4.2 
Primary Efficacy Endpoint ..............................................................................37 
4 
INVESTIGATIONAL PLAN ............................................................................................38 
4.1 
Overall Study Design and Plan Part A .............................................................38 
4.2 
Overall Study Design and Plan Part B .............................................................40 
4.3 
Dose-Limiting Toxicity (DLT) Part A Only ....................................................41 
4.4 
Dose Escalation Rules Part A Only .................................................................42 
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4.5 
Stopping Rules Part A (also applies to LTE) ...................................................43 
4.5.1 
Individual Stopping Rules................................................................................43 
4.5.2 
Study Stopping Rules .......................................................................................43 
4.6 
Stopping Rules Part B (also applies to LTE) ...................................................43 
4.6.1 
Individual Stopping Rules................................................................................43 
4.6.2 
Study Stopping Rules .......................................................................................44 
4.7 
Number of Patients ..........................................................................................44 
4.8 
Study Duration and Duration of Patient Participation .....................................44 
4.9 
End of Study Definition (Part A and Part B) ...................................................45 
4.10 
Rilzabrutinib Administration (Part A and Part B) ...........................................45 
4.11 
Treatment of Overdose ....................................................................................45 
4.12 
Concomitant Medications ................................................................................45 
4.12.1 
Allowed Part A ................................................................................................45 
4.12.2 
Allowed Part B .................................................................................................46 
4.12.3 
Prohibited .........................................................................................................47 
5 
PROTOCOL DEVIATIONS .............................................................................................48 
6 
STUDY POPULATION ....................................................................................................49 
6.1 
Part A ...............................................................................................................49 
6.1.1 
Inclusion Criteria .............................................................................................49 
6.1.2 
Exclusion Criteria ............................................................................................49 
6.2 
Part B ...............................................................................................................51 
6.2.1 
Inclusion Criteria .............................................................................................51 
6.2.2 
Exclusion Criteria ............................................................................................51 
7 
STUDY ASSESSMENTS .................................................................................................54 
8 
LIST OF STUDY ASSESSMENTS ..................................................................................55 
8.1 
Clinical Assessments .......................................................................................55 
8.2 
Laboratory & ECG Assessments .....................................................................55 
8.3 
Safety Assessments ..........................................................................................56 
8.4 
Use of biological samples and data for future research ...................................56 
9 
IDENTITY OF INVESTIGATIONAL PRODUCT ..........................................................58 
9.1 
Formulation ......................................................................................................58 
9.2 
Packaging .........................................................................................................58 
9.3 
Storage and Handling .......................................................................................58 
9.4 
Drug Accountability.........................................................................................58 
9.5 
Destruction of Investigational Product ............................................................59 
10 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ..................60 
10.1 
Primary Safety Endpoints ................................................................................60 
10.2 
Primary Efficacy Endpoints .............................................................................60 
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10.3 
Secondary Endpoints .......................................................................................60 
10.3.1 
Safety Endpoints ..............................................................................................60 
10.3.2 
Efficacy Endpoints ...........................................................................................60 
10.3.3 
Pharmacokinetic Outcome Measures ...............................................................61 
10.4 
Exploratory Measures ......................................................................................61 
10.5 
Determination of Sample Size .........................................................................62 
10.6 
Analysis Populations (Part A and Part B) ........................................................63 
10.6.1 
Safety Analysis Population ..............................................................................63 
10.6.2 
Efficacy Analysis Population ...........................................................................63 
10.6.3 
Pharmacokinetic Analysis Population .............................................................63 
10.7 
Patient Numbers and Treatment Assignments .................................................63 
10.8 
Patient Disposition, Patient Replacement, and Demographics and 
Baseline Characteristics ...................................................................................63 
10.8.1 
Disposition .......................................................................................................63 
10.8.2 
Replacement of Patients ...................................................................................64 
10.8.3 
Demographics and Baseline Characteristics ....................................................64 
10.9 
Efficacy and Exploratory Analysis ..................................................................64 
10.10 
Safety and Tolerability Analysis ......................................................................64 
10.10.1 
Adverse Events ................................................................................................65 
10.10.2 
Clinical Laboratory Tests .................................................................................65 
10.10.3 
Vital Signs ........................................................................................................66 
10.10.4 
Rescue Medication, DLTs, and Bleeding Scale Scores ...................................67 
10.10.5 
Concomitant Medications ................................................................................67 
10.11 
Pharmacokinetics Analyses .............................................................................67 
10.12 
Statistical Analysis Plan ...................................................................................67 
11 
SAFETY AND TOXICITY MANAGEMENT .................................................................68 
11.1 
Independent Data Safety Monitor (IDSM) and Safety Monitoring 
Committee (SMC) ............................................................................................68 
11.2 
Adverse Event Collection Period .....................................................................69 
11.3 
Adverse Events ................................................................................................69 
11.4 
Adverse Event Relationship to Study Drug .....................................................69 
11.5 
Treatment and Follow-Up of Adverse Events .................................................70 
11.5.1 
Laboratory and ECG Abnormalities ................................................................70 
11.6 
Adverse Event Intensity Grading .....................................................................70 
11.6.1 
Follow Up of Abnormal Laboratory Test Values ............................................71 
11.7 
Serious Adverse Event (SAE) Reporting .........................................................71 
11.7.1 
SAE Definitions ...............................................................................................71 
11.7.2 
SAE Reporting .................................................................................................71 
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11.7.3 
Other Safety Findings Requiring Expedited Reporting ...................................73 
11.8 
Pregnancy .........................................................................................................73 
11.9 
Adverse Event of Special Interest ....................................................................74 
11.10 
Medication Errors, or Misuses of Medicinal Product ......................................74 
12 
DATA QUALITY ASSURANCE .....................................................................................75 
12.1 
Assignment of Preferred Terms and Original Terminology ............................75 
13 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS .........76 
13.1 
Regulatory and ethical considerations .............................................................76 
13.2 
Data protection .................................................................................................76 
13.3 
Patient Informed Consent ................................................................................79 
13.4 
Institutional Review Board and Ethics Committee Review ............................79 
13.5 
Conditions for Modifying the Protocol ............................................................81 
13.6 
Conditions for Terminating the Study .............................................................81 
13.7 
Financial Disclosure.........................................................................................81 
14 
STUDY DOCUMENTATION, MONITORING, CASE REPORT FORMS, AND 
RECORD RETENTION REQUIREMENTS ....................................................................82 
14.1 
Investigator's File/Retention of Records ..........................................................82 
14.2 
Source Documents and Background Data .......................................................82 
14.3 
Audits and Inspections .....................................................................................83 
14.4 
Case Report Forms ...........................................................................................83 
14.5 
Study Monitoring .............................................................................................83 
14.6 
Confidentiality of Clinical Trial Documents and Patients' Medical 
Records ............................................................................................................83 
14.7 
Clinical Study Report .......................................................................................84 
14.8 
Publication of Data and Protection of Trade Secrets .......................................84 
15 
STUDY ADMINISTRATIVE PROCEDURES ................................................................85 
15.1 
Patient Recruitment Procedures .......................................................................85 
15.2 
Patient Enrollment Procedures .........................................................................85 
15.3 
Patient Premature Withdrawal – Definition .....................................................85 
15.4 
Procedures for Patients Who Withdraw from the Study ..................................85 
15.5 
Treatment Compliance .....................................................................................86 
15.6 
Recording of AEs on the CRF .........................................................................86 
15.7 
Physical Examination Procedures ....................................................................86 
15.8 
Vital Signs Procedures .....................................................................................87 
15.9 
Body Weight ....................................................................................................87 
15.10 
ECG Procedures ...............................................................................................87 
15.11 
Laboratory Test Procedures .............................................................................87 
15.11.1 
Recording of Laboratory Test Results on the CRF ..........................................88 
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15.12 
Recording of Concomitant Medications on the CRF .......................................88 
16 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS .........................................................................................................89 
16.1 
Appendix 1:
...............89 
16.2 
Appendix 2: 
............................................................................................89 
16.3 
Appendix 3: Schedule of Assessments (Part A) ..............................................90 
16.4 
Appendix 4: Schedule of Assessments (Part B) ..............................................92 
16.5 
Appendix 5: Schedule of Extension Period – First 6 Months (Part A and 
Part B) ..............................................................................................................93 
16.6 
Appendix 6: Schedule of Assessments – Extension Period Continued 
(Part A and Part B) ...........................................................................................95 
16.7 
Appendix 7:
 ........96 
16.8 
Appendix 8: Country-specific/region requirements.........................................98 
16.8.1 
European Union ...............................................................................................98 
16.9 
Appendix 9: Collection, storage and future use of data and human 
biological samples ............................................................................................99 
16.9.1 
Compliance with Member State applicable rules for the collection, 
storage and future use of human biological samples (Article 7.1h) ................99 
16.9.2 
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).......................................................................................99 
16.10 
Appendix 10: Protocol Amendment History ...................................................99 
17 
REFERENCES ................................................................................................................116 
 
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PRN1008-010 STUDY SYNOPSIS  
Study Title: 
An Adaptive, Open-Label, Dose-Finding, Phase 1/2 Study Investigating the Safety, 
Pharmacokinetics, and Clinical Activity of Rilzabrutinib (PRN1008), an Oral BTK 
Inhibitor, in Patients with Relapsed Immune Thrombocytopenia 
Study Number: 
PRN1008-010 (DFI17124) 
Indication: 
Immune Thrombocytopenia (ITP) 
Background and 
Rationale: 
There is preliminary evidence to support the role of Bruton tyrosine kinase (BTK) 
inhibition in patients with autoimmune cytopenias (2, 3) where sequential episodes of 
severe autoimmune hemolytic anemia and ITP ceased after initiation of treatment with 
ibrutinib in patients with chronic lymphatic leukemia (CLL). 
Rilzabrutinib is a high-affinity inhibitor of BTK. Pertinent to the treatment of ITP, 
rilzabrutinib treatment results in inhibited human B cell activation and blocked 
antibody (IgG, IgE) mediated activation of immune cells via Fc receptor signaling. 
In nonclinical studies, rilzabrutinib demonstrated a significant dose-dependent reduction 
of platelet loss in a mouse model of immune thrombocytopenia. Rilzabrutinib also 
showed rapid and significant anti-inflammatory effects in rat collagen-induced arthritis 
model, rat antibody-mediated arthus model, and spontaneous canine pemphigus disease. 
Mice in the anti-platelet-driven model of immune thrombocytopenia, dosed with 
rilzabrutinib at 10, 20, or 40 mg/kg/d had a dose-dependent prevention of platelet loss at 
6 hours in comparison to vehicle control treated animals. These doses are generally 
similar to doses which demonstrated efficacy in the rat CIA model (40 mg/kg/d) when 
adjusted for body-surface area dosing equivalents from mouse to rat (mouse dose = 50% 
of rat dose). These results would suggest that doses required for efficacy for ITP 
and autoimmune indications may be broadly similar (4). 
The potency of rilzabrutinib in the B-cell activation assay correlated with BTK target 
occupancy in Phase 1 studies; therefore,
 (4). 
In the completed Phase 2 study, PRN1008-005 (NCT02704429), a total of 41 patients 
with pemphigus were enrolled, 27 patients in Part A (12 weeks of rilzabrutinib and 
12 weeks of follow-up) and 15 patients in Part B (24 weeks of rilzabrutinib and 4 weeks 
of follow-up). One patient was enrolled in Part A, then enrolled in Part B 5 months after 
completing Part A. In Part A, doses ranged from 400 mg to 600 mg BID. In Part B, doses 
included 400 mg QD, 400 mg BID, and 600 mg BID. In Part A, 51.9% of patients 
achieved the primary control of disease activity (CDA) endpoint at the Week 5 visit, and 
70.4% at the Week 13 visit, further improving to 85.2% after an additional follow up of 
12 weeks off rilzabrutinib treatment. Complete response rates were observed beginning 
at the Week 13 visit in 4 patients, increasing to 6 patients by 20 weeks. In Part B, 
rilzabrutinib delivered high CDA rates with rapid onset independent of dose with 
60.0% of patients achieving CDA at the Week 5 visit and 86.7% within 12 weeks of 
treatment. Escalation to a dose of 400 mg BID and longer treatment to 24 weeks led to 
CR rates of 33.3%. Further results are provided in the PRN1008-005 clinical study report 
(5). 
The proposed study is a dose-finding study that uses an intrapatient dose-escalation 
design
 in the study and accounts for the 
biological variation in response in each patient. 
 
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 The dose finding part of the study (Part A) has completed 
and all newly enrolled patients start active treatment at the recommended 400 mg twice 
daily (BID) dose of rilzabrutinib.  
Part B is an expansion of the study that will investigate the safety and efficacy of only 
the selected dose of 400 mg BID. Part B will enroll patients with ITP who have relapsed 
or have an insufficient response to prior therapies.  
Study Sites: 
Part A: Multicenter trial (approximately 30 sites) 
Part B: Multicenter trial (approximately 30 sites)  
Study Phase: 
1/2 
Study Objectives  
Part A:  
Safety: 
• 
To characterize the safety and tolerability of up to four dose levels of rilzabrutinib 
in patients with ITP 
Efficacy: 
• 
To explore the clinical activity of up to four dose levels of rilzabrutinib 
in relapsed/refractory patients with ITP  
• 
To identify a potential dose regimen to use in future studies of rilzabrutinib in 
patients with ITP 
Pharmacokinetics:  
• 
To characterize the pharmacokinetics of rilzabrutinib in patients with ITP 
Exploratory: 
• 
To explore effect of rilzabrutinib on
• 
To explore effect of rilzabrutinib on 
• 
To explore effect of rilzabrutinib on thrombopoietin (TPO) levels 
• 
To explore effect of rilzabrutinib on quality of life (QOL) using the
) 
• 
To characterize plasma metabolites of rilzabrutinib 
Study Objectives  
Part B: 
Safety: 
• 
To characterize the safety and tolerability of the selected dose of 400 mg BID 
of rilzabrutinib in patients with ITP 
Efficacy: 
• 
To further explore the clinical activity and durability of response of the selected dose 
of 400 mg BID of rilzabrutinib in patients with ITP who have relapsed or have an 
insufficient response to prior therapies  
• 
To evaluate the predictive value of platelet response to rilzabrutinib therapy in the 
first 8 weeks of active treatment for the achievement of the primary endpoint 
Pharmacokinetics:  
• 
To characterize the pharmacokinetics of rilzabrutinib in patients with ITP 
Exploratory: 
• 
To explore effect of rilzabrutinib on 
• 
To explore effect of rilzabrutinib on thrombopoietin (TPO) levels 
• 
To explore effect of rilzabrutinib on 
ls 
• 
To explore effect of rilzabrutinib on quality of life (QOL) using the 
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Study Design 
Part A: 
This is an adaptive, open-label, dose-finding study of rilzabrutinib in patients with ITP 
who are refractory or relapsed with no available and approved therapeutic options, with 
a platelet count <30,000/µL on two counts no sooner than 7 days apart in the 15 days 
before treatment begins. 
The active treatment period is 24 weeks and the post-treatment follow-up period is 
4 weeks. 
Once a patient escalates to the 400 mg BID dose, the patient will stay at this dose for 
24 weeks (see Section 4.1 of the protocol). 
Patients will be monitored with weekly platelet counts and complete blood counts 
(CBCs) throughout the study; pharmacokinetic (PK) samples will be collected 
intensively on the first day of each new cycle and at random times following dosing at 
each on-treatment follow-up visit. Patients will have weekly study visits/laboratory tests 
throughout the study (Schedule of Assessments, Appendix 3).  
Patients may enter the study on stable doses of prednisone and/or TPO receptor agonists. 
Other
 are not permitted. 
Long Term Extension (LTE): 
After completing the active treatment period, patients who respond to rilzabrutinib will 
be allowed to enter the LTE. A platelet response for entering the LTE is defined 
as platelet count ≥50,000/μL, or ≥30,000/μL and doubling of baseline at ≥50% of the 
visits during the last 8 weeks of the active treatment period (a minimum of 4 visits per 
the Schedule of Assessments) will be required. Baseline should be calculated as an 
average of platelet counts used for enrollment per Inclusion Criterion #4.  
A patient may continue in the LTE until:  
a) The patient is no longer responding as described in the table below: 
Time in the LTE 
‘No response’ platelet counts defined as  
<30,000/µL or <20,000/µL above baseline based on: 
C1_LTE through 
C6_LTE 
4 consecutive weekly visits 
C7_LTE through 
C12_LTE 
2 consecutive monthly visits 
QX_LTE 
1 quarterly visit 
In this case, a second platelet count has to be obtained in 
one month to confirm lack of response 
 
In the LTE, patients will be monitored weekly for the first 6 months, monthly for 
an additional 6 months, then once every 3 months with the assessments as outlined in the 
LTE Schedule of Assessments Appendix 5 and Appendix 6.  
Study Design 
Part B: 
This is an open-label study of rilzabrutinib in patients with ITP who have relapsed or 
have an insufficient response to prior therapies. Eligible patients will have a platelet 
count <30,000/µL on two occasions no less than 7 days apart, within 15 days before 
treatment begins and a platelet count of ≤35,000/µL on Study Day 1 (SD1). 
The study consists of a 28-day screening period, 24-week active treatment period, 
and a long-term extension. After the last dose of rilzabrutinib there will be a 4-week 
safety follow-up period. Patients enrolled with a positive hepatitis B virus (HBV) core 
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antibody result and hepatitis B virus surface antibody (HBsAb) titer ≥100 IU/L will 
continue to have HBV DNA monitored monthly for 6 months after treatment has ended. 
Patients will have weekly study visits/laboratory tests throughout the study (Schedule of 
Assessments, Appendix 4). 
Long Term Extension (LTE): 
After completing the active treatment period, patients who respond to rilzabrutinib will 
be allowed to enter the LTE. A platelet response for entering the LTE is defined 
as platelet count ≥50,000/μL, or ≥30,000/μL and doubling of baseline at ≥50% of the 
visits during the last 8 weeks of the active treatment period (a minimum of 4 visits per 
the Schedule of Assessments) will be required. Baseline should be calculated as an 
average of platelet counts used for enrollment per Inclusion Criterion #4. 
A patient may continue in the LTE until:  
a) The patient is no longer responding as described in the table below: 
Time in the LTE 
‘No response’ platelet counts defined as  
<30,000/µL or <20,000/µL above baseline based on: 
C1_LTE through 
C6_LTE 
4 consecutive weekly visits 
C7_LTE through 
C12_LTE 
2 consecutive monthly visits 
QX_LTE 
1 quarterly visit 
In this case, a second platelet count has to be obtained in 
one month to confirm lack of response 
In the LTE, patients will be monitored weekly for the first 6 months, monthly for 
an additional 6 months, then once every 3 months with the assessments as outlined in the 
LTE Schedule of Assessments Appendix 5 and Appendix 6.  
Dose-Limiting 
Toxicity, Dose 
Escalation, and 
Stopping Rules 
Part A: 
DLT Definition: 
Hematologic: 
Non-Hematologic:  
Any ≥ Grade 3 non-hematologic toxicity per the CTCAE, version 4.0 will be considered 
a DLT, with the following exceptions: 
• Laboratory treatment-emergent adverse events (TEAEs) that are asymptomatic 
and return to baseline or to Grade 1 within 7 days 
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• Fatigue 
• Nausea, vomiting, or diarrhea that return to baseline or Grade 1 within 7 days 
• Systemic reactions (such as fever, headache) that return to baseline or Grade 1 
within 7 days 
Miscellaneous: 
Any toxicity that, at the discretion of the Investigator, is thought to warrant withholding 
the study drug for more than 7 days. 
For laboratory-based AEs, these must be confirmed by repeat testing. 
The DLT evaluation period for any patient is defined as the duration of rilzabrutinib 
dosing until the dose escalation is completed. 
Dose Escalation Rules: 
Individual: 
• Patients will dose-escalate to successive dose levels unless they are withdrawn, 
have a platelet response at the current dose level, or the next dose level has been 
determined to be ineligible for further enrollment (see Maximal Administered 
Dose [MAD], below). 
• Patients experiencing a platelet response (as defined for the primary endpoint) will 
not have their dose escalated at the next cycle. If they do not experience a platelet 
response during the second cycle of the same dose level, they may dose escalate 
for the following cycle. If they require rescue medication subsequently because the 
platelet response was only transient these patients will be discontinued from the 
study. 
Starting Dose Level: 
Further dose escalation of cohort starting dose level will not occur if: 
• A DLT occurs in two or more patients in a sentinel cohort at the current starting 
dose level or the dosing level above 
• A sustained (3 of 4 counts) platelet response occurs in two or more patients in 
a sentinel cohort at the current starting dose level 
• The Safety Monitoring Committee (SMC) feels that the number and/or severity 
of TEAEs or laboratory abnormalities occurring do not justify further 
dose-escalation 
• Previously unknown data becomes available to the SMC which raise significant 
concerns about the potential risk to patients from further dose-escalation 
Maximal Administered Dose (MAD) Level: 
If any dose level is suspended for safety reasons, that dose level will be considered the 
MAD, and any continuing patients at the MAD will be de-escalated to the dose level 
below. Further enrollment will proceed at dosing levels below the MAD. If the MAD 
is 200 mg QD, the study will be suspended. 
Individual Stopping Rules: 
• Patients experiencing a DLT will be discontinued from the study. 
• Patients requiring rescue therapy during study treatment, will be discontinued from 
the study. 
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• Pregnancy. 
•
• Any other situation which, in the opinion of the Investigator or Sponsor, continued 
study treatment may result in undue safety risk to the patient. 
Study Stopping Rules: 
The study will be stopped (no new enrollments and no further study drug administered) 
if: 
•
 
