Conditions: Huntington Disease
Keywords: Huntington Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 499
Healthy volunteers: no

Brief summary:
This study will evaluate the efficacy and safety of pridopidine 45mg twice daily (BID) in patients with early stage manifest Huntington Disease (HD).

Detailed description:
This is a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of pridopidine 45 mg BID in patients with early stage HD.

Arms:
arm 1: 45 mg pridopidine twice daily (BID) arm 2: Matching placebo

Interventions: intervention 1: Pridopidine intervention 2: Placebo
Intervention descriptions: intervention 1: Pridopidine hard gelatin capsule intervention 2: Pridopidine-matching placebo hard gelatin capsule

Protocol document:
Prot_000.pdf: 
Official Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel 
Arm, Multicenter Study Evaluating the Efficacy and Safety of Pridopidine in 
Participants with Early Stage of Huntington Disease 
NCT Number: NCT04556656 
Document Date: 10 November 2022 
 


Prilenia Therapeutics 
  
Study drug: Pridopidine 
Protocol Number: PL101-HD301 
 
CONFIDENTIAL 
1 
10 November 2022 
 
Version 7.0, Amendment 8 
CLINICAL STUDY PROTOCOL 
TITLE PAGE 
Protocol Title:  
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 
Parallel Arm, Multicenter Study Evaluating the Efficacy and 
Safety of Pridopidine in Patients with Early Stage of Huntington 
Disease 
Short Title: 
PRidopidine Outcome On Function in Huntington Disease 
(PROOF-HD) 
Protocol Number:  
PL101-HD301 
Compound Number 
(INN/Trademark):  
Pridopidine 
Study Phase:  
Phase 3 
Short Title  
Efficacy and Safety Study of Pridopidine in Huntington Disease 
Sponsor Name: 
Prilenia Therapeutics1 
Legal Registered Address: 
10 Hamenofim St. Herzliya, Israel 
Regulatory Agency 
Identifier Number(s): 
IND: 77419 
EudraCT: 2020-002822-10 
Sponsor Representative: 
 
Approval Date:  
10 November 2022 
Version: 
7.0, Amendment 8.0 
 
Confidentiality Notice 
This document contains confidential information of Prilenia Therapeutics1 the contents of which must not 
be disclosed to anyone other than the study staff and members of the respective Institutional Review 
Board/Ethics Committee. 
The information in this document cannot be used for any purpose other than the evaluation or conduct of 
the clinical investigation without the prior written consent of Prilenia Therapeutics. 
 
1 Applies to both Prilenia Therapeutics BV and Prilenia Neurotherapeutics Ltd. 
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Prilenia Therapeutics 
SPONSOR SIGNATURES 
CONFIDENTIAL 
2 
Study chug: Plidopidine 
Protocol Number: PL101-HD301 
18-Nov-22 
Date 
17-Nov-22 
Date 
10 November 2022 
Version 7.0, Amendment 8 


Prilenia Therapeutics 
  
Study drug: Pridopidine 
Protocol Number: PL101-HD301 
 
CONFIDENTIAL 
3 
10 November 2022 
 
Version 7.0, Amendment 8 
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
Protocol Title:  
A Phase 3, Randomized, Double-Blind, Placebo Controlled, 
Parallel Arm, Multicenter Study Evaluating the Efficacy and 
Safety of Pridopidine in Patients with Early Stage of Huntington 
Disease (PROOF-HD) 
Protocol Number:  
PL101-HD301 
Version and Date: 
7.0, 10 November 2022  
Amendment No.:  
8.0 
Regulatory Agency 
Identifier Number(s): 
IND: 77419 
EudraCT: 2020-002822-10 
I, the undersigned, have read this protocol and agree to personally supervise the conduct of this 
protocol in accordance with ethical principles as outlined in the International Council for 
Harmonisation (ICH) guidelines on Good Clinical Practice, any applicable laws and requirements 
(including Part 54: Financial Disclosure by Clinical Investigators) and any additional conditions 
mandated by a regulatory authority and/or Institutional Review Board/Independent Ethics 
Committee (IRB/IEC). 
I acknowledge that I am responsible for the overall study conduct; I approve of and will comply 
with all conditions, instructions and restrictions described in this protocol. I am aware that my 
adherence to the above protocol is mandatory and that any changes in the protocol or consent 
form, except those necessary to eliminate apparent immediate hazards to human subjects, must 
first be approved in writing by Prilenia Therapeutics and the respective IRB/IEC. 
I also agree that all information provided to me by the Sponsor, including this document, 
Investigator’s Brochure, case report form, and verbal and written information, will be kept strictly 
confidential and confined to the clinical personnel involved in conducting the study. It is 
recognized that this information may be related in confidence to the IRB/IEC. I also understand 
that reports of information about the study or its progress will not be provided to anyone not 
involved in the study other than to the Principal Investigator, or in confidence to the IRB/IEC or 
to the Food and Drug Administration (FDA) or other legally constituted authority. 
 
Site Principal Investigator Signature 
Date 
 
 
Printed Name 
Institution 
City, Country 
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Prilenia Therapeutics 
  
Study drug: Pridopidine 
Protocol Number: PL101-HD301 
 
CONFIDENTIAL 
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10 November 2