• The SMC deems the emerging TEAE profile unacceptable to continue the study 
• The Sponsor elects to stop the study 
• There is >1 patient with Grade 3 or higher TEAEs (except for platelet count 
and underlying disease or comorbidity-related events) 
• Any patient experiences
 except if related 
to an underlying clinical condition or event (eg, intercurrent illness, cardiovascular 
event, new sedating medication) 
Stopping Rules 
Part B (also applies 
to LTE): 
Individual Stopping Rules: 
• Pregnancy 
•
• Any other situation which, in the opinion of the Investigator or Sponsor, continued 
study treatment may result in undue safety risk to the patient. 
Study Stopping Rules: 
The study will be stopped (no new enrollments and no further study drug administered) 
if: 
• The Sponsor deems the emerging TEAE profile unacceptable to continue the study 
• The Sponsor elects to stop the study 
• Two or more life-threatening or CTCAE Grade 4 rilzabrutinib-related TEAEs 
except for AEs related to the disease under study (lack of efficacy) 
Rescue Criteria 
Guidelines  
Part A: 
Patients may receive another treatment for ITP (one form of intravenous immunoglobulin 
[IVIg], high-dose steroids, platelet infusion, or anti-D immunoglobulin infusion) if there 
is a significant safety event requiring “rescue” from a deterioration in the patient’s 
platelet count that in the opinion of the Investigator puts the patient at significant risk of 
a safety event. 
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Patients who receive rescue therapy will be discontinued from the study. 
Rescue Criteria 
Guidelines  
Part B: 
Patients may receive another treatment for ITP (one form of IVIg, high-dose steroids, 
platelet infusion, or anti-D immunoglobulin infusion) if there is a significant safety event 
requiring “rescue” from a deterioration in the patient’s platelet count that in the opinion 
of the Investigator puts the patient at significant risk of a safety event. 
Rituximab or other anti-CD20 medications, vincristine or other immunosuppressants, 
and new starts or increases in doses of eltrombopag, romiplostim, or avatrombopag are 
not permitted as rescue therapy while the patient is receiving treatment with rilzabrutinib.  
Patients who receive rescue therapy will be allowed to continue if none of the stopping 
rules apply and the Investigator agrees to continue treating the patient with rilzabrutinib. 
Study Endpoints  
Part A: 
Safety Endpoints: 
Safety will be assessed by the incidence, severity, and relationship of TEAEs, including 
clinically significant changes in physical examination, laboratory tests, electrocardiogram 
(ECG), and vital signs. Treatment-emergent adverse events in the post treatment follow-
up period will also be assessed and examined for possible relationship to the prior 
rilzabrutinib treatment. Adverse events will be categorized as treatment emergent after 
the first dose of rilzabrutinib has been received. 
In addition, safety will be assessed by the following endpoints, 
• 
Proportion of patients receiving rescue medication at each dosing level and overall 
• 
Proportion of patients with a Grade 2 or higher bleeding event at each dosing level 
and overall 
• 
Bleeding scale (ITP Bleeding Scale [IBLS]) at the end of treatment period for each 
dosing level 
Primary Efficacy Endpoint: 
Proportion of patients able to achieve two or more consecutive platelet counts, separated 
by at least 5 days, of ≥50,000/μL AND an increase of platelet count of ≥20,000/μL from 
baseline, by dose level, without use of rescue medication in the 4 weeks prior to the latest 
elevated platelet count. 
Secondary Efficacy Endpoints: 
• 
Percent of weeks with platelet counts ≥ 50,000/μL by dose level and overall  
• 
Proportion of patients with 4 out of the final 8 platelet counts ≥ 50,000/μL across 
all dose levels  
• 
Change from baseline to the average of the post Day 1 platelet counts by dose 
level and overall for patients who had >4 weeks of study drug on that given dose 
level  
• 
Number of weeks with platelet counts ≥ 50,000/μL across all dose levels  
• 
Number of weeks with platelet counts ≥ 30,000/μL across all dose levels  
• 
Time to first platelet count ≥ 50,000/μL across all dose levels 
Pharmacokinetic Endpoints: 
Plasma PK parameters of rilzabrutinib in ITP patients will be evaluated in each patient 
based on frequent sampling on Day 1 of new, higher dosing levels, and sparse sampling 
at other times. 
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Exploratory Endpoints: 
• 
Proportion of patients with any two platelet counts ≥50,000/μL AND an increase 
of platelet count of ≥20,000/μL from baseline during treatment period.  
• 
Proportion of patients with any two platelet counts ≥ 50,000/μL AND an increase 
of platelet count of ≥20,000/μL from baseline during follow-up period (without 
dose reduction of the concomitant CS or TPO-RA doses)  
• 
Proportion of patients able to achieve two or more consecutive platelet counts, 
separated by at least 5 days, of ≥ 30,000/μL OR an increase of platelet count of 
≥20,000/μL from baseline, without use of rescue medication in the 4 weeks prior 
to the latest elevated platelet count.  
• 
Proportion of patients able to achieve any platelet counts ≥100,000/μL.  
• 
Time to first of two consecutive platelet counts ≥50,000/μL  
• 
Proportion of patients with 4 out of the final 6 platelet counts ≥50,000/μL across 
all dose levels  
• 
Proportion of patients with 8 out of the final 12 platelet counts ≥50,000/μL across 
all dose levels 
• 
Effect of rilzabrutinib on TPO levels 
 
Study Endpoints  
Part B: 
Safety Endpoints: 
Safety will be assessed by the incidence, severity, and relationship of TEAEs, including 
clinically significant changes in physical examination, laboratory tests, ECG, and vital 
signs. Bleeding TEAEs will be tabulated and a proportion of patients with a Grade 2 or 
higher bleeding event will be provided. 
Primary Efficacy Endpoint: 
Proportion of patients able to achieve platelet counts ≥50,000/μL on at least 8 out of the 
last 12 weeks of the 24-week treatment period without the use of rescue medication.  
Secondary Efficacy Endpoints: 
• 
Number of weeks with platelet count ≥50,000/μL OR ≥30,000/µL and doubling 
the baseline in the absence of rescue therapy (platelet counts will be censored 
for 4 weeks after the use of rescue medication, if given) 
• 
Proportion of all treated patients able to achieve two or more consecutive platelet 
counts, separated by at least 5 days, of ≥50,000/μL AND an increase of platelet 
count of ≥20,000/μL from baseline without use of rescue medication in the 
4 weeks prior to the latest elevated platelet count  
• 
Number of weeks with platelet counts ≥30,000/μL and doubling from baseline 
over the 24-week treatment period (platelet counts will be censored for 4 weeks 
after the use of rescue medication, if given) 
• 
Proportion of patients receiving rescue medication  
• 
Change from baseline in ITP Bleeding Scale (IBLS) 
Exploratory Endpoints: 
• 
Proportion of patients who completed 24 weeks of treatment and demonstrated 
a platelet response defined as platelet counts ≥50,000/μL at 4 out of the last 
8 weeks of the active treatment period  
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• 
Proportion of patients who have a platelet count that exceeds 250,000/µL 
or 450,000/µL (for patients on concomitant TPO-RAs) 
• 
Time to first platelet count of ≥50,000/µL 
• 
Percentage of time with platelet counts ≥30,000/µL OR ≥20,000/µL above 
baseline  
 
• 
Effect of rilzabrutinib on TPO levels 
• 
Effect of rilzabrutinib on QOL  
Pharmacokinetic Endpoints: 
Plasma PK parameters of rilzabrutinib in ITP patients will be evaluated in each patient 
based on sparse sampling and population PK modeling. 
Planned Number of 
Patients:  
Part A 
Approximately 60 patients with ITP will be enrolled such that approximately 15 patients 
complete 24 weeks of dosing and at least 10 patients complete 24 weeks of treatment at a 
starting dose of 400 mg BID. Patients who drop out for reasons other than TEAEs during 
the 24-week treatment period may be replaced.  
Part B 
The study will enroll approximately 23 patients. 
Patient Selection 
Criteria  
Part A: 
Inclusion Criteria: 
1. Male or female patients, aged 18 to 80 years old (Czech Republic and Norway 
only: 18 to 65 years old) 
2. Immune-related ITP (both primary and secondary) 
3. Refractory or relapsed patients with no available and approved therapeutic options 
with a platelet count of <30,000/µL on two occasions no less than 7 days apart in 
the 15 days prior to beginning study treatment.  
4. A history of response (two or more platelet counts ≥50,000/µL with an increase 
of at least 20,000/µL) to at least one prior line of therapy (with splenectomy being 
considered a line of therapy) 
5. Adequate hematologic, hepatic, and renal function (absolute neutrophil count 
≥1.5 × 109/L, hemoglobin [Hgb] >9 g/dL, AST/ALT ≤1.5 × ULN, albumin 
≥3 g/dL, total bilirubin ≤1.5 × ULN, estimated glomerular filtration rate [eGFR] 
> 60 mL/min (Cockcroft and Gault method) (C1D1 pre-dose may be checked up to 
Day -3 prior to C1D1) 
6. Female patients who are of reproductive potential must agree for the duration of 
active treatment in the study to use a highly effective means of contraception 
(hormonal contraception methods that inhibits ovulation, intrauterine device, 
intrauterine hormone-releasing system, bilateral tubal ligation, vasectomized 
partner, or true abstinence; when this is in line with the preferred and usual 
lifestyle of the patient). Unless surgically sterile, postmenopausal females should 
have menopause confirmed by follicle-stimulating hormone (FSH) testing. 
7. Able to provide written informed consent and agreeable to the schedule of 
assessments 
Exclusion Criteria: 
1. Pregnant or lactating women 
2. ECG findings of QTcF >450 msec (males) or >470 msec (females), poorly 
controlled atrial fibrillation (ie, symptomatic patients or a ventricular rate above 
100 beats/min on ECG), or other clinically significant abnormalities  
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3. History of current, active malignancy requiring or likely to require 
chemotherapeutic or surgical treatment during the trial, with the exception 
of non-melanoma skin cancer 
4. Transfusion with blood or blood products or plasmapheresis within 2 weeks before 
Day 1  
5. Change in corticosteroid and/or TPO agonist dose within 2 weeks prior to Day 1 
(more than 10% variation from Day 1 daily doses) 
6. Use of rescue medications other than corticosteroids or TPO in Exclusion Criterion 
#5 in the two weeks before Day 1 
7.
– these drugs should be 
discontinued for at least 14 days before Day 1 
8. Treatment with rituximab or splenectomy within the 3 months prior to Day 1 
9.
 
12. Planned or concomitant use of any anticoagulants and platelet aggregation 
inhibiting drugs such as aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), 
thienopyridenes (within 14 days of planned dosing through end of follow-up) 
13. 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); patient should not be using an investigational device at the 
time of dosing 
14. Current drug or alcohol abuse 
15. Refractory nausea and vomiting, malabsorption, external biliary shunt, or 
significant bowel resection that would preclude adequate study drug absorption 
16. History of solid organ transplant 
17. Positive screening for human immunodeficiency virus (HIV), hepatitis B (surface 
antigen and core antibodies unrelated to vaccination), or hepatitis C (anti-HCV 
antibody confirmed with HCV RNA) 
18. History of serious infections requiring intravenous therapy within the last 3 months 
before Day 1 
19. Clinically significant cognitive dysfunction (≥ Grade 1) or medical history 
suggestive of increased risk for cognitive dysfunction during the study 
20.
 
21. Planned surgery in the time frame of the dosing period 
22. Any other clinically significant disease, condition, or medical history that, in the 
opinion of the Investigator, would interfere with patient safety, study evaluations, 
and/or study procedures 
Patient Selection 
Criteria  
Part B: 
Inclusion Criteria: 
1. 
Male or female patients, aged 18 to 80 years old  
2. 
Patients with immune-related ITP (both primary and secondary) as defined by 
current guidelines with at least 3 months duration  
3. 
Patients who had a response (achievement of platelet count ≥50,000/µL) to 
IVIg/anti-D or corticosteroid that was not sustained and failed at least one other 
ITP therapy (that was not IVIg or corticosteroid) 
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4. 
Patients with a platelet count of <30,000/µL on two occasions no less than 7 days 
apart in the 15 days before treatment begins, and no platelet count above 
35,000/µL on Study Day 1.  
5. 
Patients with adequate hematologic, hepatic, and renal function (absolute 
neutrophil count ≥1.5 × 109/L, Hgb >9 g/dL, AST/ALT ≤1.5 × ULN, albumin 
≥3 g/dL, total bilirubin ≤1.5 × ULN, eGFR >50 mL/min (Cockcroft and Gault 
method) (pre-dose may be checked up to Day -3) 
6. 
Female patients who are of reproductive potential must agree for the duration 
of active treatment in the study to use a highly effective means of contraception 
(hormonal contraception methods that inhibits ovulation, intrauterine device, 
intrauterine hormone-releasing system, bilateral tubal ligation, vasectomized 
partner, or true abstinence; when this is in line with the preferred and usual 
lifestyle of the patient). Unless surgically sterile, postmenopausal females should 
have menopause confirmed by FSH testing. 
7. 
Able to provide written informed consent and agreeable to the schedule of 
assessments 
Exclusion Criteria: 
1. 
Pregnant or lactating women 
2. 
ECG findings of QTcF >450 msec (males) or >470 msec (females), poorly 
controlled atrial fibrillation (ie, symptomatic patients or a ventricular rate above 
100 beats/min on ECG), or other clinically significant abnormalities  
3. 
History (within 5 years of SD1) or current, active malignancy requiring or likely to 
require chemotherapeutic or surgical treatment during the trial, with the exception 
of non-melanoma skin cancer 
4. 
Transfusion with blood, blood products, IVIg, or plasmapheresis within 2 weeks 
before SD1  
5. 
Change in corticosteroid and/or TPO agonist dose within 2 weeks prior to SD1 
(more than 10% variation) 
6. 
Use of rescue medications in the 4 weeks before SD1 
7. 
Treatment with 
 within 
2 weeks prior to SD1 
8. 
Treatment with rituximab or splenectomy within the 3 months prior to SD1 
• 
Patients treated with rituximab within 6 months from screening will have 
normal B-cell counts prior to enrollment 
9. 
12. Planned or concomitant use of any anticoagulants and platelet aggregation 
inhibiting drugs such as aspirin with the exception of up to 100 mg/day doses, 
NSAIDs, thienopyridenes (within 2 weeks of planned dosing through end of 
follow-up) 
13. 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); patient should not be using an investigational device at the 
time of dosing: 
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• 
Patients who previously received treatment with BTK inhibitors within 
30 days before receiving the first dose of study medication or who have 
previously received rilzabrutinib are not eligible for the study 
14. Current drug or alcohol abuse 
15. Refractory nausea and vomiting, malabsorption, external biliary shunt, 
or significant bowel resection that would preclude adequate study drug absorption 
16. History of solid organ transplant 
17. Positive at screening for HIV, hepatitis B (surface antigen, core antibodies), 
or hepatitis C (anti-HCV antibody confirmed with HCV RNA). 
• 
Patients who are HBV surface antigen (HBsAg) positive will not be eligible.  
• 
Patients who are HBsAg negative and HBV core 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, patients 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. 
• 
Patients who are HBcAb positive, HBsAg negative with HBsAb titer 
<100 IU/L or negative, are not eligible.  
18.
 
19. Myelodysplastic syndrome 
20. 
 
21. Planned surgery in the time frame of the dosing period 
22. Any other clinically significant disease, condition, or medical history that, in the 
opinion of the Investigator, would interfere with patient safety, study evaluations, 
and/or study procedures. 
Study Drug and 
Method of Dosing: 
Part A: 
Rilzabrutinib 100 mg, 300 mg, and 400 mg tablets. Tablets should be taken with a glass 
(~8 oz.) of water and may be taken 
 
 
Part B: 
Rilzabrutinib 400 mg tablets. Tablets should be taken with a glass (~8 oz.) of water and 
may be taken 
 
 
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Screening 
Procedures: 
Part A and Part B: 
Up to 28 days before Day 1, patients will be required to sign a consent form, after which 
screening assessments will be carried out as follows: 
• 
Review of medical history including concomitant medications 
• 
Review of inclusion and exclusion criteria 
• 
Measurement of height and weight 
• 
Physical examination 
• 
Single 12-lead ECG 
• 
Vital signs (blood pressure, heart rate, respiration rate, and temperature) 
• 
Laboratory testing per schedule of assessments including two or more platelet 
counts needed to meet inclusion criteria 
Study Assessments 
(See Schedule, 
Appendix 3, 
Appendix 4, 
Appendix 5, and 
Appendix 6): 
Patients will be screened within 28 days of Day 1 and will return for an end-of-study 
assessment approximately 28 days after receiving their final dose of study drug. During 
the study, patients will return at specified times on an outpatient basis for assessment of 
vital signs, abbreviated physical examination, assessment of AEs, concomitant 
medication use, and laboratory testing. 
Clinical Assessments: 
• 
Medical history, assessment of AEs, periodic vital signs (body temperature, heart 
rate, blood pressure), and concomitant medication use 
• 
Height (screening only), weight, full and abbreviated physical examination 
• 
IBLS 
• 
QOL assessment
) 
• 
Part B only: ITP-PAQ 
Laboratory and ECG Assessments: 
• 
Complete blood count (CBC) with differential, including reticulocyte count 
• 
ABO Blood Type (screening only, historical information is acceptable) 
• 
Immature Platelet Fraction (where available) 
• 
Mean Platelet Volume (where available) 
• 
Coagulation: prothrombin time (PT)/International Normalized Ratio (INR) 
and activated partial thromboplastin time (aPTT) 
• 
Serum chemistry: AST, ALT, total, direct, and indirect bilirubin levels, ALP, 
albumin, creatinine, urea, total protein, sodium, chloride, calcium, phosphate, 
potassium, glucose (random), and creatine phosphokinase (CPK) 
• 
FSH for post-menopausal patients who are not surgically sterile 
• 
PK: Plasma rilzabrutinib concentration 
• 
Urinalysis: pH, specific gravity, protein, glucose, ketones, bilirubin, blood, nitrites, 
urobilinogen, and leukocytes measured by dip stick or local requirement 
• 
Serology: HIV, Hepatitis B, and Hepatitis C 
• 
Pregnancy test for women of childbearing potential 
• 
Part A only: Quantitative platelet autoantibody panel (Australia only: test 
excluded) 
• 
Hemolysis panel: Coombs test, haptoglobin levels 
• 
TPO levels 
• 
  
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• 
Part B only:
• 
Part B only: BTK occupancy (at selected sites) 
• 
Part A only: 12-lead ECG: single at screening, triplicate ECGs pre-dose 
and post-dose on days of intensive PK draws  
• 
Part B only: 12-lead ECG: single at screening and at monthly clinical visits 
Safety Assessments 
and Monitoring 
Part A: 
Specific assessments to evaluate treatment safety include the following: the frequency, 
severity and relationship of AEs, clinical laboratory test changes, physical examination, 
and vital signs.  
Patients will remain under observation in the clinic for 6 hours after administration of the 
first dose at the beginning of each cycle during which time PK sampling will occur.  
An Independent Safety Data Monitor (IDSM) who is not a study Investigator will be 
chosen from expert clinicians in the ITP field. A Safety Monitoring Committee (SMC), 
comprised of the IDSM as Chairperson, lead Investigator, Study Medical Monitor, and 
Sponsor’s Medical Monitor, will closely supervise the conduct of the study. The IDSM 
will make sentinel cohort safety evaluations. 
The sentinel patients at each dose level will have their data reviewed by the IDSM, 
in order to choose the starting dose for additional, new patients. After review, the IDSM 
may determine that a starting dose for new patients should be dropped for futility (lack 
of platelet response), increased to the next planned dosing level, kept the same or 
reduced. New patients entering the study will commence at the dose level determined 
by the IDSM based on:  
• 
If ≥2/3 or ≥2/6 of those sentinel patients have a DLT at any dose level, that level 
shall be determined the “Maximal Administered Dose” and starting doses (new 
patients) and continuing doses (patients already on study) set at lower dosing levels 
(or study suspended if the current sentinel dose cohort was 200 mg QD) 
• 
If two or more patients with sustained platelet responses (as defined in the primary 
endpoint and sustained for at least 3 of 4 consecutive platelet counts) in the 
sentinel patients are seen at the current starting dose level the starting dose will 
not be escalated 
The SMC will meet approximately quarterly and recommend study modification or 
termination to the Sponsor, based on review of safety and efficacy information. 
Safety Assessments 
and Monitoring 
Part B: 
Specific assessments to evaluate treatment safety include the following: the frequency, 
severity and relationship of AEs, clinical laboratory test changes, physical examination, 
and vital signs. The assessments will be conducted as part of ongoing medical monitoring 
and at Sponsor Quarterly Safety Reviews where safety events and trends across 
rilzabrutinib studies are considered. 
Statistical Methods  
Part A: 
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. 
Sample Size: 
The sample size for this study is based on clinical considerations. Assuming an expected 
efficacy rate for the primary endpoint of 40% (platelet response), with 15 evaluable 
patients there will be 80% confidence that the true proportion will be 24% and above 
(80 ±16% confidence interval [CI]) using normal approximation methods. 
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Analysis Populations: 
Safety Analysis Population:  
All patients who have received at least one dose of rilzabrutinib will be included in the 
safety analysis. The Safety Analysis Population will be defined for all safety analyses. 
Efficacy Analysis Population:  
All patients who have enrolled in the study will be included in the Intent to treat (ITT) 
population. Enrolled patient is defined as a patient who signed the informed consent form 
and met eligibility criteria. Efficacy analysis will be based on the ITT population. 
Pharmacokinetic Analysis Population:  
All patients who have received at least one dose of rilzabrutinib and have at least 
one measurable plasma concentration value will be included in the pharmacokinetic 
analysis. 
Analysis Methods: 
Efficacy: 
Qualitative efficacy data will be summarized by frequencies and percentages. 
Quantitative efficacy data will be summarized by descriptive statistics (arithmetic mean, 
standard deviation, median, minimum, and maximum). Data will be summarized over 
time by dose level and overall. The time course of mean changes in platelet count over 
time will also be described graphically, annotated for dosing levels. 
Safety and Tolerability: 
The incidence, severity, and relationship of TEAEs, laboratory tests, rescue treatment 
usage, and vital signs will be summarized descriptively. Qualitative safety data will be 
summarized by frequencies and percentages at each dose level. Quantitative safety data 
will be summarized by descriptive statistics (arithmetic mean, standard deviation, 
median, minimum, and maximum) at each dose level. Summaries will also be presented 
for the change from baseline, when appropriate. The proportion of patients with Grade 2 
or higher bleeding events will also be summarized.  
Pharmacokinetics: 
PK data will be summarized using descriptive statistics, tabulated, and displayed 
graphically as appropriate. Non-compartmental analysis will be utilized to derive PK 
parameters for each individual. PK data may also be pooled with the data from other 
studies for population PK modeling. Individual patient PK values within this study may 
be used for exploratory analyses of exposure and effect. 
Statistical Methods  
Part B: 
A detailed SAP will be developed and finalized before the study database is locked and 
will supersede the statistical analysis methods described in the protocol. 
Sample Size: 
 
Analysis Populations: 
Safety Analysis Population:  
All patients who have received at least one dose of rilzabrutinib will be included in the 
safety analysis.  
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Efficacy Analysis Population: 
All patients who have enrolled in the study will be included in the Intent to treat (ITT) 
population. Enrolled patient is defined as a patient who signed the informed consent form 
and met eligibility criteria. Efficacy analysis will be based on the ITT population. 
Pharmacokinetic Analysis Population:  
All patients who have received at least one dose of rilzabrutinib and have at least 
one measurable plasma concentration value will be included in the pharmacokinetic 
analysis. 
Analysis Methods: 
Efficacy: 
Qualitative efficacy data will be summarized by frequencies and percentages. 
Quantitative efficacy data will be summarized by descriptive statistics (arithmetic mean, 
standard deviation, median, minimum, and maximum). The time course of mean changes 
in platelet count over time will also be described graphically. 
Other efficacy analyses:  
• 
Estimate the predictive value of platelet count to achieve the primary endpoint 
for each of the three predictors separately or in combination: 
o 
≥30,000/μL on Study Day 8  
o 
≥20,000/μL above baseline on Study Day 8  
o 
≥50,000/μL at any time over first 8 weeks of the treatment period  
Safety and Tolerability: 
The incidence, severity, and relationship of TEAEs, laboratory tests, rescue treatment 
usage, and vital signs will be summarized descriptively. Qualitative safety data will be 
summarized by frequencies and percentages at each dose level. Quantitative safety data 
will be summarized by descriptive statistics (arithmetic mean, standard deviation, 
median, minimum, and maximum). Summaries will also be presented for the change 
from baseline, when appropriate. The proportion of patients with Grade 2 or higher 
bleeding events will also be summarized.  
Pharmacokinetics: 
PK data will be summarized using descriptive statistics, tabulated, and displayed 
graphically as appropriate. PK data will be pooled with the data from other studies for 
population PK modeling, with the results reported outside the main clinical study report.  
Study Duration: 
Part A:  
Approximately 18 months from the first patient treated to last patient completing, 
and approximately 32 weeks per patient. For patients who receive additional treatment 
cycles to complete 24 weeks at the 400 mg BID dose, the study duration could be up to 
55 weeks.  
Part B:  
Approximately 28 months from the first patient treated to last patient completing. 
The study duration for each patient will be approximately 32 weeks. 
Long Term Extension (LTE) Part A and Part B: 
Study duration for the patients who enter the LTE will be determined by the durability 
of the platelet response, the occurrence of DLTs, and/or other criteria as described in the 
Study Design section of the Study Synopsis. 
 
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GLOSSARY OF ABBREVIATIONS AND TERMS  
ABBREVIATION OR TERM 
DEFINITION 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
BID 
twice daily (morning and evening) 
BP 
blood pressure 
BTK 
Bruton tyrosine kinase 
CA 
Competent Authority 
CBC 
complete blood count 
CDA 
control of disease activity 
CI 
confidence interval 
CL/F 
apparent total clearance of the drug from plasma after oral administration  
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum observed plasma concentration 
CPK 
creatine phosphokinase 
CRF 
case report form 
CRO 
Contract Research Organization 
CS 
corticosteroid 
CTCAE 
Common Terminology Criteria for Adverse Events 
 
D 
day 
 
DLT 
dose-limiting toxicity 
EC 
Ethics Committee  
ECG 
electrocardiogram 
EDC 
electronic data capture 
eGRF 
estimated glomerular filtration rate 
 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
H2 
histamine two (receptor) 
HBcAb 
Hepatitis B core antibody 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HDPE 
high-density polyethylene 
HIV 
human immunodeficiency virus 
HR 
heart rate 
IB 
Investigator’s Brochure 
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ABBREVIATION OR TERM 
DEFINITION 
IBLS 
ICH 
Idiotic Thrombocytopenic Purpura Bleeding Scale 
International Council for Harmonisation  
IDSM 
Independent Data Safety Monitor 
IR 
immediate release 
IRB 
Institutional Review Board (Human Research Ethics Committee) 
ITP 
Immune thrombocytopenia 
ITP-PAQ 
Idiopathic Thrombocytopenic Purpura Patient Assessment Questionnaire 
ITT 
Intent-to-treat 
IVIg 
intravenous immunoglobulin 
LPLV 
last patient last visit  
LTE 
long term extension 
MAD 
Maximal Administered Dose 
MedDRA 
Medical Dictionary for Regulatory Activities  
NK 
natural killer (cell) 
NSAID 
non-steroidal anti-inflammatory drug 
OTC 
over the counter 
PK 
pharmacokinetic 
PT/INR 
prothrombin time/international normalized ratio 
PV 
pemphigus vulgaris 
PVG 
pharmacovigilance 
QD 
once daily 
QOL 
Quality of Life 
QTcF 
QT interval corrected for heart rate (Fridericia Correction) 
RR 
resting rate 
SAE 
serious adverse event 
SAP 
Statistical Analytical Plan 
SI 
Système international d’unités (International system of units) 
SMC 
Safety Monitoring Committee 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
treatment-emergent adverse event 
Tmax 
time of observed maximum plasma concentration 
TPO 
thrombopoietin 
t½ 
elimination half-life 
ULN 
upper limit of normal 
USUBJID 
unique patient identifier 
VAS 
visual analog scale 
V/F 
apparent volume of distribution of the drug after oral administration 
WBC 
white blood cell 
WHODD 
World Health Organization Drug Dictionary 
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1 
BACKGROUND  
1.1 
Scientific Rationale for Treatment of ITP with Rilzabrutinib  
Idiopathic thrombocytopenic purpura, now more commonly referred to as 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, intravenous immunoglobulin [IVIg], or anti-D) 
is used for symptomatic patients with low platelet counts for reducing platelet destruction. While 
a majority of patients respond initially to corticosteroids, 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 (6) are approved for the treatment of 
patients with chronic ITP who have not had sufficient responses to corticosteroids, IVIg, or 
splenectomy. Novel, safe, and effective oral treatments in this setting to maintain platelet counts 
would be a significant therapeutic advantage. Thus, there remains a high unmet medical need for 
novel, safe, and effective oral therapies for ITP.  
There is preliminary evidence to support the role of Bruton tyrosine kinase (BTK) inhibition in 
patients with autoimmune cytopenias (2, 3), where sequential episodes of severe autoimmune 
hemolytic anemia and ITP ceased after initiation of treatment with ibrutinib, a BTK/EGFR/ITK 
inhibitor, in patients with chronic lymphatic leukemia (CLL).  
Rilzabrutinib is a high-affinity inhibitor of BTK.
 rilzabrutinib 
treatment in vitro profoundly inhibited human B cell activation and blocked antibody (IgG, IgE) 
mediated activation of immune cells via Fc receptor signaling. In nonclinical studies, 
rilzabrutinib demonstrated a significant dose dependent reduction of platelet-loss (consumption) 
in a mouse model of immune thrombocytopenia. Rilzabrutinib also showed rapid and significant 
anti-inflammatory effects in rat collagen-induced arthritis model, rat antibody mediated arthus 
model, spontaneous canine pemphigus foliaceus and human pemphigus vulgaris (PV). 
1.2 
Summary of Rilzabrutinib Clinical Experience  
To date, rilzabrutinib has been administered to more than 170 healthy volunteers and patients 
in Phase 1 and Phase 2 studies. Rilzabrutinib has been generally well tolerated. In the completed 
Phase 2 study, PRN1008-005 (NCT02704429), a total of 41 patients with pemphigus were 
enrolled, 27 patients in Part A (12 weeks of rilzabrutinib and 12 weeks of follow-up) and 
15 patients in Part B (24 weeks of rilzabrutinib and 4 weeks of follow-up). One patient was 
enrolled in Part A, then enrolled in Part B 5 months after completing Part A. In Part A, doses 
ranged from 400 mg to 600 mg BID. In Part B, doses included 400 mg QD, 400 mg BID, and 
600 mg BID. In Part A, 51.9% of patients achieved the primary control of disease activity (CDA) 
endpoint at the Week 5 visit, and 70.4% at the Week 13 visit, further improving to 85.2% after 
an additional follow up of 12 weeks off rilzabrutinib treatment. Complete response rates were 
observed beginning at the Week 13 visit in 4 patients, increasing to 6 patients by 20 weeks. In 
Part B, rilzabrutinib delivered high CDA rates with rapid onset independent of dose with 
60.0% of patients achieving CDA at the Week 5 visit and 86.7% within 12 weeks of treatment. 
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Escalation to a dose of 400 mg BID and longer treatment to 24 weeks led to CR rates of 33.3%. 
Further results are provided in the PRN1008-005 clinical study report (5). Preliminary results of 
PRN1008-010 after 47 patients were enrolled (05 May 2020 data cutoff) were presented at 
European Hematology Association annual meeting (7). 
Analysis of hematology and coagulation measurements in prior healthy volunteer studies showed 
1.3 
Clinical Pharmacokinetics and Pharmacodynamics of Rilzabrutinib  
Rilzabrutinib is rapidly absorbed following oral administration, with a fast half-life (3–4 hours), 
and variable pharmacokinetics (PK). 
 
Rilzabrutinib demonstrates a slow BTK off-rate, with BTK occupancy observed for more than 
24 hours after plasma concentrations are undetectable. With multiple dosing, equivalent doses 
of 428 mg of the immediate-release (IR) tablet and above (QD or BID) appear to achieve near 
maximal peak BTK occupancy, however twice daily dosing regimens maintained higher 
occupancy at trough compared to once daily dosing.  
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2 
DOSE RATIONALE AND STUDY DESIGN  
2.1 
Rationale for the Study Design  
An adaptive, open-label, dose-finding study of 15 patients, using rule-based intrapatient dose 
escalation, is an appropriate Phase 1/2 design to evaluate the safety and effect of rilzabrutinib in 
patients with ITP – a relatively rare autoimmune disease. This study
 and is similar in design to one used to study the 
initial efficacy and safety of fostamatinib in ITP (8). 
Patients enrolled in this study will have low platelet counts having relapsed on or been refractory 
to prior therapies with no available and approved therapeutic options, and may continue 
corticosteroids and/or thrombopoietin mimetics during the study. Compared to a sequential 
group dose-escalation study, this design will not expose the initial cohorts of patients to 
ineffective dose levels for a prolonged period and will thus potentially minimize the use 
of rescue medication.
The active treatment period of 24 weeks and the post-treatment follow up period of 4 weeks 
and the Long Term Extension (LTE) are justified by safety and efficacy seen to date in human 
and animal studies. The “sentinel cohorts” at each dose level consist of the first 3 patients, or 6, 
if 3 extra are added for a dose-limiting toxicity (DLT) or platelet response (as defined in the 
primary endpoint and sustained for at least 3 of 4 consecutive counts over one or two 28-day 
cycles). To be evaluable in a sentinel cohort, patients must have ≥75% compliance over the 
28-day dosing period. The sentinel cohort data is reviewed for by the Independent Data Safety 
Monitor (IDSM, who is also Chairperson of the Safety Monitoring Committee [SMC]), in order 
to choose the starting dose for additional, new patients entering the study. After safety review, 
the IDSM may determine that a starting dose for new patients should be dropped for futility 
(lack of platelet response), increased to the next planned dosing level, kept the same or reduced 
(Section 4.4). 
Patients will be monitored frequently by weekly platelet counts and complete blood counts 
(CBCs) throughout the active treatment period and will continue in the LTE weekly for 6 months, 
then monthly for six months, and every three months thereafter. PK samples will be collected 
intensively on the first day of each new, higher dose level and at random times following dosing 
at each on-treatment follow up visit. The other clinical and laboratory assessments used in this 
study are standard and used in clinical practice for assessment of patients with ITP. The bleeding 
assessment (Idiopathic Thrombocytopenic Purpura Bleeding Scale [IBLS]) (9) has been used in 
prior studies. 
2.1.1 Rationale for Doses Used and Duration of Study Part A  
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 Dosing above 400 mg BID is thought 
unlikely to result in greater target inhibition. 
Pemphigus vulgaris is an autoantibody-driven disease like ITP. In Study PRN1008-005 a rapid 
onset of clinical effect was seen in most pemphigus patients within 4 weeks, with continued 
improvement to very low levels of skin inflammation by the end of 12 weeks of therapy. 
Therefore 28-day cycles to assess the initial platelet response, and trigger intrapatient dose-
escalation are appropriate. A 24-week overall treatment period is preferred for this dose-finding 
study to enable all patients to potentially dose-escalate to the higher doses and be fully evaluated 
at those doses.  
A 24-week treatment period and the LTE are supported by completed long term Good 
Laboratory Practice (GLP) animal safety toxicology studies, and a favorable risk benefit profile 
observed in completed and ongoing human studies (4). 
2.1.2 Rationale for Doses Used and Duration of Study Part B  
The dose-finding portion of the study (Part A) has been completed. All doses were evaluated 
and the 400 mg BID dose has been selected as a safe and efficacious dose for further 
investigation in Part B. Similar to Part A, there will be a 24-week treatment period to assess 
the primary endpoint and an LTE for patients who demonstrate a platelet response. 
The primary endpoint in Part B will assess the durability of response in the last 12 weeks 
of the 24-week treatment period, and a key secondary endpoint will assess the
 
platelet response in the first 8 weeks of treatment for the achievement of the primary endpoint.  
2.2 
Overall Benefit-Risk Assessment  
Safety Profile 
Rilzabrutinib was well tolerated in the clinical development program, including single and 
multiple doses. The most common treatment-emergent adverse events (TEAEs) were 
 The majority of TEAEs were 
mild to moderate in severity.  
Until 02 January 2024, no SUSAR has been reported in the ITP Phase 2 PRN1008-010 Study. 
There was one SUSAR of serious infection reported in the ongoing ITP Phase 3 Study 
(PRN1008-018), and a causal association with blinded IMP (rilzabrutinib/placebo) was deemed 
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unlikely by the Sponsor. No major bleeding events occurred in the clinical experience with 
rilzabrutinib. Refer to the Investigator’s Brochure for additional and updated information. 
Risk Assessment  
Based on the review of the cumulative data, as of 2 January 2024, with an estimated exposure of 
1137 participants who received at least one dose of rilzabrutinib or placebo (826 participants on 
rilzabrutinib with approximately 545 patient-years, estimated based on randomization ratio) 
across multiple disease conditions, there are 
for rilzabrutinib.The 
following are considered as important potential risks for rilzabrutinib: 
•
Details of important potential risks together with a summary of the cumulative clinical safety 
data are provided below. 
Table 1 - Risk assessment 
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Benefit assessment 
Patients with ITP were expected to only transiently benefit from rilzabrutinib with the initial 
dose escalation scheme and 12-weeks of treatment, although anecdotal evidence from the 
Phase 2 study of rilzabrutinib in pemphigus suggests a durable effect post-treatment may occur 
in some patients. The additional non-clinical data supported longer treatment durations enabling 
amending to 24 weeks of treatment and allowing dose escalation to the highest dose level, as 
well as an LTE for patients with platelet response. 
Preliminary review of the efficacy data in Part A of this study demonstrated a dose response 
and that patients with ITP who failed multiple treatments were able to achieve a fast and durable 
platelet response at the 400 mg BID dose of rilzabrutinib. Patients treated with once daily doses 
were less likely to achieve fast platelet response and the primary endpoint (10). This evidence of 
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treatment effect supports initiation of Part B of the study that will focus on further investigating 
this dose of rilzabrutinib in this patient population. Preliminary results of Part A and Part B 
provide evidence that treatment with rilzabrutinib 400 mg BID induces a rapid and durable 
platelet response  and continued to be well tolerated in patients with ITP (11, 12). 
Benefit-risk: To date, preliminary analyses of efficacy and safety in patients with ITP support an 
overall favorable benefit-risk profile, and to continue the development of rilzabrutinib for 
patients with ITP. 
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3 
OBJECTIVES AND OUTCOME MEASURES OF THE STUDY  
3.1 
Objectives of the Study: Part A  
3.1.1 Safety Objective  
• To characterize the safety and tolerability of up to four dose levels of rilzabrutinib 
in patients with ITP  
3.1.2 Efficacy Objectives  
• To explore the clinical activity of up to four dose levels of rilzabrutinib 
in relapsed/refractory patients with ITP  
• To identify a potential dose regimen to use in future studies of rilzabrutinib in patients 
with ITP 
3.1.3 Pharmacokinetics Objective  
• To characterize the pharmacokinetics of rilzabrutinib in patients with ITP 
3.1.4 Exploratory Objectives  
• To explore effect of rilzabrutinib on thrombopoietin (TPO) levels 
• To explore effect of rilzabrutinib on quality of life (QOL) using the 
•
of rilzabrutinib 
3.2 
Objectives of the Study: Part B  
3.2.1 Safety Objective  
• To characterize the safety and tolerability of 400 mg BID dose of rilzabrutinib in patients 
with ITP  
3.2.2 Efficacy Objectives  
• To further explore the clinical activity and durability of response of the selected dose 
of 400 mg BID of rilzabrutinib in patients with ITP who have relapsed or have an 
insufficient response to prior therapies  
• To evaluate the predictive value of platelet response to rilzabrutinib therapy in the first 
8 weeks of active treatment for the achievement of the primary endpoint 
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3.2.3 Pharmacokinetics Objective  
• To characterize the pharmacokinetics of rilzabrutinib in patients with ITP 
3.2.4 Exploratory Objectives  
•
• To explore effect of rilzabrutinib on thrombopoietin (TPO) levels 
•
• To explore effect of rilzabrutinib on quality of life (QOL) using the 
and Idiopathic Thrombocytopenic Purpura Patient Assessment Questionnaire (ITP-PAQ) 
3.3 
Outcome Measures of the Study: Part A  
3.3.1 Primary Safety Endpoints  
Safety will be assessed by the incidence, severity, and relationship of TEAEs, including 
clinically significant changes in physical examination, laboratory tests, and vital signs. 
Treatment-emergent adverse events in the post treatment follow-up period will also be assessed 
and examined for possible relationship to the prior rilzabrutinib treatment. Adverse events (AEs) 
will be categorized as treatment emergent after the first dose of rilzabrutinib has been received. 
3.3.2 Primary Efficacy Endpoint  
Proportion of patients able to achieve two or more consecutive platelet counts, separated by at 
least 5 days, of ≥50,000/μL AND an increase of platelet count of ≥20,000/μL from baseline, 
by dose level, without use of rescue medication in the 4 weeks prior to the latest elevated platelet 
count. 
Secondary efficacy endpoints are described in Section 10. 
3.4 
Outcome Measures of the Study: Part B  
3.4.1 Primary Safety Endpoints  
Safety will be assessed by the incidence, severity, and relationship of TEAEs, including 
clinically significant changes in physical examination, laboratory tests, and vital signs. Bleeding 
TEAEs will be tabulated and a proportion of patients with a Grade 2 or higher bleeding event 
will be provided. 
3.4.2 Primary Efficacy Endpoint  
Proportion of patients able to achieve platelet counts ≥50,000/μL on at least 8 out of the last 
12 weeks of the 24-week treatment period without the use of rescue medication after 10 weeks 
of active treatment. 
Secondary efficacy endpoints are described in Section 10. 
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4 
INVESTIGATIONAL PLAN  
4.1 
Overall Study Design and Plan Part A  
This is an adaptive, open-label, dose-finding study of rilzabrutinib in patients with ITP who are 
refractory or relapsed with no available and approved therapeutic options, with a platelet 
count <30,000/µL on two counts no sooner than 7 days apart in the 15 days before treatment 
begins. 
The active treatment period is 24 weeks and the post-treatment follow up period is 4 weeks. 
Once a patient escalates to the 400 mg BID dose in the active treatment period, the patient will 
stay at this dose for 24 weeks. 
Each patient is enrolled in the study and allowed to up-titrate their dose after 28 days of 
rilzabrutinib therapy at each dose level if they do not experience a platelet response (as defined 
in the primary endpoint) or a DLT at the last dose level. If they experience a platelet response in 
the first cycle at any one dose level but do not have a platelet response in the second cycle at that 
dose, they may dose escalate at the end of the second cycle. Patients experiencing a platelet 
response (as defined for the primary endpoint) will not have their dose escalated at the next 
cycle.  
The “sentinel cohorts” at each dose level consist of the first 3 patients, or 6, if 3 extra are added 
for a DLT or platelet response (as defined in the primary endpoint and sustained for at least 3 of 
4 consecutive platelet counts at any dose level). To be evaluable in a sentinel cohort, patients 
must have ≥75% compliance over the 28-day dosing period. The sentinel cohort data is reviewed 
by the IDSM, in order to choose the starting dose for additional, new patients entering the study. 
After review, the IDSM may determine that a starting dose for new patients should be dropped 
for futility (lack of platelet response), increased to the next planned dosing level, kept the same 
or reduced (Section 4.4). 
Doses levels will be: 200 mg QD; 400 mg QD; 600 mg per day (300 mg BID); 800 mg per day 
(400 mg BID) (see table below). Due to the design, not all patients will necessarily be dosed at 
all dose levels. 
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Adaptive Cohort Dosing Table 
Cohort 
Starting dose 
level (n*) 
4 weeks 
Next dose 
level** 
4 weeks 
Next dose 
level** 
4 weeks 
Next dose 
level** 
Next dose 
level** 
Next dose 
level** 
1 
200 mg QD 
(3–6) 
400 mg QD 
300 mg BID 
400 mg BID 
400 mg BID 
400 mg BID 
2 
400 mg QD 
(≤6) 
300 mg BID 
400 mg BID 
400 mg BID 
400 mg BID 
400 mg BID 
3 
300 mg BID 
(≤6) 
400 mg BID 
400 mg BID 
400 mg BID 
400 mg BID 
400 mg BID 
4 
400 mg BID 
(≤6) 
400 mg BID 
400 mg BID 
400 mg BID 
400 mg BID 
400 mg BID 
* 
Unless a sustained platelet response is seen or a DLT, in which case 3 extra patients are added to that group. A starting 
dose level may be dropped for futility after 3 or 6 patients are evaluated, or retained if efficacy is observed. 
** Individual patients will not dose-escalate when there is a platelet response at a lower dose level or toxicity 
(see dose-escalation rules). If several dose levels are therapeutic, some or all patients may not reach the higher dose levels. 
Dose down-titration is permitted where, in the opinion of the Investigator, tolerability is poor 
and a satisfactory platelet response was seen in that patient on a lower dose previously studied 
or as mandated by the SMC. Otherwise, patients with clinically significant intolerance to 
rilzabrutinib should be discontinued from the study.  
Patients experiencing a DLT or requiring rescue therapy for low platelet counts must be 
discontinued from the study. 
Patients will be monitored with weekly platelet counts and CBCs throughout the study; PK 
samples will be collected intensively on the first day of each new, higher dose level and at 
random times following dosing at each on-treatment follow up visit. Patients will have weekly 
study visits/laboratory tests throughout the Part A of the study (Schedule of Assessments, 
Appendix 3). 
Patients may enter the study on stable doses of prednisone and/or TPO receptor agonists 
(TPO-RAs). Other 
 are not permitted. 
Long Term Extension (LTE) Part A and Part B 
After completing the active treatment period, patients who respond to rilzabrutinib will be 
allowed to enter the LTE. A platelet response is defined as platelet count ≥50,000/μL, 
or ≥30,000/μL and doubling of baseline at ≥50% of the visits during the last 8 weeks of the 
active treatment period (a minimum of 4 visits per the Schedule of Assessments) will be 
required. Baseline should be calculated as an average of platelet counts used for enrollment per 
Inclusion Criterion #4.  
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A patient may continue in the LTE until:  
a) The patient is no longer responding as described in the table below: 
Time in the LTE 
‘No response’ platelet counts defined as  
<30,000/µL or <20,000/µL above baseline based on: 
C1_LTE through 
C6_LTE 
4 consecutive weekly visits 
C7_LTE through 
C12_LTE 
2 consecutive monthly visits 
QX_LTE 
1 quarterly visit 
In this case, a second platelet count has to be obtained in 
one month to confirm lack of response 
 
 
Patients who continue into the LTE will be monitored with weekly platelet counts and CBC’s for 
the first 6 months, and then monthly for an additional 6 months, then once every 3 months with 
the assessments as outlined in the LTE Schedule of Assessments (Appendix 5 and Appendix 6).  
4.2 
Overall Study Design and Plan Part B  
Part B is an open-label study of rilzabrutinib in patients with ITP who have relapsed or have an 
insufficient response to prior therapies. Eligible patients will have a platelet count <30,000/µL 
on two occasions no less than 7 days apart, within 15 days before treatment begins, and a platelet 
count of ≤35,000/µL on Study Day 1 (SD1). 
The study consists of a 28-day screening period, 24-week active treatment period, 
and a long-term extension. After the last dose of rilzabrutinib there will be a 4-week safety 
follow-up period. Patients enrolled with a negative hepatitis B virus (HBV) DNA result 
and hepatitis B virus surface antibody (HBsAb) titer ≥100 IU/L will continue to have HBV DNA 
monitored monthly for 6 months after treatment has ended. 
Patients will have weekly study visits/laboratory tests throughout the Part B of the study 
(Schedule of Assessments, Appendix 4). 
Long Term Extension (LTE) 
After completing the active treatment period, patients who respond to rilzabrutinib will be 
allowed to enter the LTE. A platelet response is defined as platelet count ≥50,000/μL, 
or ≥30,000/μL and doubling of baseline at ≥50% of the visits during the last 8 weeks of the 
active treatment period (a minimum of 4 visits per the Schedule of Assessments) will be 
required. Baseline should be calculated as an average of platelet counts used for enrollment per 
Inclusion Criterion #4.  
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A patient may continue in the LTE until:  
a) The patient is no longer responding as described in the table below: 
Time in the LTE 
‘No response’ platelet counts defined as  
<30,000/µL or <20,000/µL above baseline based on: 
C1_LTE through 
C6_LTE 
4 consecutive weekly visits 
C7_LTE through 
C12_LTE 
2 consecutive monthly visits 
QX_LTE 
1 quarterly visit 
In this case, a second platelet count has to be obtained in 
one month to confirm lack of response 
 
In the LTE, patients will be monitored weekly for the first 6 months, monthly for an additional 
6 months, then once every 3 months with the assessments as outlined in the LTE Schedule of 
Assessments Appendix 5 and Appendix 6.  
4.3 
Dose-Limiting Toxicity (DLT) Part A Only  
Hematologic: 
•
Non-Hematologic:  
Any ≥ Grade 3 non-hematologic toxicity per the CTCAE, version 4.0 will be considered a DLT, 
with the following exceptions: 
• Laboratory TEAEs that are asymptomatic and return to baseline or to Grade 1 within 
7 days 
• Fatigue 
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• Nausea, vomiting or diarrhea that return to baseline or Grade 1 within 7 days 
• Systemic reactions (such as fever, headache) that return to baseline or Grade 1 within 
7 days. 
Miscellaneous: 
Any toxicity that, at the discretion of the Investigator, is thought to warrant withholding the 
study drug for more than 7 days. 
For laboratory-based AEs, these must be confirmed by repeat testing. 
The DLT evaluation period for any patient is defined as the duration of rilzabrutinib dosing until 
the dose escalation is completed. 
4.4 
Dose Escalation Rules Part A Only  
Individual: 
• Patients will dose-escalate to successive dose levels unless they are withdrawn, have 
a platelet response at the current dose level, or the next dose level has been determined to 
be ineligible for further enrollment (see Maximal Administered Dose [MAD], below) 
• Patients experiencing a platelet response (as defined for the primary endpoint) will not 
have their dose escalated at the next cycle. If they do not experience a platelet response 
during the second cycle of the same dose level they may dose escalate for the following 
cycle. If they require rescue medication subsequently because the platelet response was 
only transient, these patients will be discontinued from the study. 
Starting Dose Level: 
Further dose-escalation of cohort starting doses will not occur if: 
• A DLT occurs in two or more patients in a sentinel cohort at the current starting dose 
level or the dosing level above 
• A sustained platelet response (3 of 4 counts) occurs in two or more patients in a sentinel 
cohort at the current starting dose level 
• The SMC feels that the number and/or severity of TEAEs or laboratory abnormalities 
occurring do not justify further dose-escalation 
• Previously unknown data becomes available to the SMC which raise significant concerns 
about the potential risk to patients from further dose-escalation. 
Maximal Administered Dose (MAD) Level: 
If any dose level is suspended for safety reasons, that dose level will be considered the MAD, 
and any continuing patients at the MAD will be de-escalated to the dose level below. Further 
enrollment will proceed at dosing levels below the MAD. If the MAD is 200 mg QD, the study 
will be suspended. 
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4.5 
Stopping Rules Part A (also applies to LTE)  
4.5.1 Individual Stopping Rules  
• Patients experiencing a DLT will be discontinued from the study. 
• Patients requiring rescue therapy during study treatment will be discontinued from the 
study. 
• Pregnancy. 
•
• Any other situation which, in the opinion of the Investigator or Sponsor, continued study 
treatment may result in undue safety risk to the patient. 
4.5.2 Study Stopping Rules  
The study will be stopped (no new enrollments and no further study drug administered) if: 
• The MAD is determined to be 200 mg QD 
• The SMC deems the emerging TEAE profile unacceptable to continue the study  
• The Sponsor elects to stop the study 
• There is >1 patient with Grade 3 or higher TEAEs (except for platelet count and 
underlying disease or comorbidity-related events) 
• 
4.6 
Stopping Rules Part B (also applies to LTE)  
4.6.1 Individual Stopping Rules  
• Pregnancy. 
•
• Any other situation which, in the opinion of the Investigator or Sponsor, continued study 
treatment may result in undue safety risk to the patient. 
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4.6.2 Study Stopping Rules  
The study will be stopped (no new enrollments and no further study drug administered) if: 
• The Sponsor deems the emerging TEAE profile unacceptable to continue the study  
• The Sponsor elects to stop the study 
• Two or more life-threatening or CTCAE Grade 4 rilzabrutinib-related TEAEs except for 
AEs related to the disease under study (lack of efficacy). 
4.7 
Number of Patients  
Part A:  
Approximately 60 patients with ITP will be enrolled such that approximately 15 patients 
complete 24 weeks of dosing and at least 10 patients complete 24 weeks of treatment at a starting 
dose of 400 mg BID. Patients who drop out for reasons other than TEAEs during the 24-week 
treatment period may be replaced.  
Part B:  
The study will enroll approximately 23 patients.  
4.8 
Study Duration and Duration of Patient Participation  
Part A:  
Patients will receive rilzabrutinib treatment for 24 weeks, starting on Day 1 and ending on Study 
Day 169, followed by 4 weeks of post-treatment safety follow-up. The expected study duration is 
approximately 18 months from the first patient treated to the last patient completing, and 
approximately 32 weeks per patient.  
Patients who are dose escalated to 400 mg BID will continue in the active treatment period until 
24 weeks of treatment at the 400 mg BID dose is completed.  
Part B:  
After a screening period of up to 4 weeks, patients will receive rilzabrutinib treatment for up to 
24 weeks, starting on Study Day 1. All patients will complete 4 weeks of post-treatment safety 
follow-up. 
The expected study duration is approximately 28 months from the first patient treated to last 
patient completing. Study duration for individual patient is approximately 32 weeks. 
The duration of the LTE will be determined by the rules outlined in Section 4.6. 
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4.9 
End of Study Definition (Part A and Part B)  
The end of the study is defined as the date of the final safety follow-up visit after the last patient’s 
last visit (LPLV).  
4.10 
Rilzabrutinib Administration (Part A and Part B)  
Rilzabrutinib
 
4.11 
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 should: 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
rilzabrutinib can no longer be detected systemically (at least 20 hours). 
• Evaluate the participant to determine, if possible, whether study intervention should be 
interrupted or whether the dose should be reduced. 
• Obtain a plasma sample for PK analysis within 20 hours from the date of the last dose of 
study intervention if possible.  
• Document appropriately in the eCRF. 
4.12 
Concomitant Medications  
4.12.1 Allowed Part A  
• All patients may receive, but are not required to be taking, concomitant corticosteroids. 
The dose should be fixed (±10%) for at least 2 weeks before Day 1 and remain 
unchanged throughout the study unless rescue criteria are triggered. If the patient requires 
rescue treatment or concomitant ITP drug increases of more than 10% of the Day 1 daily 
dose, the patient will be discontinued from the study and receive rescue treatment per 
standard of care. These drugs may not have their dose increased as part of “rescue” 
medication. 
• Patients who continue in the LTE period will be able to taper corticosteroid dose if 
platelet counts are ≥100,000/μL. Tapering 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 
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- 
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. 
• All patients may receive, but are not required to be taking, eltrombopag or romiplostim. 
The dose should be fixed for at least 2 weeks before Day 1 and remain constant 
(10% variation from Day 1 daily dose is allowed) throughout the study unless there 
are safety concerns related to those drugs. These drugs may not have their dose increased 
as part of “rescue” medication. 
•
4.12.2 Allowed Part B  
• All patients may receive, but are not required to be taking, concomitant corticosteroids. 
The dose should be fixed (±10%) for at least 2 weeks before Day 1 and remain 
unchanged throughout the active treatment period of the study unless rescue criteria are 
triggered or patient experiences corticosteroid-associated adverse events that require a 
reduction of steroid dose. Patients who continue in the LTE period will be able to taper 
corticosteroid dose if platelet counts are ≥100,000/μL. Tapering 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 
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- 
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 
• All patients may receive, but are not required to be taking, eltrombopag, romiplostim, 
or avatrombopag. The dose should be fixed for at least 2 weeks before Day 1 and remain 
constant (10% variation from Day 1 daily dose is allowed) throughout the study unless 
there are safety concerns related to those drugs.  
• Patients may receive another treatment for ITP (one form of IVIg, high-dose steroids, 
platelet infusion, or anti-D immunoglobulin infusion) if there is a significant safety event 
requiring “rescue” from a deterioration in the patient’s platelet count that in the opinion 
of the Investigator puts the patient at significant risk of a safety event. Patients who 
receive rescue therapy will be allowed to continue if none of the stopping rules apply 
(Section 4.6) and the Investigator agrees to continue treating the patient with 
rilzabrutinib.  
•
4.12.3 Prohibited  
•
• Concomitant use of any immunosuppressant medication, other than corticosteroids, as 
described in this protocol. Participants who need other immunosuppressant therapy 
during the study must be withdrawn. See Exclusion Criterion #7 in Section 6.1.2 and 
Section 6.2.2 for washout periods. 
• Rituximab or other anti-CD20 medications, vincristine or other immunosuppressants, 
and new starts or increases in doses of eltrombopag, romiplostim, or avatrombopag are 
not permitted as rescue therapy while the patient is receiving treatment with rilzabrutinib. 
• Live vaccines are not permitted during the study. See Section 6.1.2 and Section 6.2.2  for 
Exclusion Criterion # 20. 
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5 
PROTOCOL DEVIATIONS  
The Principal Investigator is responsible for complying with all protocol requirements, 
and applicable global and local laws regarding protocol deviations. Principia does not allow 
intentional or prospective deviations from the protocol unless necessary to eliminate 
an immediate hazard to study patients. The Principal Investigator is responsible for immediately 
(within 24 hours) notifying the CRO of a major protocol deviation to permit Principia to 
determine the impact of the deviation on the patient and/or the study.  
The Principal Investigator is responsible for notifying Independent Ethics Committee 
(IEC)/Independent Review Board (IRB) regulatory authorities. The contract research 
organization (CRO) Clinical Monitors will notify the Sponsor. 
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6 
STUDY POPULATION  
6.1 
Part A  
6.1.1 Inclusion Criteria  
1. Male and female patients, aged 18 to 80 years old (Czech Republic and Norway only: 
aged 18 to 65 years old)   
2. Immune-related ITP (both primary and secondary)  
3. Refractory or relapsed patients with no available and approved therapeutic options with a 
platelet count of count <30,000/µL on two occasions no less than 7 days apart in the 
15 days prior to beginning study treatment   
4. A history of response (two or more platelet counts ≥50,000/µL with an increase 
of ≥20,000/µL) to at least one prior line of therapy (with splenectomy being considered a 
line of therapy)  
5. Adequate hematologic, hepatic, and renal function (absolute neutrophil count 
≥1.5 × 109/L, hemoglobin [Hgb] >9 g/dL, AST/ALT ≤1.5 × ULN, albumin ≥3 g/dL, total 
bilirubin ≤1.5 × ULN, estimated glomerular filtration rate [eGFR] >60 mL/min 
(Cockcroft and Gault method) (C1D1 pre-dose may be checked up to Day 3 prior to 
C1D1)  
6. Female patients who are of reproductive potential must agree for the duration of active 
treatment in the study to use a highly effective means of contraception (hormonal 
contraception methods that inhibits ovulation, intrauterine device, intrauterine 
hormonereleasing system, bilateral tubal ligation, vasectomized partner, or true 
abstinence: when this is in line with the preferred and usual lifestyle of the patient). 
Unless surgically sterile, postmenopausal females should have menopause confirmed 
by follicle-stimulating hormone (FSH) testing.  
7. Able to provide written informed consent and agreeable to the schedule of assessments. 
6.1.2 Exclusion Criteria   
1. Pregnant or lactating women   
2. Electrocardiogram (ECG) findings of QTcF >450 msec (males) or >470 msec (females), 
poorly controlled atrial fibrillation (ie, symptomatic patients or a ventricular rate above 
100 beats/min on ECG), or other clinically significant abnormalities   
3. History or current, active malignancy requiring or likely to require chemotherapeutic or 
surgical treatment during the trial, with the exception of non-melanoma skin cancer  
4. Transfusion with blood or blood products or plasmapheresis within 2 weeks before 
Day 1   
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5. Change in corticosteroid and/or TPO agonist dose within 2 weeks prior to Day 1 (more 
than 10% variation from Day 1 daily doses)  
6. Use of rescue medications other than corticosteroids or TPO in Exclusion Criterion #5 in 
the two weeks before Day 1  
7
8. Treatment with rituximab or splenectomy within the 3 months prior to Day 1  
9.
12. Planned or concomitant use of any anticoagulants and platelet aggregation inhibiting 
drugs such as aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), thienopyridenes 
(within 14 days of planned dosing through end of follow-up)  
13. 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); patient should not be using an investigational device at the time of dosing  
14. Current drug or alcohol abuse  
15. Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant 
bowel resection that would preclude adequate study drug absorption  
16. History of solid organ transplant  
17. Positive for screening for human immunodeficiency virus (HIV), hepatitis B (surface 
antigen and core antibodies unrelated to vaccination), or hepatitis C (anti-HCV antibody 
confirmed with HCV RNA)  
 
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20.
  
21. Planned surgery in the time frame of the dosing period  
22. Any other clinically significant disease, condition, or medical history that, in the opinion 
of the Investigator, would interfere with patient safety, study evaluations, and/or study 
procedures. 
6.2 
Part B   
6.2.1 Inclusion Criteria   
1. Male or female patients, aged 18 to 80 years old   
2. Patients with immune-related ITP (both primary and secondary) as defined by current 
guidelines with at least 3 months duration   
3. Patients who had a response (achievement of platelet count ≥50,000/µL) to IVIg/anti-D 
or corticosteroid that was not sustained and failed at least one other ITP therapy (that was 
not IVIg or corticosteroid)  
4. Patients with a platelet count of <30,000/µL on two occasions no less than 7 days apart in 
the 15 days before treatment begins, and no platelet count above 35,000/µL on Study 
Day 1.   
5. Patients with adequate hematologic, hepatic, and renal function (absolute neutrophil 
count ≥1.5 × 109/L, Hgb >9 g/dL, AST/ALT ≤1.5 × ULN, albumin ≥3 g/dL, total bilirubin 
≤1.5 × ULN, eGFR >50 mL/min (Cockcroft and Gault method) (pre-dose may be 
checked up to Day -3)  
6. Female patients who are of reproductive potential must agree for the duration of active 
treatment in the study to use a highly effective means of contraception (hormonal 
contraception methods that inhibits ovulation, intrauterine device, intrauterine 
hormonereleasing system, bilateral tubal ligation, vasectomized partner, or true 
abstinence; when this is in line with the preferred and usual lifestyle of the patient). 
Unless surgically sterile, postmenopausal females should have menopause confirmed by 
FSH testing.  
7. Able to provide written informed consent and agreeable to the schedule of assessments.  
6.2.2 Exclusion Criteria   
1. Pregnant or lactating women  
2. ECG findings of QTcF >450 msec (males) or >470 msec (females), poorly controlled 
atrial fibrillation (ie, symptomatic patients or a ventricular rate above 100 beats/min on 
ECG), or other clinically significant abnormalities   
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3. History (within 5 years of SD1) or current, active malignancy requiring or likely to 
require chemotherapeutic or surgical treatment during the trial, with the exception of non-
melanoma skin cancer  
4. Transfusion with blood, blood products, IVIg, or plasmapheresis within 2 weeks before 
SD1   
5. Change in corticosteroid and/or TPO agonist dose within 2 weeks prior to SD1 (more 
than 10% variation)  
6. Use of rescue medications in the 4 weeks before SD1  
7. Treatment with
 within 2 weeks prior 
to SD1  
8. Treatment with rituximab or splenectomy within the 3 months prior to SD1  
• Patients treated with rituximab within 6 months from screening will have normal B-
cell counts prior to enrollment. 
9. 
10.
 
11. 
 
12. Planned or concomitant use of any anticoagulants and platelet aggregation inhibiting 
drugs such as aspirin with the exception of up to 100 mg/day doses, NSAIDs, 
thienopyridenes (within 2 weeks of planned dosing through end of follow-up)  
13. 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); patient should not be using an investigational device at the time of dosing  
• Patients who previously received treatment with BTK inhibitors within 30 days before 
receiving the first dose of study medication or who have previously received 
rilzabrutinib are not eligible for the study  
14. Current drug or alcohol abuse  
15. Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant 
bowel resection that would preclude adequate study drug absorption  
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16. History of solid organ transplant  
17. Positive at screening for HIV, hepatitis B (surface antigen, core antibodies), or hepatitis C 
(anti-HCV antibody confirmed with HCV RNA).  
• Patients who are HBV surface antigen (HBsAg) positive will not be eligible.   
• Patients who are HBsAg negative and HBV core 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, patients 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.  
• Patients who are HBcAb positive, HBsAg negative with HBsAb titer <100 IU/L 
or negative, are not eligible.   
18. 
  
19. Myelodysplastic syndrome  
20. 
21. Planned surgery in the time frame of the dosing period  
22. Any other clinically significant disease, condition, or medical history that, in the opinion 
of the Investigator, would interfere with patient safety, study evaluations, and/or study 
procedures.  
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7 
STUDY ASSESSMENTS  
The Schedule of Assessments is presented in Appendix 3 for Part A, Appendix 4 for Part B, and 
for the LTE in Appendix 5 and Appendix 6. All patients must sign and date the most current 
IRB/IEC-approved written informed consent form before any study specific assessments or 
procedures are performed. An original signed consent form will be retained by the Investigator 
and the patient will be given a copy of the signed consent form. 
Patients must fulfill all entry criteria to be enrolled into the study. Patients who fail to meet the 
entry criteria may be rescreened once at the discretion of the Investigator after informing the study 
Medical Monitor. A record of eligibility screening documenting the Investigator’s assessment of 
each screened patient with regard to the protocol’s inclusion and exclusion criteria, including 
screen failures, is to be completed and signed by the Investigator or designee. Ethnicity of patients 
will be recorded, since this information might be important to evaluate a potential impact of ethnic 
factors on drug properties; see ICH Guideline E5 (R1). 
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8 
LIST OF STUDY ASSESSMENTS  
The Schedule of Assessments is presented in Appendix 3 for Part A, Appendix 4 for Part B, 
and for the LTE in Appendix 5 and Appendix 6. 
• Study procedures and their timing are summarized in the Schedule of Assessments. 
Protocol waivers or exemptions are not allowed. 
• Adherence to the study design requirements, including those specified in the Schedule of 
Assessments is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  
8.1 
Clinical Assessments  
• Medical history 
• Concomitant medications 
• Physical examination 
• Weight, height 
• Vital signs 
• IBLS 
• QOL assessment 
 
• Part B: ITP-PAQ 
• Safety assessments. 
8.2 
Laboratory & ECG Assessments  
Note: Laboratory assessments will be performed at both central and local laboratories, if required. 
• CBC with differential, including reticulocyte count 
• ABO Blood Type (screening only, historical information is acceptable) 
• Immature Platelet Fraction (where available) 
• Mean Platelet Volume (where available) 
• Coagulation: prothrombin time (PT)/International Normalized Ratio (INR) and activated 
partial thromboplastin time (aPTT) 
• 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, glucose (random), and 
creatine phosphokinase (CPK) 
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• FSH for post-menopausal patients who are not surgically sterile 
• PK: plasma rilzabrutinib concentration 
• Urinalysis: pH, specific gravity, protein, glucose, ketones, bilirubin, blood, nitrites, 
urobilinogen and leukocytes measured by dip stick or local requirement 
• Serology: HIV, Hepatitis B, and Hepatitis C 
• Pregnancy test for women of childbearing potential 
• Part A only: quantitative platelet autoantibody panel (Australia Only: test excluded) 
• Hemolysis panel: Coombs test, haptoglobin levels 
• TPO levels 
• 
• Part B only: BTK occupancy (at selected sites) 
• Part A only: 12-lead ECG: single at screening, triplicate ECGs pre-dose and post-dose on 
days of intensive PK draws  
• Part B only: 12-lead ECG: single at screening and at monthly clinical visits. 
8.3 
Safety Assessments  
Safety assessments include the following: the frequency, severity and relationship of AEs, 
clinical laboratory test changes, physical examination, ECGs, and vital signs. 
Part A: 
Patients will remain under observation in the clinic for 6 hours after administration of the first 
dose at the beginning of each new, higher dosing level while having intensive PK sampling 
performed. 
Part B:  
Patients will remain under observation in the clinic for 2 hours after administration of the first 
dose on Study Day 1, Study Day 29, and Study Day 57 for PK sampling. 
8.4 
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.  
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Coded study data and biological samples will be stored and used for future research only when 
consented to by participants (see Section 13.3) and, when applicable, further information on the 
future research will be 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. 
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 13.2). 
Use of leftover samples and additional samples for future research 
Leftover samples from the study will be used only after the end of main treatment period of both 
Part A and Part B. 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. 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. 
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9 
IDENTITY OF INVESTIGATIONAL PRODUCT  
9.1 
Formulation  
9.2 
Packaging  
Rilzabrutinib 100 mg and 300 mg tablets, 35 count per bottle and 400 mg tablets, 70 count per 
bottle are packaged in white high-density polyethylene (HDPE) bottles with child-resistant 
induction-sealed caps. 
9.3 
Storage and Handling  
The bottles of 100 mg and 300 mg tablets are stored at 2–8°C. The bottles can be transported 
without ice at room temperature and can be kept at room temperature conditions for up to 
2 weeks. 
The bottles of 400 mg tablets are stored at 2–25°C. The bottles can be kept at room temperature 
conditions. 
9.4 
Drug Accountability  
The Investigator or his/her designated representatives will dispense study drug per the Schedule 
of Assessments (Appendix 3 for Part A, Appendix 4 for Part B, and for the LTE in Appendix 5 
and Appendix 6). 
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 drug must be maintained. The Investigational Drug Dispensing Log must be kept 
current and should contain the following information: 
• the identification of the patient to whom the study drug was dispensed (for example 
patient identification number, patient initials, and date of birth) 
• the date(s), quantity, and lot number(s) of the study drug dispensed to the patient 
• the identification of the person who dispensed the study drug. 
All records and drug supplies must be available for inspection by the Study Monitor at every 
monitoring visit. When the study is completed, the Investigator will return any used and unused 
study drug (eg, empty, partially used, and unused containers), occluded labels (or the equivalent) 
to the Sponsor as requested, or the drug may be destroyed at the site with Sponsor approval. 
The completed Drug Dispensing Log and Drug Return Record(s) will be returned to the Local 
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Sponsor. The Investigator's copy of the Drug Return Record(s) must accurately document the 
return of all study drug supplies to the Sponsor. 
9.5 
Destruction of Investigational Product  
Local or institutional regulations may require immediate destruction of used investigational 
medicinal product for safety reasons. In these cases, it may be acceptable for investigational study 
center staff to destroy dispensed investigational product before a monitoring inspection, provided 
that written authorization is obtained from the Sponsor before destruction, and 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. 
Study drug that has not been stored properly or is damaged should not be destroyed until the final 
temperature excursion or packaging and storage deviation report has been completed, and Sponsor 
approval for drug destruction is obtained. 
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 investigational product(s) destroyed 
• Quantity of investigational product(s) destroyed 
• Date of destruction 
• Method of destruction 
• Name and signature of responsible person who destroyed the investigational products. 
If a site does not have a destruction SOP, study drug can be returned to the depot. 
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10 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE  
10.1 
Primary Safety Endpoints  
Safety will be assessed by the incidence, severity, and relationship of TEAEs, including 
clinically significant changes in physical examination, laboratory tests, ECG, and vital signs. 
Treatment-emergent adverse events in the post treatment follow-up period will also be assessed 
and examined for possible relationship to the prior rilzabrutinib treatment. Adverse events will 
be categorized as treatment emergent after the first dose of rilzabrutinib has been received. 
10.2 
Primary Efficacy Endpoints  
Part A: 
The Primary Efficacy Endpoint is the proportion of patients able to achieve two or more 
consecutive platelet counts, separated by at least 5 days, of ≥50,000/μL AND an increase 
of platelet count of ≥20,000/μL from baseline, by dose level, without use of rescue medication in 
the 4 weeks prior to the latest elevated platelet count. 
Part B: 
Proportion of patients able to achieve platelet counts ≥50,000/μL on at least 8 out of the last 
12 weeks of the 24-week treatment period without the use of rescue medication. 
10.3 
Secondary Endpoints  
10.3.1 Safety Endpoints  
In addition, safety will be assessed by the following endpoints, 
• Proportion of patients receiving rescue medication at each dosing level and overall 
• Proportion of patients with a Grade 2 or higher bleeding event at each dosing level 
and overall 
• Bleeding scale (IBLS) at the end of treatment period for each dosing level 
10.3.2 Efficacy Endpoints  
Part A: 
• Percent of weeks with platelet counts ≥50,000/μL by dose level and overall 
• Proportion of patients with 4 out of the final 8 platelet counts ≥50,000/μL across all dose 
levels 
• Change from baseline to the average of the post Day 1 platelet counts by dose level and 
overall for patients who had >4 weeks of study drug on that given dose level 
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• Number of weeks with platelet counts ≥50,000/μL across all dose levels 
• Number of weeks with platelet counts ≥30,000/μL across all dose levels 
• Time to first platelet count ≥50,000/μL across all dose levels 
Part B:  
• Number of weeks with platelet count ≥50,000/μL OR ≥30,000/µL and doubling the 
baseline in the absence of rescue therapy (platelet counts will be censored for 4 weeks 
after the use of rescue medication, if given) 
• Proportion of all treated patients able to achieve two or more consecutive platelet counts, 
separated by at least 5 days, of ≥50,000/μL AND an increase of platelet count 
of ≥20,000/μL from baseline without use of rescue medication in the 4 weeks prior to the 
latest elevated platelet count  
• Number of weeks with platelet counts ≥ 30,000/μL and doubling from baseline over the 
24-week treatment period (platelet counts will be censored for 4 weeks after the use of 
rescue medication, if given) 
• Proportion of patients receiving rescue medication  
• Change from baseline in ITP Bleeding Scale (IBLS). 
10.3.3  Pharmacokinetic Outcome Measures   
Plasma PK parameters (maximum observed plasma concentration [Cmax], Tmax, area under the 
plasma concentration-time curve [AUC], elimination half-life [t½], apparent volume of 
distribution of the drug after oral administration [V/F], apparent total clearance of the drug from 
plasma after oral administration [CL/F]) of rilzabrutinib in ITP patients will be evaluated in each 
patient based on frequent sampling on Day 1 of a new, higher dosing level and reported by dose 
(Part A only) and, if relevant, overall. Results will be reported by descriptive statistics. 
Exploratory analyses will pool these data with the data from other studies of rilzabrutinib.  
10.4 
Exploratory Measures  
Part A: 
•  Proportion of patients with any two platelet counts ≥50,000/μL AND an increase of 
platelet count of ≥20,000/μL from baseline during treatment period. 
• Proportion of patients with any two platelet counts ≥50,000/μL AND an increase of 
platelet count of ≥20,000/μL from baseline during follow-up period (without dose 
reduction of the concomitant CS or TPO-RA doses) 
• Proportion of patients able to achieve two or more consecutive platelet counts, separated 
by at least 5 days, of ≥30,000/μL OR an increase of platelet count of ≥20,000/μL from 
baseline, without use of rescue medication in the 4 weeks prior to the latest elevated 
platelet count. 
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• Proportion of patients able to achieve any platelet counts ≥100,000/μL. 
• Time to first of two consecutive platelet counts ≥50,000/μL 
• Proportion of patients with 4 out of the final 6 platelet counts ≥50,000/μL across all dose 
levels  
• Proportion of patients with 8 out of the final 12 platelet counts ≥50,000/μL across all 
dose levels 
• Effect of rilzabrutinib on platelet autoantibody levels  
• Effect of rilzabrutinib on QOL using 
• Plasma metabolite analysis. 
Part B: 
• Proportion of patients who completed 24 weeks of treatment and demonstrated a platelet 
response defined as platelet counts ≥50,000/μL at 4 out of the last 8 weeks of the active 
treatment period  
• Proportion of patients who have a platelet count that exceeds 250,000/µL or 450,000/µL 
(for patients on concomitant TPO-RAs) 
• Time to first platelet count of ≥50,000/µL 
• Percentage of time with platelet counts ≥30,000/µL OR ≥20,000/µL above baseline  
•
• Effect of rilzabrutinib on
• Effect of rilzabrutinib on TPO levels 
• Effect of rilzabrutinib on QOL. 
10.5 
Determination of Sample Size  
Part A 
The sample size for this study is based on clinical considerations. Assuming an expected efficacy 
rate for the primary endpoint of 40% (platelet response), with 15 evaluable patients there will be 
80% confidence that the true proportion will be 24% and above (80 ±16% confidence interval 
[CI]) using normal approximation methods. 
The results from this study will be used to 
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Part B 
The sample size is designed to provide an estimate the true response rate. Part B will enroll 
approximately 23 patients. If 5 responders are observed out of 23 treated patients, the observed 
response rate is 
 which is the historical standard of care response rate estimated from a pooled analysis of 
8 randomized studies in ITP patients.  
10.6 
Analysis Populations (Part A and Part B)  
10.6.1 Safety Analysis Population  
All patients who have received at least one dose of rilzabrutinib will be included in the safety 
analysis. The Safety Analysis Population will be used for all safety analyses. 
Part A only: 
For assessment of safety by the IDSM, with regard to dropping a dose level for futility, 
3 evaluable patients, defined as compliance of ≥75% of doses for that dose level, are required. 
Patients will be replaced if necessary to fulfill this requirement. 
10.6.2 Efficacy Analysis Population  
All patients who have enrolled in the study will be included in the Intent to treat (ITT) 
population. Enrolled patient is defined as a patient who signed the informed consent form and 
met eligibility criteria. Efficacy analysis will be based on the ITT population. 
10.6.3 Pharmacokinetic Analysis Population  
All patients who have received at least one dose of rilzabrutinib and have at least one measurable 
plasma concentration value will be included in the PK analysis. The Pharmacokinetic Analysis 
Population will be used for all PK analyses.  
10.7 
Patient Numbers and Treatment Assignments  
As they are enrolled in the study, patients will be assigned a unique consecutive number. 
The site, in conjunction with the Sponsor, will be responsible for assignment of all unique patient 
numbers and dose assignments. 
10.8 
Patient Disposition, Patient Replacement, and Demographics and Baseline 
Characteristics  
10.8.1 Disposition  
The numbers of patients enrolled, completing, and withdrawing, along with reasons for 
withdrawal, will be tabulated. The number of patients in each analysis population will be 
reported. 
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10.8.2 Replacement of Patients  
Patients prematurely discontinued from the study, for reasons other than TEAEs, may be 
replaced at the discretion of the Sponsor to ensure adequate numbers of evaluable patients. Each 
patient who provides informed consent will be assigned a unique patient identifier (USUBJID). 
Patients recruited to be replacement patients will be assigned the next available patient identifier. 
10.8.3 Demographics and Baseline Characteristics  
Demographic and baseline characteristics (age, sex, race, ethnicity, weight, height, and body 
mass index) will be summarized for the Safety Analysis Population using descriptive statistics. 
No formal statistical analyses will be performed, and no inferential statistics reported. 
Prior and concomitant medications will be listed, classified using World Health Organization 
Drug Dictionary (WHODD) Anatomical Therapeutic Chemical classes and preferred terms. 
Baseline demographics and patient characteristics will be summarized for the Safety Population. 
10.9 
Efficacy and Exploratory Analysis  
Part A 
Qualitative efficacy data will be summarized by frequencies and percentages. Quantitative 
efficacy data will be summarized by descriptive statistics (arithmetic mean, standard deviation, 
median, minimum, and maximum). Data will be summarized over time by dose level and overall. 
The time course of mean changes in platelet count over time will also be described graphically, 
annotated for dosing levels. All analyses will be based on the Intent-to-treat (ITT) Population.  
Full details of the analyses for Part A will be provided in the Statistical Analysis Plan (SAP). 
Part B 
Qualitative efficacy data will be summarized by frequencies and percentages. Quantitative 
efficacy data will be summarized by descriptive statistics (arithmetic mean, standard deviation, 
median, minimum, and maximum). The time course of mean changes in platelet count over time 
will also be described graphically. All analyses will be based on the ITT Population. 
Full details of the analyses for Part B will be provided in the SAP. 
10.10 Safety and Tolerability Analysis  
The incidence, severity, and relationship of TEAEs, laboratory tests, rescue treatment usage, 
and vital signs will be summarized descriptively. Qualitative safety data will be summarized by 
frequencies and percentages at each dose level, using the time boundaries of that dosing level 
(Part A only). Quantitative safety data will be summarized by descriptive statistics (arithmetic 
mean, standard deviation, median, minimum, and maximum) at each dose level (Part A only) 
and overall for Part B. Summaries will also be presented for the change from baseline, when 
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appropriate. The proportion of patients with a Grade 2 or higher bleeding event will also be 
summarized. Non-TEAEs will be described in separate listings.  
10.10.1 
Adverse Events  
The original verbatim AE terms recorded on the patient’s case report form (CRF) by the 
Investigator will be standardized by assigning preferred terms and system organ classes from the 
most recent available version of the Medical Dictionary for Drug Regulatory Affairs (MedDRA). 
Adverse events will be codified using the NCI CTCAE v5.0, which provides a mechanism 
for grading the severity of the AE. 
Treatment emergent adverse events include all AEs that start on or after the first dose of study 
medication, or AEs that are present prior to the first dose of study medication, but worsen after 
the first dose of study medication up to and including the final study medication dosing date. 
Adverse events that occur after the first dose of study medication or worsen after the first dose of 
study medication are treatment-emergent adverse events (TEAEs). Adverse events that occur 
prior to the first dose of study medication are pre-treatment adverse events (ie, non-TEAEs). The 
number and percent of patients with any TEAEs will be displayed by system organ class and 
preferred term by dosing level and overall. Within each preferred term, patients will be counted 
only once if they had more than one event reported during the dosing period. The same summary 
will be performed for all serious TEAEs and all TEAEs causing discontinuation of study drug. 
Treatment-emergent adverse events will also be summarized by greatest reported severity grade 
(Grades 1–5) for each event/preferred term. Counts will indicate patients reporting one or more 
TEAEs that map to the severity grade classification for each preferred term. At each level of 
summarization (system organ class or event preferred term) patients are only counted once. 
TEAEs will be summarized by greatest reported relationship in a similar manner. A listing will 
be produced for all patients who reported serious TEAEs or who discontinued study medication 
due to TEAEs. 
All TEAEs will be listed individually by patient. In addition, a separate listing will be produced 
for AEs that are not treatment-emergent. 
10.10.2 
Clinical Laboratory Tests  
All clinical laboratory data will be stored in the database in the units in which they were reported. 
Normal ranges for the local laboratory parameters must be provided to Principia/designee before 
the study starts. Patient listings and summary statistics at each assessment time, including change 
from baseline, will be presented using the International System of Units (SI units; Système 
International d’Unités). Laboratory data not reported in SI units will be converted to SI units 
before analysis.  
Part A 
Clinical laboratory results will be summarized descriptively for baseline and each time point. 
The numerical change from baseline to each time point will be computed. Exploratory analysis 
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of the relationship between dose level and laboratory changes will be explored if any are seen in 
the initial analyses. In addition, laboratory shift tables will be provided for all laboratory 
parameters where low/normal/high or abnormal/normal status can be ascertained for shift from 
baseline to each time point. Listings of individual laboratory parameters by visit with normal 
ranges and abnormality assessments will also be completed by patient. 
Part B 
Clinical laboratory results will be summarized descriptively for baseline and each monthly clinic 
visit. The numerical change from baseline to each visit will be computed. Laboratory shift tables 
will be provided for all laboratory parameters where low/normal/high or abnormal/normal status 
can be ascertained for shift from baseline to each monthly clinic visit. Listings of individual 
laboratory parameters by visit with normal ranges and abnormality assessments will also be 
completed by patient. 
Part A and Part B 
10.10.3 
Vital Signs  
Vital signs data will be presented by individual listings. Systolic blood pressure values 
<90 or >140 mmHg and diastolic blood pressure values <60 or >80 mmHg will be flagged as 
outside the normal range. Resting heart rate <40 or >100 beats per minute will be flagged as 
outside the normal range. Descriptive statistics of values and changes from baseline (mean, 
median, standard deviation) will be reported for quantitative variables separately for each dosing 
level, using the time boundaries for that level in Part A and overall in Part B. In addition, tabular 
and graphical summaries will be used, as appropriate. 
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10.10.4 
Rescue Medication, DLTs, and Bleeding Scale Scores  
The percentage of patients receiving rescue medication at each dosing level (Part A only) and at 
any time during dosing for Part A, and at any time during dosing for Part B.  
The percentage of patients with a DLT will be summarized at each dosing level, overall for 
Part A, and overall for Part B.  
Bleeding scale (IBLS) scores will be summarized over time at each dosing level, overall for 
Part A, and overall for Part B. 
10.10.5 
Concomitant Medications  
The original terms recorded on the patients’ CRF by the Investigator for concomitant medications 
will be standardized by assigning preferred terms from the WHODD drug terms dictionary for 
treatments or coded via generic name of the concomitant medication. 
Concomitant medications will be presented in summary tables and listings. 
10.11 Pharmacokinetics Analyses  
Part A 
Pharmacokinetic data will be summarized using descriptive statistics, tabulated, and displayed 
graphically as appropriate. Non-compartmental analysis will be utilized to derive PK parameters 
for each individual. Pharmacokinetic data may also be pooled with the data from other studies 
for population PK modeling. Individual patient PK values within this study may be used for 
exploratory analyses of exposure and effect.  
Part B 
Pharmacokinetic data will be summarized using descriptive statistics, and tabulated, 
and displayed graphically as appropriate. Pharmacokinetic data may also be pooled with the data 
from other studies for population PK modeling.  
10.12 Statistical Analysis Plan  
A detailed SAP will be developed and finalized before the study database is locked, which will 
supersede the statistical analysis methods described in the protocol. 
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11 
SAFETY AND TOXICITY MANAGEMENT  
This section provides detailed information on reporting requirements and interpretation of safety 
assessments for AEs and reporting requirements for SAEs. Guidance and reporting requirements 
for pregnancy are also outlined below. 
11.1 
Independent Data Safety Monitor (IDSM) and Safety Monitoring Committee (SMC)  
Part A 
An IDSM who is not a study Investigator will be chosen from expert clinicians in the ITP field. 
A Safety Monitoring Committee (SMC), comprised of the IDSM as Chairperson, lead 
Investigator, Study Medical Monitor, and Sponsor’s Medical Monitor, will closely supervise the 
conduct of the study. The IDSM will make “sentinel cohort” safety evaluations. 
The “sentinel patients” for each dose level will have their data reviewed by the IDSM, in order to 
choose the starting dose for additional, new patients. After review, the IDSM may determine that 
a starting dose for new patients should be dropped for futility (lack of platelet response), 
increased to the next planned dosing level, kept the same, or reduced. New patients entering the 
study will commence at the dose level determined by the IDSM based on: 
• If ≥2/3 or ≥2/6 of those sentinel patients have a DLT at any dose level, that level shall be 
determined the “Maximal Administered Dose” and starting doses (new patients) 
and continuing doses (patients already on study) set at lower dosing levels (or study 
suspended if the current sentinel dose cohort was 200 mg QD) 
• If two or more sustained platelet responses (3 of 4 counts) in the sentinel patients are seen 
at the current starting dose level the starting dose will not be escalated. 
The SMC will meet approximately quarterly and recommend study modification or termination 
to the Sponsor, based on review of safety and efficacy information. Any SMC findings that 
impact the safety of patients in this study will be immediately reported to the local Competent 
Authority (CA) and IRB/EC. 
An SMC Charter outlining the SMC composition and responsibilities will be in place prior to the 
first scheduled meeting. 
Part B 
There will be no independent SMC in Part B. 
Specific assessments to evaluate treatment safety include the following: the frequency, severity 
and relationship of AEs, clinical laboratory test changes, physical examination, and vital signs. 
The assessments will be conducted as part of ongoing medical monitoring and at Sponsor 
Quarterly Safety Reviews where safety events and trends across rilzabrutinib studies are 
considered. 
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11.2 
Adverse Event Collection Period  
The AE Collection Period begins at the time of the first screening/eligibility assessment and ends 
at the end of the study for each patient. 
11.3 
Adverse Events  
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with the intervention. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of an investigational product, whether or not considered related to the 
product. All AEs encountered during the clinical study will be recorded in detail in the source 
documents and entered in the CRF from the date of patient consent throughout the study follow-
up period. Pre-existing conditions that worsen during a study are reported as AEs, with the 
expectation 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 CRF unless the event meets the definition 
of an SAE or is not consistent with the typical clinical course of the patient’s disease as 
established by the patient’s medical history. Worsening of the disease under study or other 
disease-related symptoms should be recorded as an AE only if the event meets the 
definition of an SAE or is not consistent with the typical clinical course of the disease. 
11.4 
Adverse Event Relationship to Study Drug  
Investigators should use their knowledge of the study patient, the circumstances surrounding the 
event, and an evaluation of any potential alternative causes to determine whether an AE may be 
considered as related to the study drug, indicating "yes" or "no" accordingly. 
The following information should be considered: 
• Temporal relationship of event onset to the initiation of study drug 
• Course of the event, considering especially the effects of dose reduction, discontinuation 
of study drug, or reintroduction of study drug (if applicable) 
• Known association of the event with the study drug or with similar treatments 
• Known association of the event with the disease under study 
• Presence of risk factors in the study patient or use of concomitant medications known to 
increase the occurrence of the event 
• Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event. 
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11.5 
Treatment and Follow-Up of Adverse Events  
Adverse events, especially those for which the severity is Grade 3 or higher, should be followed 
up until stabilization or until 4 weeks post last dose (considered as the last follow up), based on 
the PK profile of the drug.  
11.5.1 Laboratory and ECG Abnormalities  
Laboratory test results will be recorded on the laboratory results pages of the CRF or merged 
electronically with the CRF data, and will appear on electronically produced laboratory reports 
provided to the Investigator. Data will be reported to Principal Investigators in laboratory reports 
and merged with CRF data on the back end. Some laboratory data may be manually entered, if 
necessary. 
Any treatment-emergent abnormal laboratory or ECG result that is clinically significant 
(ie, meeting one or more of the following conditions) should be recorded as a single diagnosis 
on the AE page in the CRF: 
• Accompanied by clinical symptoms 
• Leading to a change in study drug (eg, dose modification, interruption, or permanent 
discontinuation) 
• Requiring a change in concomitant therapy (eg, addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy, 
or treatment) 
Note: Any laboratory or ECG result abnormality fulfilling the criteria for an SAE must be 
reported as such, in addition to being recorded as an AE in the CRF. 
11.6 
Adverse Event Intensity Grading  
All clinical AEs encountered during the clinical study will be reported on the AE page of the CRF. 
Intensity of AEs will be graded based on the NCI CTCAE, version 4.0 or higher and reported in 
detail as indicated on the CRF. For any AEs not found in the CTCAE, a description of intensity 
grading can be found below: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living. 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living. 
Any life-threatening events or any event with an outcome of death should be reported as 
a serious adverse event as outlined in Section 11.7. 
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11.6.1 Follow Up of Abnormal Laboratory Test Values  
In the event of unexplained clinically significant abnormal laboratory test values, the tests should 
be repeated as soon as possible and followed up until they have returned to the normal range 
and/or an adequate explanation of the abnormality is found. If a clear explanation is established, 
it should be recorded on the CRF. 
11.7 
Serious Adverse Event (SAE) Reporting  
11.7.1 SAE Definitions  
A serious adverse event (experience) or reaction is any untoward medical occurrence that at any 
dose:  
• results in death*  
•  is life-threatening, NOTE: The term "life-threatening" in the definition of "serious" refers 
to an event in which the patient 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.  
• requires inpatient hospitalization or prolongation of existing hospitalization,  
• results in persistent or significant disability/incapacity, or  
• is a congenital anomaly/birth defect. 
Important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent one of 
the other outcomes listed in the definition above, should also usually be considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
*Note that the term "sudden death" is only used when the cause is of a cardiac origin as per 
standard definition. The terms "death" and "sudden death" are clearly distinct and are not used 
interchangeably. 
11.7.2 SAE Reporting  
For the European Union, safety reporting to the agency is described in Section 16.8.1. 
Any adverse event that is serious and occurs during the course of the study (as defined above), 
occurring from the signing of the informed consent (start of study screening procedures), and 
including long term follow up must be reported: 
• In the Medidata RAVE EDC within 24 hours of the Investigator becoming aware of the 
event (expedited reporting) 
• The investigational site’s IRB by the Investigator in accordance with their regulations. 
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If the EDC is unavailable the SAE must be reported by the Investigator on an SAE 
Reporting Form within 24 hours of Investigator’s awareness to Principia 
Pharmacovigilance: 
SAE Reporting Information 
mailto: 
ssf.1008010sae@sanofi.com 
The 4 minimum criteria for a valid SAE report include: 
• Identifiable reporter 
• Single identifiable patient 
• Adverse event term 
• Suspect medicinal product. 
The Investigator should not wait to receive additional information to document fully the event 
before notification of a SAE. As soon as the 4 minimum mentioned above criteria are fulfilled, 
the Investigator must report the SAE within 24 hours of awareness. In addition, all further 
information requested on the SAE Reporting Form should be completed and sent to PVG contact 
as soon as possible. 
Receipt of the initial notification of an SAE will be confirmed in writing within 24 hours from the 
time the investigational team first becomes aware of the event, if possible. 
Copies of paper SAE report forms must be retained in the Investigator Site File. 
Any further information, including SAE follow-up information should be documented within the 
RAVE system. 
After informed consent, but prior to initiation of study medications, only SAEs caused by 
a protocol-mandated intervention must be reported within 24 hours (eg, SAEs related to invasive 
screening procedures such as biopsies, medication washout, or no treatment run-in). After first 
study medication, all SAEs must be reported within 24 hours. 
Related SAEs MUST be collected and reported regardless of the time elapsed from the last study 
drug administration, even if the study has been closed. 
Unrelated SAEs must be collected and reported during the study and/or for up to 30 days after the 
last dose of study medication, whichever is longer. 
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Suspected Unexpected Serious Adverse Reactions (SUSARs) are reported to Investigators at each 
site and associated IRB when the following conditions occur: 
• The event is a SAE 
• There is a reasonable possibility that the event is an adverse reaction caused by the 
administered drug 
• The adverse reaction is unexpected, that is to say, not listed in the Investigator’s Brochure 
•  Individual SUSAR reports will be forwarded to the site and its associated IRB on 
an expedited basis. 
Individual SUSARs considered a significant safety issue and/or which result in a change to the 
informed consent form will be reported in an expedited manner to all Investigators and IRBs. 
Reporting of any SAEs to applicable regulatory authorities will be the responsibility of the Local 
Sponsor in compliance with local regulations. 
11.7.3 Other Safety Findings Requiring Expedited Reporting  
Significant safety findings will be reported to the Investigator by Principia or designee as 
obtained. The Investigator is responsible for reporting to the investigational site’s IRB in 
accordance with their regulations. Reporting to applicable regulatory authorities will be the 
responsibility of Principia (or designee) in compliance with local regulations. 
Investigators will report all potential DLT events to the Medical Monitor within 24 hours from 
the time the investigational team first becomes aware of the event. 
11.8 
Pregnancy  
Pregnancy in a Female Clinical Trial Patient: If a female clinical trial patient becomes pregnant 
during the study, she must be instructed to stop taking the study drug and immediately inform the 
Investigator. Pregnancies occurring up to 4 weeks after the completion of the study drug must 
also be reported to the Investigator. The patient should be counseled by a specialist, to discuss 
the risks of continuing with the pregnancy and the possible effects on the fetus. Monitoring of 
the patient should continue until the outcome of the pregnancy is known. The Investigator should 
report all pregnancies in clinical trial patients to the Sponsor within 24 hours of becoming aware 
of them, using the Clinical Trial Pregnancy Reporting Form. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of pregnancy for medical reasons will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
abnormalities, ectopic pregnancy) are considered SAEs and will be reported as such. 
Any post-study pregnancy-related SAE considered reasonably related to the study drug by the 
Investigator will be reported to the Sponsor.  
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11.9 
Adverse Event of Special Interest  
An adverse event of special interest (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 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 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 Section 11.7). 
- 
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 (Section 11.8) 
• Symptomatic overdose (serious or non-serious) with IMP 
• Increase in alanine transaminase (ALT): >3 × ULN (refer to the flow chart, Section 16.7.) 
• Any Grade 4 or 5 infection where the participant is hospitalized ≥24 hours and/or 
requires emergency care and/or requires IV antibiotics. 
• 
11.10 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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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 CRF 
against the Investigator’s records by the study monitor (source document verification), and the 
maintenance of a study drug dispensing log by the Investigator. 
Data for this study will be recorded in the study Electronic Data Capture (EDC) CRFs. The data 
will be entered by the study center from the source documents into the CRF or will be loaded 
from electronic files (eg, safety lab data). In no case is the CRF 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 all data entered in the database will be independently compared with the 
original Investigator’s records. 
12.1 
Assignment of Preferred Terms and Original Terminology  
For classification purposes, preferred terms will be assigned to the original terms recorded on the 
CRF, using the MedDRA for AEs, diseases and surgical and medical procedures, and the 
WHODD for drug and herbal treatments as specified in the SAP. 
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13 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS  
This section provides information for the Investigator on the ethics requirements for the study, 
including patient informed consent, IRB/EC 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. 
13.1 
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. 
13.2 
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 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. 
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 are expected to 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 will be identifiable 
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only by the unique identifier; participant names or any information which would make 
the participant identifiable will not be transferred to the Sponsor.  
• The participant must be informed that his/her 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.  
• The participant must be informed that his/her 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. 
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 of the Sponsor’s studies. In case the 
professionals have already been involved in a study with this Sponsor, they will not be 
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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 company 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, 
- 
The Sponsor’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 thirty (30) 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 
data up-to-date once for all 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 Sanofi 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). 
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13.3 
Patient Informed Consent  
It is the responsibility of the Investigator, or a person designated by the Investigator 
[if acceptable by local regulations], to obtain signed and dated informed consent from each 
patient prior to participating in this study after adequate explanation of the aims, methods, 
objectives, and potential hazards of the study. The Investigator or designee must also explain 
that the patients are completely free to refuse to enter the study or to withdraw from it at any 
time, for any reason. 
The CRFs for this study contain a field for documenting informed patient consent, and this must 
be completed appropriately. If new safety information results in significant changes in the 
risk/benefit assessment, the consent form should be reviewed and updated if necessary. 
All patients should be informed of the new information, given a copy of the revised form and 
give their consent to continue in the study. 
13.4 
Institutional Review Board and Ethics Committee Review  
• The protocol, protocol amendments, ICF, Investigator’s Brochure, 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: 
- 
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  
- 
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 
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 
reproductive importance, AND has analytical validity, AND has clinical 
validity.  
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• 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. 
- 
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 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 
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 clinical trial 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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13.5 
Conditions for Modifying the Protocol  
Any protocol modifications must be prepared and approved by a representative of The Sponsor. 
All protocol modifications must be submitted to the appropriate IRB/IEC for information 
and/or approval in accordance with local requirements, and to Regulatory Agencies if required. 
Approval must be obtained before any changes can be implemented, except for changes 
necessary to eliminate an immediate hazard to study patients, or when the change(s) involves 
only logistical or administrative aspects of the study (eg, change in monitor[s], change of 
telephone number[s]). 
13.6 
Conditions for Terminating the Study  
The Sponsor, the Investigator, and the IRB responsible for the study reserve the right to 
terminate the study at any time. Should this be necessary, the parties will consult and arrange 
the termination procedures on an individual study basis. In terminating the study, the Sponsor 
and the Investigator will assure that adequate consideration is given to the protection of the 
patient’s interests. The appropriate IRB/IEC and Regulatory Agencies should be informed 
accordingly. 
13.7 
Financial Disclosure  
The Investigator(s) will provide the Sponsor with sufficient accurate financial information to 
allow the Sponsor to submit complete and accurate financial certification or disclosure 
statements to the appropriate regulatory authorities. The Investigator is responsible to promptly 
update any information provided to the Sponsor if relevant changes occur in the course of the 
investigation and for 1 year following the completion of the study (last patient, last visit). 
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14 
STUDY DOCUMENTATION, MONITORING, CASE REPORT FORMS, AND 
RECORD RETENTION REQUIREMENTS  
14.1 
Investigator's File/Retention of Records  
The Investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These documents 
should be classified into two different separate categories (1) Investigator’s Study File, 
and (2) patient clinical source documents. 
The Investigator’s Study File will contain the protocol/amendments, CRF data 
and Discrepancies, IRB and regulatory authority approval with correspondence, sample informed 
consent, drug records, staff curriculum vitae and authorization forms and other appropriate 
documents/correspondence, etc. 
Patient clinical source documents independent of the CRF would include patient hospital/clinic 
records, physician’s and nurse’s notes, original laboratory reports, ECG, EEG, X-ray, pathology 
and special assessment reports, signed informed consent forms, consultant letters, and patient 
screening and enrollment logs.  
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 25 years after the signature of the final study report unless local 
regulations or institutional policies or by agreement with the Sponsor require a different retention 
period. No records may be destroyed during the retention period without the written approval of 
the Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
Should the Investigator wish to assign the study records to another party or move them to another 
location, the Sponsor must be notified in advance. 
If the Investigator cannot guarantee this archiving requirement at the investigational site for any 
or all of the documents, special arrangements must be made between the Investigator and the 
Sponsor to store these in a sealed container(s) outside of the site so that they can be returned 
sealed to the Investigator in case of a regulatory audit. Where source documents are required for 
the continued care of the patient, appropriate copies should be made for storing outside of the 
site. 
14.2 
Source Documents and Background Data  
The Investigator shall supply the Sponsor on request with any required background data from 
the study documentation or clinic records. This is particularly important when CRFs are 
illegible or when errors in data transcription are suspected. In case of special problems 
and/or governmental queries or requests for audit inspections, it is also necessary to have access 
to the complete study records, provided that patient confidentiality is protected. 
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14.3 
Audits and Inspections  
The Investigator should understand that source documents for this study should be made 
available to appropriately qualified personnel from the Sponsor or its designees, or to health 
authority inspectors after appropriate notification. The verification of the CRF data must be by 
direct inspection of source documents. 
14.4 
Case Report Forms  
The data collected in the source documents for this study will be entered into the study EDC 
CRF. 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 patient enrolled, a CRF must be 
completed and signed by the Principal Investigator or authorized delegate from the study staff. 
If a patient withdraws from the study, the reason must be noted in the CRF. If a patient is 
withdrawn from the study because of a treatment-limiting adverse event, thorough efforts should 
be made to clearly document the outcome. 
The Investigator should ensure the accuracy, completeness and timeliness of the data reported to 
the Sponsor in the CRFs and in all required reports. 
14.5 
Study Monitoring  
It is understood that the responsible Sponsor study monitor (or designee) will contact and visit 
the Investigator regularly and will be allowed, on request, to inspect the various records of the 
study (CRFs and other pertinent data) provided that patient confidentiality is maintained in 
accordance with local requirements. 
It will be the monitor's responsibility to inspect the EDC CRFs at regular intervals throughout 
the study, to verify the adherence to the protocol and the completeness, consistency and accuracy 
of the data being entered on them. The monitor must verify that the patient received the assigned 
dose. The monitor should have access to laboratory test reports and other patient records needed 
to verify the entries in the EDC CRF. The Investigator (or deputy) agrees to cooperate with the 
monitor to ensure that any problems detected in the course of these monitoring visits are 
resolved. 
14.6 
Confidentiality of Clinical Trial Documents and Patients' Medical Records  
The Investigator must assure that patients’ anonymity will be maintained and that their identities 
are protected from unauthorized parties. In the EDC CRF or other documents submitted to the 
Sponsor, patients must not be identified by their names, but by an identification code. 
The Sponsor already maintains rigorous confidentiality standards for clinical studies by “coding” 
(ie, assigning a unique patient identification [ID] number at the Investigator site) all patients 
enrolled in Sponsor clinical studies. This means that patient names are not included in data sets 
that are transmitted to any Sponsor location.  
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14.7 
Clinical Study Report  
A Clinical Study Report will be submitted to relevant IRB/EC and regulatory authorities in 
accordance with local requirements. 
14.8 
Publication of Data and Protection of Trade Secrets  
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments.  
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual site 
data. In this case, a coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
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15 
STUDY ADMINISTRATIVE PROCEDURES  
This section provides additional information on study-related administrative procedures, 
definitions, requirements, and record-keeping activities related to the study assessments 
described in Section 8. 
15.1 
Patient Recruitment Procedures  
Patients will be identified for potential recruitment by the Investigator, possibly including 
activities such as, but not limited to, a listing from study center, patient database, 
newspaper/radio/internet advertisement, or mailing list. 
15.2 
Patient Enrollment Procedures  
Patients cannot commence enrollment procedures until all entry criteria have been fulfilled. 
Where the clinical significance of an abnormal screening test result (lab or any other tests) is 
uncertain, the test may be repeated. 
The Investigator or designee will enter data for each enrolled patient in the study CRF and enter 
the corresponding number for allocation to the treatment groups in the appropriate place on each 
patient’s CRF. A patient enrollment and Identification Code List must be maintained by the 
Investigator or Pharmacist, or designee. 
Under no circumstances will patients who enroll in this study and complete treatment as 
specified be permitted to re-enroll in the study. 
15.3 
Patient Premature Withdrawal – Definition  
A patient who withdraws from the study before the planned end of study visit is considered to 
have withdrawn from the study early. 
15.4 
Procedures for Patients Who Withdraw from the Study  
Patients have the right to withdraw from the study at any time for any reason. In the event that 
a patient decides to discontinue from the study, he/she should be asked if he/she will complete 
the Early Withdrawal/Unscheduled Visit and be contacted for further information. The outcome 
of that discussion should be documented in both the medical records and in the CRF. 
When applicable, patients should be informed of circumstances under which their participation 
may be terminated by the Investigator without the patient's consent. The Investigator may 
withdraw patients from the study in the event of intercurrent illness, AEs, treatment failure after 
a prescribed procedure, lack of compliance with the study and/or study procedures or any other 
reasons where the Investigator feels it is in the best interest of the patient to be terminated from 
the study. 
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Reasons for withdrawal must be documented and explained to the patient. It is understood by all 
concerned that an excessive rate of withdrawals can render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided. Should a patient decide to withdraw, all 
efforts should be made to complete and report the observations as thoroughly as possible, 
particularly the follow-up examinations. 
The Investigator should contact the patient or a responsible relative either by telephone (followed 
by registered mail) or through a personal visit to determine as completely as possible the reason 
for the withdrawal. A complete final evaluation at the time of the patient’s withdrawal should be 
made, with an explanation of why the patient is withdrawing from the study. If the reason for 
removal of a patient from the study is an AE, the principal specific event must be recorded on the 
CRF. The patient should be followed until the AE is resolved, if possible. 
15.5 
Treatment Compliance  
Accountability and patient compliance will be assessed by maintaining adequate study drug 
dispensing records and medication counts. The Investigator is responsible for ensuring that 
dosing is administered in compliance with the protocol. See Section 9.4 for instructions on Drug 
Accountability procedures. 
15.6 
Recording of AEs on the CRF  
All AEs encountered during the clinical study will be reported in detail in the source documents 
and documented in the CRF, from the date of patient consent throughout the follow-up visit. All 
AEs, especially Grade 3 or higher, should be followed up until they have returned to the baseline 
status or stabilized. If the cause of the AE is established, it should be described in detail, 
including supporting information, in the source documents and on the CRF. 
15.7 
Physical Examination Procedures  
At screening and follow-up visits, a complete physical examination will consist of checking 
the normality or abnormality of the following body systems: general appearance, skin, eyes, ears, 
nose, throat, heart, chest/breast, abdomen, neurological system, lymph nodes, spine, 
and extremities (skeletal). 
An abbreviated physical examination will consist of checking the normality or abnormality 
of the following body systems: general appearance, skin, abdomen, and cardiorespiratory 
examination. 
The results of the physical examination will be summarized as normal/abnormal. In case 
of abnormality, details will be recorded in the patient notes and in the CRF. 
Height will be recorded at screening only. 
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15.8 
Vital Signs Procedures  
Blood pressure (BP), pulse rate, body temperature, and respiratory rate will be recorded at the 
time points specified in the Schedule of Assessments (Appendix 3 for Part A, Appendix 4 
for Part B, and for the LTE in Appendix 5 and Appendix 6). 
15.9 
Body Weight  
Body weight should be measured on the same digital clinic scale, after checking for accurate 
zero calibration each time. Weight is recorded in kg to one decimal place. 
15.10 ECG Procedures  
Single 12-lead ECG assessments will be obtained as specified in the Schedule of Assessments 
(Appendix 3 for Part A, Appendix 4 for Part B, and for the LTE in Appendix 5 and Appendix 6) 
to confirm eligibility and to ensure real time safety evaluation of the patients in the study, 
as specified in the Schedule of Assessments. 
Patients should be in a resting position for at least 10 minutes prior to any measurement. Body 
position should also be consistently maintained for each ECG evaluation. In particular, changes 
in heart rate should be avoided. There should be no environmental distractions (TV, radio, 
conversation) during the pre-ECG rest and the ECG recording time. 
Heart rate (HR), QRS duration, RR interval, and QT intervals will be recorded. Changes of the 
T-wave and U-wave morphology and overall ECG interpretation will be documented. 
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements. 
For triplicate ECG assessments, three interpretable ECG recordings (without artifacts) must be 
collected per time point within a ±10 minute period per time point. 
For safety monitoring purposes, the Investigator must review, sign and date all ECG tracings. 
Paper copies will be kept at the study center with the patient's clinical file as part of the 
permanent record. The ECG intervals and interpretation will be recorded on the CRF. 
15.11 Laboratory Test Procedures  
The laboratory assessments will be performed at a central laboratory, with the provision for 
occasional local laboratory testing, if required. Laboratory safety tests shall be collected at time 
points specified in the Schedule of Assessments (Appendix 3 for Part A, Appendix 4 for Part B, 
and for the LTE in Appendix 5 and Appendix 6). 
Additional blood or urine samples may be taken at the discretion of the Investigator if the results 
of any test fall outside the reference ranges, or clinical symptoms necessitate additional testing to 
monitor patient safety. Where the clinical significance of abnormal lab results is considered 
uncertain, screening lab tests may be repeated before Day 1 to confirm eligibility. In the event 
of unexplained abnormal clinically significant laboratory test values, the tests should be repeated 
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immediately and followed up until they have returned to the normal range, are considered to be 
clinically stable, and/or an adequate explanation of the abnormality is found. 
15.11.1 
Recording of Laboratory Test Results on the CRF  
Results of clinical laboratory testing will be recorded on the CRF or be received as electronically 
produced laboratory reports submitted directly from the local or central laboratory, if applicable. 
The procedures for the collection, handling and shipping of laboratory samples will be specified 
in the Sample Collection, Handling, and Logistics Manual. 
15.12 Recording of Concomitant Medications on the CRF  
All medications (prescription and over-the-counter [OTC]) taken within 28 days prior to study 
screening (reference Exclusion Criteria) will be recorded in the CRF. 
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16 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS  
16.1 
Appendix 1:
  
 
Strong 
Moderate 
16.2
 
 
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16.3 
Appendix 3: Schedule of Assessments (Part A)  
 
Screening  
(D-28 to 
D-1) 
On-treatment clinic visits, treatment cycles of 28days, X≤614 
Weekly lab visit 
between clinic visits13 
Early 
Withdrawal/ 
Unscheduled 
visit 
C1D1 
only 
CXD1 (first day 
of each cycle)12 
CXD15 
D169 (last day of active 
rilzabrutinib treatment) 
End of Study 
D197 / 4 weeks 
post last dose 
Clinic visits1 
X 
 
X 
X 
X 
X 
 
X 
Laboratory Only Visits for 
Hematology, differential & retics 
 
 
 
 
 
 
X 
 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X1 
 
 
 
 
 
 
AEs 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant Medications 
X 
 
X 
X 
X 
X 
 
X 
Dose-escalation points2 
 
 
X 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
X 
X 
 
X 
Physical exam/med history3 
X 
 
X 
X 
X 
X 
 
X 
ECG (12-lead, single) 
X 
 
 
 
 
X 
 
X 
ECG (12-lead, triplicate)4 
 
 
X 
 
 
 
 
 
Vital Signs 
X 
 
X 
X 
X 
X 
 
X 
Urinalysis 
X 
 
X 
X 
X 
X 
 
X 
Hep B &C, HIV 
X 
 
 
 
 
 
 
 
Pregnancy test5 
X 
 
X 
 
X 
X 
 
X 
FSH6 
X 
 
 
 
 
 
 
 
ABO and Rh Blood Type 
X 
 
 
 
 
 
 
 
Serum Chem 
X 
 
X 
 
X 
X 
 
X 
Hematology, differential, retics. 
X 
 
X 
X 
X 
X 
 
X 
 
PT/INR PTT 
X 
 
X 
 
X 
X 
 
 
TPO levels 
 
 
X 
 
X 
X 
 
 
Hemolysis panel7 
 
 
X 
 
X 
 
 
 
Platelet Auto antibodies8 
 
X 
 
 
X 
 
 
X 
Mean platelet volume 
 
 
X 
 
 
 
 
 
Immature platelet fraction 
 
 
X 
 
 
 
 
 
PK sample & metabolites9 
 
 
X 
X 
X 
 
 
X10 
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Screening  
(D-28 to 
D-1) 
On-treatment clinic visits, treatment cycles of 28days, X≤614 
Weekly lab visit 
between clinic visits13 
Early 
Withdrawal/ 
Unscheduled 
visit 
C1D1 
only 
CXD1 (first day 
of each cycle)12 
CXD15 
D169 (last day of active 
rilzabrutinib treatment) 
End of Study 
D197 / 4 weeks 
post last dose 
QOL 
X 
 
X 
 
X 
X 
 
 
IBLS11 
X 
 
X 
X 
X 
X 
 
X 
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16.4 
Appendix 4: Schedule of Assessments (Part B)  
 
Screening  
(D-28 to 
D-1) 
Active Treatment Period for 24 Weeks and 4 Week Follow Up Period1 
 
Early 
Withdrawal/ 
Unscheduled 
visit 
Enrolment 
Week 1 SD1 
Week 5 
SD29 
Week 9 
SD57 
Week 13 
SD85 
Week 17 
SD113 
Week 21 
SD141 
Last Day of 
Treatment 
Week 25 
SD169 
End of 
Study 
SD197  / 
4 weeks 
post last 
dose 
Weekly 
Lab 
Visits 
Between 
Clinic 
Visits1 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X1 
 
 
 
 
 
 
 
 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Physical exam/med history2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
ECG (12-lead, single) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Hep B & C, HIV12 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
FSH4 
X 
 
 
 
 
 
 
 
 
 
 
ABO and Rh Blood Type5 
X 
 
 
 
 
 
 
 
 
 
 
Serum Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Hematology, differential, 
reticulocytes 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PT/INR PTT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
TPO levels 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Hemolysis panel7 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Mean platelet volume13 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Immature platelet fraction13 
BTK Occupancy9 
 
X 
X 
X 
 
 
 
X 
 
 
 
PK sample10 
 
X 
X 
X 
 
 
 
 
 
 
 
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Screening  
(D-28 to 
D-1) 
Active Treatment Period for 24 Weeks and 4 Week Follow Up Period1 
 
Early 
Withdrawal/ 
Unscheduled 
visit 
Enrolment 
Week 1 SD1 
Week 5 
SD29 
Week 9 
SD57 
Week 13 
SD85 
Week 17 
SD113 
Week 21 
SD141 
Last Day of 
Treatment 
Week 25 
SD169 
End of 
Study 
SD197  / 
4 weeks 
post last 
dose 
Weekly 
Lab 
Visits 
Between 
Clinic 
Visits1 
QOL Questionnaires11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
IBLS  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
16.5 
Appendix 5: Schedule of Extension Period – First 6 Months (Part A and Part B)  
 
Day 169 
Visit/rollover
 
On-treatment clinic visits, treatment cycles of 28days, X≤6 
Early Withdrawal/ 
Unscheduled visit 
 
Clinic visits1 
X 
X 
 
 
 
X 
Laboratory Only Visits for Hematology, 
differential & retics 
 
 
X 
X 
X 
 
AEs 
X 
X 
 
 
 
X 
Concomitant Medications 
X 
X 
 
 
 
X 
Weight 
X 
X 
 
 
 
X 
Physical Exam7 
X 
X 
 
 
 
 
ECG (12-lead, single) 
X 
 
 
 
 
 
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Day 169 
Visit/rollover/C1D1_LTE 
On-treatment clinic visits, treatment cycles of 28days, X≤6 
Early Withdrawal/ 
Unscheduled visit 
CXD1_LTE (first 
day of each cycle)  
CXD8_LTE 
CXD15_LTE 
CXD22_LTE 
Vital Signs 
X 
X 
 
 
 
X 
Urinalysis 
X 
X 
 
 
 
X 
Pregnancy test2 
X 
X 
 
 
 
X 
Serum Chem 
X 
X 
 
 
 
X 
Hematology, differential, retics. 
X 
X 
 
 
 
X 
PT/INR PTT4 
X 
X 
 
 
 
 
TPO levels 
X 
X 
 
 
 
 
Hemolysis panel9 
X 
 
 
 
 
 
Mean platelet volume12 
X 
 
 
 
 
 
Immature platelet fraction12 
X 
 
 
 
 
 
Immunoglobulins10 
X 
 
 
 
 
 
BTK Occupancy11 
X 
 
 
 
 
 
Platelet Auto antibodies5 
X 
 
 
 
 
X 
PK sample & metabolites6 
X 
X 
 
 
 
X 
QOL questionnaire13 
X 
X 
 
 
 
 
IBLS 
X 
X 
 
 
 
X 
HBV8 
X 
X 
 
 
 
X 
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16.6 
Appendix 6: Schedule of Assessments – Extension Period Continued (Part A and Part B)  
 
On-treatment clinic visits, visits every 28 days for 6 months, then every 3 months8 
Early Withdrawal/ 
Unscheduled visit 
 (first day 
of each cycle) Every 
28 days for 6 months 
Every 3 Months 
Last day of active 
rilzabrutinib 
treatment 
End of Study 
(4 week post last 
dose) 
Clinic visits1 
X 
X 
X 
X 
X 
AEs 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
Physical Exam7 
X 
X 
X 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
Pregnancy test2 
X 
X 
X 
X 
X 
Serum Chem 
X 
X 
X 
X 
X 
Hematology, differential, retics. 
X 
X 
X 
X 
X 
PT/INR PTT4 
X 
X 
X 
X 
 
TPO levels 
X 
X 
X 
X 
 
Platelet Auto antibodies5 
 
 
X 
 
X 
PK sample & metabolites6 
X 
X 
X 
 
X 
QOL questionnaire10 
X 
X 
X 
X 
 
IBLS 
X 
X 
X 
X 
X 
HBV9 
X 
X 
 
X 
X 
1.
 
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16.7 
Appendix 7: 
 
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16.8 
Appendix 8: Country-specific/region requirements  
16.8.1 European Union  
16.8.1.1 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. 
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16.9 
Appendix 9: Collection, storage and future use of data and human biological 
samples  
16.9.1 Compliance with Member State applicable rules for the collection, storage and future 
use of human biological samples (Article 7.1h)  
This appendix is provided separately. 
16.9.2 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)  
This appendix is provided separately. 
16.10 Appendix 10: Protocol Amendment History  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the table of contents (TOC). 
Amended protocol 15.0: (19 Mar 2021)  
This amended protocol (amendment 15) 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 number to include 
“(DFI17124)”; added amendment 
number “15”; updated protocol 
version and date; added 
“SAR444671” to header; added “a 
Sanofi Company” after “Principia 
Biopharma”; added company logo. 
Administrative and per Sanofi template. 
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 protocol acceptance 
page. 
For consistency with current Sanofi 
protocol template and processes. A 
separate signature page will be available. 
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Section # and Name 
Description of Change 
Brief Rationale 
Protocol amendment summary of 
changes 
Inserted document history table 
and protocol amendment summary 
of changes table. 
Per Sanofi protocol template and 
process. 
PRN1008-010 Study synopsis, 
Background and Rationale; Section 1.2, 
Summary of rilzabrutinib clinical 
experience 
Updated the paragraph regarding 
PRN1008-005 study results and 
added cross-reference to the 
PRN1008-005 Clinical Study 
Report. 
Update. 
PRN1008-010 Study synopsis, Study 
Design Part B, Patient selection criteria 
Part B; Section 4.2, Overall study 
design and plan Part B; Appendix 4, 
Schedule of assessments (Part B); 
Appendix 5, Schedule of extension 
period – first 6 months (Part A and 
Part B); Appendix 6, Schedule of 
assessments extension period 
continued (Part and Part B) 
Corrected units for HBsAb titer from 
IU/mL to IU/L. 
Correction. 
PRN1008-010 Study synopsis, Study 
stopping rules; Section 4.6.2, Study 
stopping rules 
Revised third bullet from “3 or more 
life-threatening (Grade 4) 
rilzabrutinib-related TEAEs” to “Two 
or more life-threatening or CTCAE 
Grade 4 rilzabrutinib-related TEAEs 
except for AEs related to the 
disease under study (lack of 
efficacy).” 
Health authority request and consistency 
with other Principia Biopharma Phase 3 
immune thrombocytopenia (ITP) 
protocols. 
PRN1008-010 Study synopsis, Study 
endpoints Part A; Section 10.3.1, Safety 
endpoints 
Added additional safety endpoints. 
Consistency with Statistical Analysis Plan 
(SAP). 
PRN1008-010 Study synopsis, Study 
endpoints Part A; Section 10.3.2, 
Efficacy endpoints 
Revised secondary efficacy 
endpoints. 
Consistency with SAP. 
PRN1008-010 Study synopsis, Study 
endpoints Part A, Exploratory 
endpoints; Section 10.4, Exploratory 
measures, Part A 
Added additional exploratory 
endpoints. 
Consistency with SAP. 
PRN1008-010 Study synopsis, Study 
Drug and Methods of Dosing; Section 
4.10, Rilzabrutinib administration (Part 
A and Part B) 
Added sentence to state that 
 
Clarification to align with Investigator’s 
Brochure. 
PRN1008-010 Study synopsis, Study 
assessments (Laboratory and ECG 
assessments) ; Section 8.2, Laboratory 
and ECG assessments 
Bullet 3: Added “(where available)” 
to bullet for immature platelet 
fraction. 
Correction, previously removed in error. 
PRN1008-010 Study synopsis, Study 
assessments (Laboratory and ECG 
assessments); Section 8.2, Laboratory 
and ECG assessments 
Bullet 15: Removed Part A only: 
monocytes counts and B-cell 
subsets. 
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Section # and Name 
Description of Change 
Brief Rationale 
Appendix 3, Schedule of Assessments 
(Part A) 
 removed footnote 7. 
 
PRN1008-010 Study synopsis, 
Statistical methods Part A, Statistical 
methods Part B; Section 10.6.2, 
Efficacy Analysis Population 
Text revised to specify that all 
efficacy analysis will be based on 
the ITT population, and added 
definition of the ITT population. 
Consistency with SAP. 
Section 1.2, Summary of rilzabrutinib 
clinical experience 
Updated text regarding preliminary 
results of PRN1008-010 and added 
cross reference to Kuter 2020. 
Update. 
Section 3.3, Outcome measures of the 
study: Part A; Section 3.4, Outcome 
measures of the study: Part B 
Revised headings to specify 
primary safety and primary efficacy 
endpoints. 
Clarification. 
Section 4.11.1, Allowed Part A; Section 
4.11.2, Allowed Part B; Section 4.11.3, 
Prohibited 
Added text (last bullet) regarding 
the use of clinically relevant drugs 
that are
 to 
Section 4.11.1 and Section 4.11.2; 
removed previous corresponding 
text from Section 4.11.3.  
Update based on new drug-drug 
interaction data. 
Section 6.2.2, Exclusion Criteria 
(Criterion #17) 
Corrected HBsAb units from IU/mL 
to IU/L; corrected to read “HBsAb 
titer “is “≥” 100 IU/L (rather than 
“>100 IU/L”). 
Correction. 
Section 10.9, Efficacy and exploratory 
analysis, Part A, Part B 
Replaced “ITT-E” population with 
“ITT” population. 
Correction and consistency with SAP. 
Section 11.6, Adverse event intensity 
grading 
Corrected NCI CTCAE version 
back to 4.0 from 5.0. 
Correction, previously changed in error. 
Section 11.8, Pregnancy 
Revised text to state that 
pregnancies occurring up to 
4 weeks (rather than 90 days) after 
completion of the study drug must 
also be reported to the Investigator. 
Consistency with current standard text in 
other Principia BioPharma ITP protocols 
and is supported by reproductive toxicity 
data. 
 
Added information regarding 
reporting pregnancy AEs/SAEs, 
including complication or elective 
termination, abnormal pregnancy 
outcomes. and post-study 
pregnancy related SAEs. 
Clarification. 
Section 16, References 
Added reference for Kuter 2020. 
Per update in Section 1.2. 
 
Added reference for PRN1008-005 
CSR. 
Per update in Synopsis, Background and 
Rationale. 
Appendix 3, Schedule of Assessments 
(Part A); Appendix 4, Schedule of 
Assessments (Part B) 
In header, clarified that end of 
study is 4 weeks post last dose. 
Clarification. 
Appendix 4, Schedule of assessments 
(Part B) 
Removed Hep B & C and HIV 
testing except at screening. 
Clarification as to when Hep B & C and 
HIV testing is needed. 
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Section # and Name 
Description of Change 
Brief Rationale 
Appendix 7, Protocol Amendment 
History 
Added new appendix to include 
protocol amendments history. 
Per Sanofi template and process. 
Protocol header throughout document 
Updated header. 
Per Sanofi template. 
Throughout document 
Replaced “PRN1008” with 
“rilzabrutinib” as applicable. Added 
Sanofi study number “DFI17124” as 
applicable. 
Administrative update. 
Amended protocol 14.0: (12 Aug 2020) 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis, Study sites 
Updated Part B from “approximately 
50 sites” to “approximately 30 sites.” 
Update to number of study sites in 
Part B. 
Synopsis, Study Design Part A; 
Section 4.1, Overall study design 
and plan Part A 
LTE: Updated text to further define the 
response criteria for entrance into the LTE 
from Part A, and the patient monitoring 
frequency. 
Clarification. 
Synopsis, Study design Part B; 
Section 4.2, Overall study design 
and plan Part B 
LTE: Updated to further define the response 
criteria for entrance into the LTE from 
Part A, and the patient monitoring 
frequency. 
Clarification to Part B assessments. 
Synopsis, Study design Part B; 
Section 4.2, Overall study design 
and plan Part B 
Updated to reflect requirements for HBV 
DNA monitoring of affected Part B patients 
as specified in Exclusion Criterion #17. 
Clarification to Part B assessments. 
Synopsis, Study design Part B; 
Section 4.2, Overall study design 
and plan Part B 
Updated to further define the response 
criteria for entrance into the LTE from 
Part B, and the patient monitoring 
frequency. 
Clarification to Part B assessments. 
Synopsis, Dose limiting toxicity, 
dose escalation, and stopping rules 
Part A 
Added text as follows: The DLT evaluation 
period for any patient is defined as the 
duration of rilzabrutinib dosing until the dose 
escalation is completed. 
Harmonization of synopsis text with text 
in the protocol body. 
Synopsis, Study stopping rules 
Part B; Section 4.6.2, Study 
stopping rules 
Revised text to specify that the study will be 
stopped if the Sponsor (rather than the 
SMC) deems the emerging TEAE profile 
unacceptable to continue the study. 
As the treatment-emergent adverse 
event profile is acceptable for 
continuation of the study, there will not 
be a Safety Monitoring Committee in 
Part B. 
Safety in Part B will be monitored via 
Sponsor Quarterly Safety Reviews 
established after the original protocol 
was implemented.  
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Section # and Name 
Description of Change 
Brief Rationale 
Sponsor Quarterly safety reviews will 
include analyses of safety events and 
trends across rilzabrutinib studies. 
Synopsis, Study endpoints Part B; 
Section 10.2, Primary efficacy 
endpoint 
Text revised to specify that patients who 
used rescue medications are not considered 
responders. 
Updated to reflect discussion with FDA. 
Synopsis, Study endpoints Part B; 
Section 10.3, Secondary efficacy 
endpoints 
Text moved to Statistical Methods Part B 
section of synopsis. 
Per analysis population definition in 
Section 10.7.2. 
Synopsis, Planned number of 
patients; Section 4.7, Number of 
patients 
Revised text to specify enrollment of 
“approximately 60 patients” in Part A and 
“approximately 23 patients” in Part B. 
Clarification of expected enrollment. 
Synopsis, Patient selection Part A; 
Section 6.1.2, Exclusion criteria 
Updated exclusion text to specify “hepatitis 
B (surface antigen and core antibodies 
unrelated to vaccination).” 
Updated to clarify intended exclusion for 
Hepatitis B surface antigen. 
Synopsis, Patient Section Criteria 
Part B; Section 6.2.2 Exclusion 
criteria 
Criterion 17: Revised text intent for 
exclusion or inclusion of patients meeting 
hepatitis B virus serology, and follow-up for 
those patients who are enrolled with stated 
conditions. 
Clarification of intent for exclusion of 
patients. 
Synopsis, Safety assessments and 
monitoring Part B 
Revised text to state that “The assessments 
will be conducted as part of ongoing medical 
monitoring and at Sponsor-Quarterly Safety 
Reviews where safety events and trends 
across rilzabrutinib studies are considered.” 
Removed text regarding independent SMC. 
As the treatment-emergent adverse 
event profile is acceptable for 
continuation of the study, there will not 
be a Safety Monitoring Committee in 
Part B.   
Safety in Part B will be monitored via 
Sponsor Quarterly Safety Reviews 
established after the original protocol 
was implemented.  
Sponsor Quarterly safety reviews will 
include analyses of safety events and 
trends across rilzabrutinib studies. 
 Synopsis, Statistical methods 
Part A 
Revised text as follows: “The proportion of 
patients with a Grade 2 or higher bleeding 
events will also be summarized.” 
Updated to reflect decision to 
summarize all bleeding events. 
Synopsis, Statistical methods 
Part B; Section 10.6, Determination 
of sample size Part B 
Updated text to reflect revised sample size 
estimate. 
Updated to reflect changes to the efficacy 
analysis and the revised sample size 
(deleted text), and to reflect the move of the 
inserted text from the Study Endpoints 
Part B section of the synopsis. 
Updated to reflect decision to summarize all 
bleeding events. 
Updates to reflect revised sample size 
estimate, efficacy analysis, and 
summarization of all bleeding events. 
Section 1.1, Scientific rationale for 
treatment of ITP with rilzabrutinib 
(PRN1008) 
Added text as follows: Idiopathic 
thrombocytopenic purpura, now more 
commonly referred to as immune 
thrombocytopenia (ITP) .  .  . “ 
Updated to reflect American Society of 
Hematology guidelines of indication 
name. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 2.2, Overall benefit risk 
assessment 
Revised safety profile text. 
Updated text to reflect revised 
information in the Investigator’s 
Brochure v11. 
Section 4.3, Dose limiting toxicity 
(DLT) Part A only 
Harmonized text in the protocol body with 
text in the synopsis. 
Revised for protocol consistency. 
Section 4.11.1, Allowed Part A 
Updated text o address corticosteroid taper 
in Part A LTE. 
Clarification. 
Section 4.11.2, Allowed Part B 
Updated text o address corticosteroid taper 
in Part B LTE. 
Harmonization of text in the protocol body 
with text in the Rescue Criteria Guidelines 
Part B section of the synopsis. 
Clarification and protocol consistency. 
Original Section 10.7.1, Screening 
population 
Orphaned unused section header removed, 
and all subsequent level 3 header numbers 
adjusted. 
Administrative. 
Section 10.7.2, Efficacy analysis 
population 
Revised text to remove legacy analysis 
population and harmonize text with the 
synopsis for the efficacy analysis population. 
Administrative and protocol consistency. 
Section 10.10, Efficacy and 
exploratory analysis 
Part A: Text updated to remove unneeded 
analysis. 
Part B: Text updated to remove unneeded 
analysis. 
Consistency with other revisions. 
 
Unneeded analysis as a result of 
revised sample size. 
Section 11.1, Independent data 
safety monitor (IDSM) and safety 
monitoring committee (SMC) 
Text added to specify that there will no 
independent SMC in Part B; details 
regarding SMC removed.  
Added text specifying that safety in Part B 
will be monitored via Sponsor Quarterly 
Safety Reviews established after the original 
protocol was implemented.  
As the TEAE profile is acceptable for 
continuation of the study, there will not 
be a Study Monitoring Committee in 
Part B.  
Sponsor Quarterly safety reviews will 
include analyses of safety events and 
trends across rilzabrutinib studies. 
Section 13.1, Local 
regulations/declaration of Helsinki 
Revised text to clarify ethical requirements. 
Clarification. 
Appendix 3, Schedule of 
assessments (Part A) 
Footnote 3 updated to provide clarification of 
intent regarding physical examination at 
Cycle 1 Day 1. 
Clarification 
Appendix 4, Schedule of 
assessments (Part B) 
Footnote 2 updated to provide clarification of 
intent regarding physical examination at 
Cycle 1 Day 1. 
Clarification 
 
Footnote 12 updated to reflect requirement 
noted in Part B exclusion criterion #17 for 
monthly monitoring of affected patients. 
Clarification and consistency with other 
protocol revisions. 
Appendix 5, Schedule of extension 
period - first 6 months (Part A and 
Part B 
Removed “informed consent form” row from 
table. 
Added row for HBV testing and added 
footnote 8 with HBV testing details. 
Consent for LTE is included within the 
main consent form. 
Updated to reflect requirement noted in 
Part B Exclusion Criterion #17 for 
monthly monitoring of affected patients. 
Appendix 6, Schedule of extension 
period – extension period continued 
(Part A and Part B 
Added row for HBV testing and added 
footnote 9 with HBV testing details. 
Updated to reflect requirement noted in 
Part B Exclusion Criterion #17 for 
monthly monitoring of affected patients. 
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Section # and Name 
Description of Change 
Brief Rationale 
Protocol title and throughout the 
document. 
Rilzabrutinib (PRN1008) – in protocol title, 
first use, and when referring to the physical 
tablets 
Rilzabrutinib or rilzabrutinib PRN1008 – 
elsewhere in the protocol 
Updated with recommended name by 
the World Health Organization (WHO) 
International Nonproprietary Names 
(INN) Committee as well as the United 
States Adopted Names (USAN) 
Council. 
 
Replaced” participants” with “patients.” 
Administrative change to terminology. 
In addition, other minor editorial changes (eg, grammatical, stylistic, and minor typographical 
error corrections) were implemented throughout the protocol. 
Amended protocol 13.1: (16 April 2020) 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis, Participant selection 
criteria Part B : inclusion criteria; 
Section 6.2.1, Inclusion criteria 
Criterion #4: Revised to specify that patients must have 
platelet count of <30,000/µL on two occasions no less 
than 7 days apart in the 15 days before treatment 
begins, and no (rather than “a”) platelet count above 
(rather than “of”) 35,000/µL on Study Day 1. 
Clarification. 
Synopsis, Participant selection 
criteria Part B : Exclusion criteria ; 
Section 6.2.2, Exclusion Criteria 
Criterion #17: Revised sentence as follows: “If HBV 
DNA is negative and HBsAb titer is >100 IU/ml, patients 
may be enrolled in study.” To “If HBV DNA is negative 
and HBsAb titer is ≥100 IU/ml or negative, patients may 
be enrolled in study.” 
Clarification. 
Synopsis, Study assessments; 
Section 8.2, Laboratory & ECG 
assessments 
Revised text to specify that monocyte counts and B-cell 
subsets assessments will be done for Part A only. 
Clarification to Part A 
assessments. 
Appendix 4, Schedule of 
assessments (Part B); Appendix 5, 
Schedule of extension period – first 
6 months (Part A and Part B); 
Appendix 6, Schedule of extension 
period continued (Part A and 
Part B) 
Removed monocytes from 
assessments. 
Clarification to Part B 
assessments. 
Appendix 5, Schedule of extension 
period – first 6 months (Part A and 
Part B); Appendix 6, Schedule of 
extension period continued (Part A 
and Part B) 
Specifies that the platelet autoantibody panel to be 
collected at D169, last day of treatment and early 
withdrawal will not be performed in Australia. 
Clarification to Part A 
assessments. 
In addition, other minor editorial changes (eg, grammatical, stylistic, and minor typographical 
error corrections) were implemented throughout the protocol. 
 
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Amended protocol 13: (05 Mar 2020) 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title page (study title) and 
throughout the document 
Revised title: replaced 
“thrombocytopenic purpura” with 
“thrombocytopenia.” 
Updated indication name to reflect 
American Society of Hematology 
guidelines. 
Synopsis, Background and rationale 
Added text to indicate the status of 
ongoing study and introduce addition of 
Part B. 
The dose escalation part of the study has 
been completed and all patient currently 
enrolling start the study at the 400 mg BID 
dose, 
 
Part B will assess the 400 mg BID dose in 
patients who had initial response to IVIg or 
corticosteroids that was not sustained and 
failed at least one other ITP therapy 
Synopsis, Study sites 
Revised to the following: 
Part A: Multicenter trial (approximately 
30 sites) 
Part B: Multicenter trial (approximately 
30 sites) 
Addition of new sites to participate in 
Part B. 
Synopsis, Study Objectives Part B; 
Section 3.2, Objectives of the study: 
Part B 
Added new text for Part B safety, 
efficacy, pharmacokinetics, and 
exploratory objectives. 
Addition of objectives specific or for Part B/ 
Synopsis, Study design 
Part A; Updated requirements for 
continuing in the LTE part of the study. 
Clarification. 
 
Part B: Deleted text regarding dose-
escalation part of the study. 
The dose-escalation part of the study has 
been completed. 
Synopsis, Stopping rules Part B; 
Section 4.6, Stopping rules Part B 
(also applies to LTE) 
Section 4.6.1, Individual stopping rules 
and Section 4.6.2 Study stopping rules: 
Added text for Part B stopping rules. 
Inclusion of Part B of the study. 
Synopsis, Rescue criterial 
guidelines for Part B 
Added text to reflect rescue criteria for 
Part B, which allows patients who need 
rescue medication to continue the 
study. 
Inclusion of Part B of the study. 
Synopsis, Study endpoints Part B; 
Section 3.4, Outcome measures of 
the study: Part B 
Added text for safety, primary efficacy, 
secondary efficacy, exploratory, and 
pharmacokinetic endpoints. 
Addition of study endpoints specific for 
Part B patient population which will enable 
assessment of both the primary endpoint 
and clinically meaningful endpoints for this 
difficult to treat patient population. 
 
Secondary efficacy endpoints: Added 
secondary efficacy endpoint for 
analyzing patients in the LTE. 
Addition of LTE to study design. 
Synopsis, Planned number of 
participants 
Added “Part A” before previous text in 
this section. Added new text for Part B. 
Added the maximum number of 
participants in Part B. 
Synopsis, Participant selection 
criteria Part B 
Added inclusion and exclusion criteria 
for Part B. 
Inclusion of Part B of the study. 
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Section # and Name 
Description of Change 
Brief Rationale 
Synopsis, Study drug and method 
of dosing. 
Added “Part A” before previous text. 
Added text for Part B. 
Addition of only 400mg tablets to be used 
for Part B with the same method of dosing 
as Part A 
Synopsis, Study assessments 
Addition of assessments: 
(immunoglobulin levels, ITP-PAQ tool, 
BTK occupancy at selected sites) for 
Part B. Minor revisions to multiple Part 
A assessments. 
Addition of assessments specific for Part B 
and clarifications for Part A assessments. 
Synopsis, Safety Assessments and 
monitoring Part B; Section 11.1, 
Independent data safety monitor 
(IDSM) and safety monitoring 
committee (SMC) 
Added new section. 
Addition of Part B safety assessments and 
monitoring with adjustments made for the 
end of dose escalation. 
Synopsis, Statistical methods 
Part B; Section 10.12, 
Pharmacokinetics analysis 
New section added. 
Addition of Part B statistical methods to 
incorporate historical standard of care. 
Synopsis, Study Duration 
Added “Part A” before previous text. 
Added new text for Part B. Added “Long 
Term Extension (LTE) Part A and Part 
B” before text regarding the LTE. 
Platelet autoantibody panel cannot be 
completed on patients in Australia due to 
stability and shipment timelines. 
Section 1.2, Summary of PRN1008 
Clinical Experience 
Updated text to include preliminary data 
from the ongoing studies in alignment 
with the data presented at ASH 2019 
(Kuter 2019). 
Addition of available data. 
Section 1.3, Clinical 
Pharmacokinetics and 
Pharmacodynamics of PRN1008 
Updated text to include additional 
information from pharmacology studies. 
Addition of available data. 
Section 2.2.1, Rationale for doses 
used and duration of the study 
Added new Section 2.2.2, Rationale for 
doses used and duration of study 
Part B. 
Addition of Part B dose and duration 
j
 In addition, to reflect 
the change in primary endpoint to allow for 
better assessment of durability of platelet 
response. 
Section 2.3, Overall benefit-risk 
assessment, Safety profile 
Revised text to state: “Importantly, there 
were no related thrombin or major 
bleeding events in the clinical 
experience with PRN1008 up to date.” 
Updated clinically relevant safety 
information. 
Section 2.3, Overall benefit-risk 
assessment, Efficacy 
Added text from preliminary review of 
the efficacy data in Part A. 
Section 4.1, Overall study design 
and plan Part A, Long term 
extension; Section 4.2, Overall 
study design and plan Part B 
Updated criteria to better define the 
population that may receive clinical 
benefit of the study drug. Delete text to 
reflect the completion of the dose 
escalation part of the study. Addition of 
Part B overall study design and plan. 
Clarification, updates related to completion 
of the dose-escalation part of the study, 
addition of Part B to the study. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 4.7, Number of participants 
Added text for Part B 
Addition of the maximum number of 
participants in Part B. 
Section 4.8, study duration and 
duration of patient participation 
Added text for Part B. 
Addition of Part B study duration and 
duration of patient participation. 
Section 4.11, Concomitant 
medications, Section 4.11.2, 
Allowed Part B 
Added permitted concomitant 
medications for Part B. 
Inclusion of Part B of the study. 
Section 8.3, Safety assessments 
Added “Part A” before existing text. 
Added text for Part B. 
Addition of Part B PK sampling information. 
Section 10.7.1, Screening 
population 
This section was deleted. 
There will no longer be an analysis of the 
screening population as it is the same as 
the ITT population. 
Section 10.9.3, Reconsenting of 
patients 
This section was deleted. 
Requirement for reconsenting removed. 
Section 10.10, Efficacy and 
exploratory analysis 
Added text for Part B statistical 
analysis. 
Inclusion of Part B of the study. 
Section 10.11, Safety and 
tolerability analysis 
Text revised. 
Clarification. 
Section 10.11.1, Adverse events 
Updated text to define the reported AEs 
that start before the first dose of study 
drug as pre-treatment events and those 
events that start after the first dose of 
study drug or worsen after the first dose 
of study drug as TEAEs. 
Clarification. 
Section 10.11.2, Clinical laboratory 
tests 
Added text for Part B. 
Inclusion of Part B of the study. 
Section 10.11.3, Vital signs 
Text revised. 
Addition of Part B changes regarding only 
1 dose to be used in Part B. 
Section 10.11.4, Rescue 
medication, DLTs, and bleeding 
scale scores 
Revised text to clarify that the history of 
rescue medication collection in Part A 
was not limited to 12 weeks and that 
Part B will assess only 1 dose of 
PRN1008. 
Clarification; inclusion of Part B of the 
study. 
Section 11.3, Clinical adverse 
events 
Updated text regarding pre-existing 
conditions to be reported as AEs. 
The platelet count is part of the 
assessment of efficacy in the ITP patients.  
As such it is expected to fluctuate and is 
captured in the efficacy assessments. Text 
updated in this section to clarify that the 
disease under study is only recorded as an 
event if it meets serious criteria or is not 
consistent with the typical clinical course 
for that patient. 
Section 11.7.1, SAE definitions 
Text revised. 
Text streamlined for operational ease of 
use to locate the definition of an SAE. 
Section 11.7.2, SAE reporting 
Revised text specifying the 4 minimum 
criteria for a valid SAE report. 
Streamlined text for operational ease and 
reconciliation with the safety database. 
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Section # and Name 
Description of Change 
Brief Rationale 
 
Revised text for SUSAR reporting. 
Clarified that expectedness for a SUSAR is 
based upon what is listed in the IB. 
Clarified that individual SUSARs are sent 
to all sites which is expected until the site is 
officially closed for the study. 
Section 16, references. 
Reference added for Kuter DJ et al, 
2019. 
Addition of ASH reference in support of 
preliminary data provided in protocol 
Section 2.3. 
Appendix 3, Schedule of 
assessments (Part A) 
Footnote 10 revised. 
Updated for clarify and for operational 
ease. 
Appendix 4, Schedule of 
assessments (Part B) 
New table added. 
Inclusion of Part B of the study. 
Throughout document 
Global changes to headings and 
appendix numbering as follows: 
Revised heading titles to identify Part 
and the addition of new headings for 
Part B. 
Appendix numbers revised to 
accommodate the addition of the 
schedule of assessment for Part B 
(Appendix 4). 
Editorial changes. 
In addition, other minor editorial changes (eg, grammatical, stylistic, and minor typographical 
error corrections) were implemented throughout the protocol. 
Amended protocol 12: (5 December 2019) 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis, Planned number of 
participants and interim analysis 
Number of patients revised from “up to 40” to “up to 
60.” 
Increase in number of patients 
to be enrolled. 
Synopsis, Study drug and method 
of dosing; Section 9.1, Formulation 
Text revised to allow for patients to take 400 mg BID 
in any dosage form (100 mg + 300 mg tables or 
400 mg tablet). 
More flexible dosing. 
In addition, other minor editorial changes (eg, grammatical, stylistic, and minor typographical 
error corrections) were implemented throughout the protocol. 
Amended protocol 11: (24 October 2019) 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis, Screening procedure, 
Study Assessment; Section 8.1, 
Clinical Assessments; Section 8.3, 
Safety Assessments; Section 15.7, 
Physical examination procedure 
Removed Cogstate testing.  
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Section # and Name 
Description of Change 
Brief Rationale 
Section 16 References 
Removed reference Cataland SR et al, 
2011. 
Removal of Cogstat testing. 
Appendix 3, Schedule of 
assessments; Appendix 4, 
Schedule of assessments – 
extension period – first 6 months 
Removal of footnote 15 regarding 
cognitive testing. 
Removal of Cogstat testing. 
Appendix 6, Description of 
computerized cognitive monitoring 
Removed table. 
Removal of Cogstat testing. 
In addition, other minor editorial changes (eg, grammatical, stylistic, and minor typographical 
error corrections) were implemented throughout the protocol. 
Amended protocol 10.1 (Norway): (21 January 2020) 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis, Participant selection 
criteria: Inclusion criteria 
Criterion #4: Revised to specify that patients must have 
“A history of response (2 [rather than 1] or more platelet 
counts of ≥50,000/µL with an increase of at least 
20,000/ µL) to at least 1 prior line of therapy (with 
splenectomy being considered a line of therapy) 
Correction as synopsis and 
body of protocol did not 
match. 
Synopsis, Participant selection 
criteria: Inclusion criteria 
Criterion 67: Updated text regarding sexual abstinence 
to “true abstinence; when this is in line with the 
preferred and usual lifestyle of the patient).” 
Updated to define 
abstinence in line with a 
request from the MHRA. 
Synopsis, Study drug and method 
of dosing 
Updated text to read “PRN1008 100 mg, 300 mg, and 
400 mg tablets.” 
Updated to introduce the 
400 mg tablets. 
Section 4.1, Overall study design 
and plan 
Paragraph regarding dose down-titration inserted. 
Paragraph copied from 
synopsis into Section 4.1 for 
consistency. 
Section 9.1 Formulation 
Paragraph was revised to include the 400 mg drug 
substance and to describe the 400 mg tablet. 
Updated to introduce the 
400 mg tablets. 
Section 9.3, Storage and handling 
Text updated to specify storage for
 
tables, and storage for 
 tablets, separately. 
Updated to include the 
 tablet storage 
conditions. 
In addition, other minor editorial changes (eg, grammatical, stylistic, and minor typographical 
error corrections) were implemented throughout the protocol. 
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Amended protocol 10: (27 September 2019) 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis, Inclusion criteria 
Criterion 4: Definition of history of response was 
updated from “one or more” to “two or more” 
platelet counts ≥50,000/µL with an increase of at 
least 20,000/µL)  
Correction to match inclusion 
criterion 4 in the body of the 
protocol. 
 
Criterion 6: Revised text regarding highly effective 
means of contraception, specifically abstinence. 
Updated in line with a request 
from the MHRA. 
Synopsis, Study drug and method 
of dosing; Section 9.1, Formulation 
Added text regarding 400 mg tablets that will be 
administered to patients who enter the LTE. 
Addition of 400 mg tablets for 
LTE. 
Appendix 4, Schedule of 
assessments – extension period – 
first 6 months 
Footnote 1: Changed clinical/laboratory visit 
windows from ±7 days to ±3 days for all dosing 
period and lab visits. 
Correction as visits in the first 
6 months are weekly.  
In addition, other minor editorial changes (eg, grammatical, stylistic, and minor typographical 
error corrections) were implemented throughout the protocol. 
 
Amended protocol 9: (6 May 2019) 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title page 
Page updates to clarify that EudraCT 
number, not CTN number is listed. 
Company address and Principia 
medical monitor information updated. 
Administrative change. 
Protocol signature page 
Updated to reflect new Chief Medical 
Officer at Principia. 
Administrative change. 
Synopsis, Background and rationale 
Revised text. 
Updated to reflect the final data for the 
PRN1008-005 Part A study, to update the 
number of exposed patients per IB, and to 
refer investigators to the IB version 10 for the 
current updates on the preclinical studies. 
Synopsis, Study sites 
Revised “approximately 25 sites” to 
“approximately 30 sites.” 
Updated to reflect additional sites. 
Synopsis, Study Design 
Added text to allow patients who 
received lower doses to receive 
24 weeks of treatment at the 
 dose level. Added text regarding 
the LTE for patients who responded to 
continue to receive 
 study 
drug beyond 24 weeks of treatment. 
Text added to reflect updated study design. 
 
Long Term Extension: Added text 
regarding monitoring of LTE patients. 
Added to describe the frequency of study 
visits for responders who enter the LTE. 
Synopsis, Dose-limiting toxicity, 
dose escalation and stopping rules 
Individual stopping rules: 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Synopsis, Rescue criterial 
guidelines 
Added a statement that the rescue 
medications listed are not permitted 
while the patient is receiving treatment 
with PRN1008. 
Clarification. 
Synopsis, Outcome measures 
Added text specifying that AEs will be 
categorized as treatment-emergent 
after the first dose of PRN1008 has 
been received.. 
Clarification of safety endpoint. 
 
Secondary efficacy endpoints: Added 
secondary efficacy endpoint for 
analyzing patients in the LTE. 
Addition of LTE to study design. 
Synopsis, Planned number of 
participants and interim analysis 
Number of participants updated from 24 
to 40; added text that at least 
10 patients complete 24 weeks of 
treatment at a starting dose of
Updated to the new number of patients to be 
enrolled and completed. 
Synopsis, Exclusion criteria 
Removed “fish oil supplements (within 
30 days of planned dosing through end 
of follow-up).” 
Updated to reflect current understanding of 
drug-drug interactions with PRN1008 as there 
are no expected interactions with fish oil 
supplements. 
Synopsis, Study duration 
Added text to describe the duration of 
treatment expected for those patients 
who receive up to 6 cycles of
 and duration of the LTE 
Addition of LTE to study. 
Section 4.9.2, Allowed concomitant 
medication 
Text revised. 
Clarification. 
Section 5, Protocol Deviations 
Removed specific Principia contacts. 
The site is responsible to notify the CRA and 
CRO of the protocol deviations. The CRO is 
then responsible for notifying Principia. 
Section 6.1, Inclusion criteria 
Criterion 3: Updated text. 
Correction so text is consistency with 
inclusion criterion 3 in the synopsis. 
Section 8.2, Laboratory and ECG 
assessments 
Added text to specify that platelet 
antibody panel will not be done for 
patients in Australia. 
Platelet autoantibody panel cannot be 
completed on patients in Australia due to 
stability and shipment timelines. 
Section 10.7.3, Efficacy population 
ITT Population: Text revised to define 
an ITT population and to clarify that 
there is only 1 population, not different 
populations for each dose. 
Clarification. 
Section 10.9.3, Reconsenting of 
patients 
Text revised to add reconsent for 
additional treatment cycles of
 and entry into LTE. 
Addition of LTE to study design. 
Section 10.10, Efficacy and 
exploratory variables 
Added analysis of primary endpoint. 
Correction, previously missing. 
Section 11.5, Treatment and follow-
up of adverse events 
Updated to reflect the practice of 
following any AEs of Grade 3 or higher 
regardless of relationship to study drug. 
Clarification. 
Section 11.7.2, SAE reporting 
Updated text to reflect that SAE 
reporting is now done directly in the 
EDC system Medidata RAVE. If the 
Update to reflect new electronic reporting of 
SAEs of the party responsible to Principia 
Biopharma. 
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Section # and Name 
Description of Change 
Brief Rationale 
system in not available, a paper form 
can be sent directly to Principia 
Biopharma. 
Section 12.1, Assignment of 
preferred term and original 
terminology 
Updated text to specify that the SAP will 
contain information regarding the 
version of MedDRA and WHO used in 
the study. 
This is no longer specified in the protocol. 
Section 15.3, Patient premature 
withdrawal - definition 
Text revised to clarify that any patient 
who leaves the study before the 
planned of study visit is considered to 
be an early withdrawal. 
Clarification. 
In addition, other minor editorial changes (eg, grammatical, stylistic, and minor typographical 
error corrections) were implemented throughout the protocol. 
Amended protocol 8 (24 August 2018) 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis, Background and 
rationale; Section 1.2, Summary of 
PRN1008 clinical experience 
Updated to include safety data from N= 
27 PV patients and current numbers of 
healthy volunteers and patients treated. 
Updates to add new safety data. 
Synopsis, Study sites 
Revised “up to 15” to “approximately 25 
sites.” 
Updated to allow for a greater number of 
sites. 
Synopsis, Study Design 
Revised text.  
Updated to reflect the change in study drug 
treatment and post-treatment follow-up from 
12 weeks to 24 weeks, and 12 weeks to 
4 weeks respectively and to clarify the 
definition of a sustained platelet response. 
 
Revised Adaptive Cohort Dosing Table. 
Updated to reflect the change in study drug 
treatment from 12 weeks to 24 weeks, clarify 
the dose escalation rules after the first cycle 
and to clarify the definition of a sustained 
platelet response. 
Synopsis, Dose-limiting toxicity, 
dose escalation and stopping rules 
Revised dose-escalation rules, 
individual. 
Updated to clarify the dose escalation rules 
after the first cycle and to clarify the 
definition of a  sustained platelet response. 
 
Revised starting dose level by adding 
“sustained (3 or 4 counts).” 
Updated to clarify the definition of a 
sustained platelet response. 
 
Revised individual stopping rules. 
Updated to harmonize country specific 
requests into one protocol. 
Synopsis, Outcome measures 
Revised safety endpoints by replacing 
“12-week” with “post-treatment” follow-
up period. 
Updated to reflect the shorter post-treatment 
follow-up period. 
Synopsis, Planned number of 
participants and interim analysis. 
Revised “12” to “24” weeks of dosing. 
Updated to reflect the change in study drug 
treatment from 12 weeks to 24 weeks. 
Synopsis, Inclusion criteria 
Criterion 1: added aged 18 to 65 years 
old for Czech Republic only. 
Updated to reflect a Czech Republic only 
request (creation of a global protocol). 
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Section # and Name 
Description of Change 
Brief Rationale 
 
Criterion 5: Added text to specify that 
C1D1 pre dose may be checked up to 
Day -3 prior to C1D1. 
Updated to clarify that Inclusion Criteria lab 
values may be drawn up to 3 days before 
the Cycle 1 Day 1 enrollment visit. 
 
Revised criterion 6 (female 
contraception requirements); removed 
previous criterion 7 (male contraception 
requirements). 
Updated based to reflect data in IB Version 
9 regarding the reproductive toxicity data 
which support change in inclusion criteria 
with text conforming with current ICH 
guidance (Heads of Medicines Agencies 
Clinical Trial Facilitation Group [HMA CTFG] 
Recommendations Related to Contraception 
and Pregnancy Testing in Clinical Trials). 
Synopsis, Study assessments 
Revised end-of-study assessment 
approximately 28 (rather than 84) days 
after receiving final does of study drug. 
Updated to reflect the change in study drug 
treatment from 12 weeks to 24 weeks and of 
follow up for 12 weeks to 4 weeks. 
 
Clinical assessments: Text added to 
urinalysis assessment so specify by dip 
stick “or local regulations.” 
Updated to allow for urinalysis as measured 
by dipstick or through sites laboratory as  
sites local rules require. 
Synopsis, Safety assessments 
Revised text to specify that patients will 
remain under observation in the clinic 
for 6 hours (rather than 8) after 
administration of the first dose. 
Updated to remove the 8-hour post-dose PK 
timepoint as the timing exceeds an 8 hour 
day and places undue burden on 
participants.   
 
Revised text regarding sentinel patients. 
Updated to clarify the definition of a 
sustained platelet response. 
Synopsis, Study Duration 
Revised text to specify that study 
duration will be approximately 32 (rather 
than 28) weeks per subject. 
Updated to reflect the change in study drug 
treatment from 12 weeks to 24 weeks and of 
follow up for 12 weeks to 4 weeks. 
Section 2.1.1, Rationale for doses 
used and duration of study 
Revised text. 
Updated to describe the rationale for 
increasing treatment from 12 weeks to 
24 weeks. 
Section 2.2, Overall benefit risk 
assessment 
Efficacy text revised. 
Text revised with the new extension of 
treatment to 24 weeks. 
Section 3, Objectives and outcome 
measures of the study 
Added Section 3.5, Safety Endpoints; 
added Section 3.6, Primary Efficacy 
Endpoint. 
In addition to information in Section 10.0, the 
primary and secondary endpoints were 
added to the objectives Section 3.0. 
Section 5, Protocol deviations 
Updated contact details as appropriate. 
Administrative change. 
Section 10.2, Primary efficacy 
endpoint 
Text revised. 
Correction to match the wording of the 
primary endpoint in the Synopsis. 
Section 10.9.3, Reconsenting of 
subjects 
New section added. 
Added to confirm that subjects currently in 
the 12-week treatment period when the 
protocol is approved can reconsent to 
receive 24 weeks of treatment 
Section 10.11.2, Clinical Laboratory 
Tests 
Added text for clinical laboratory tests 
believed to be the i
i
 
Added per country-specific requirement. 
Section 10.11.3, Vital signs 
Replaced “abnormal” with “outside the 
normal range.” 
Clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 11.6, Adverse Events 
Intensity grading 
Revised text. 
Updated to clarify intensity grading scale if 
an event is not included in the Common 
Toxicity Criteria (CTCAE). 
Section 11.8, Pregnancy 
Removed text regarding pregnancy in 
the partner of a male clinical trial 
participant.  
Text is no longer relevant with new 
reproductive toxicity data as outlined in IB 
Version 9.0.   
In addition, other minor editorial changes (eg, grammatical, stylistic, and minor typographical 
error corrections) were implemented throughout the protocol.  
Amendment 7: (1 December 2017) 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis, Study objectives 
Deleted Idiopathic Thrombocytopenic 
Purpura Patient Assessment (ITP-PAQ) 
from the exploratory study objectives. 
The ITP-PAQ questionnaire is not available 
for licensing from Amgen. 
Section 6.2, Exclusion criteria 
Criteria reordered to be consistent with 
order in the Synopsis. 
Correction. 
Section 8.2, Laboratory and ECG 
assessments 
First bullet: Deleted “Serum pregnancy 
texts at screening, urine pregnancy 
tests at other visits.”  
Correction as the bullet is duplicate within the 
same section. 
Appendix 3, Schedule of 
assessments – weekly lab visit 
between clinic visits 
Added subscript 14 to this column. 
Clarification – footnote added to clarify when 
the weekly lab visits between in clinic visits 
are to take place. 
Appendix 3, Schedule of 
assessments – laboratory only visits 
Added subscript 1 to this line. 
Clarification to make it clear that footnote 
1 visit windows apply to this laboratory visit. 
Appendix 3, Schedule of 
assessments – pregnancy test 
Added pregnancy test assessment to 
the Early withdrawal/unscheduled visit. 
Clarification to allow for unscheduled 
pregnancy testing. 
Appendix 3, Schedule of 
assessments – platelet auto 
antibodies 
Removed platelet auto antibodies from 
Screening,
 text 
added to C1D1. 
Collection timepoints updated to reduce 
burden on subjects as the test requires 40 mL 
of blood per timepoint. 
In addition, other minor editorial changes (eg, grammatical, stylistic, and minor typographical 
error corrections) were implemented throughout the protocol.  
Amended protocols 1-6: (3 April 2017 - 7 July 2017) 
Protocol versions (versions 1.0 [2 Apr 17] through 5.0 [7 Jul 17]) were not submitted to sites. 
Thus, they are not detailed here.  
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17 
REFERENCES  
1. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. 
U.S. FDA [Internet]. 2023; Available from: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIn
teractionsLabeling/ucm093664.htm 
2. 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(2):346-50. 
3. Montillo M, O’Brien S, Tedeschi A, Byrd JC, Dearden C, Gill D, et al. Ibrutinib in 
previously treated chronic lymphocytic leukemia patients with autoimmune cytopenias in 
the RESONATE study. Blood Cancer J. 2017;7(2):e524. 
4. PRN1008 Investigator Brochure, Principia Biopharma. 
5. Clinical Study Report PRN1008-005, An open-label phase 2, pilot study investigating the 
safety, clinical activity, pharmacokinetics, and pharmacodynamics of oral treatment with 
the BTK inhibitor PRN1008 in patients with newly diagnosed or relapsing phemphigus 
vulgaris, Principia Biopharma, Inc., South San Fransisco, CA, 94080, USA, 2020. 
6. Bussel JB, Cheng G, Saleh MN, Psaila B, Kovaleva L, Meddeb B, et al. Eltrombopag for 
the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 
2007;357:2237-47. 
7. Kuter DJ, Boccia RV, Lee EJ, Efraim M, Tzvetkov N, Mayer J, et al. Safety and efficacy 
of rilzabruntinib (PRN1008), and oral Bruton tyrosine kinase inhibitor, in 
relapsed/refractory patients with primary or secondary immune thrombocytopenia: phase 
I/II adaptive study. European Hematology Association (EHA) annual meeting. (abstract 
S316). Poster presentation. 2020;4(S1):118-9. 
8. Podolanczuk A, Lazarus AH, Crow AR, Grossbard E, Bussel JB. Of mice and men: an 
open-label pilot study for treatment of immune thrombocytopenic purpura by an inhibitor 
of Syk. Blood. 2009;113:3154-60. 
9. Page LK, Psaila B, Provan D, Michael Hamilton J, Jenkins JM, Elish AS, et al. The 
immune thrombocytopenic purpura (ITP) bleeding score: assessment of bleeding in 
patients with ITP. Br J Haematol. 2007;138(2):245-8. 
10. Kuter DJ, Boccia RV, Lee EJ, Efraim M, Tzvetkov N, Mayer J, et al. Phase I/II, Open-
Label, Adaptive Study of Oral Tyrosine Inhibitor Patients With Relapsed/Refractory 
Primary or Secondary Immune Thrombocytopenia. 61st ASH Annual Meeting & 
Exposition, Abstract (presentation), Orlando, FL, 2019:134(S1):87. 
11. Kuter DJ, Efraim M, Mayer J, Trneny M, McDonald V, Bird RC, et al. Rilzabrutinib, an 
Oral BTK Inhibitor, in Immune Thrombocytopenia. NEJ of Medicine. 2022;386(15):1421-
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12. Cooper N, Jansen G, Bird R, Mayer J, Sholzberg M, Tarantino MD, et al. Initial Report of 
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Rilzabrutinib in Patients with Relapsed Immune Thrombocytopenia. Blood. 2023 Nov 
28;142(S1):685. 
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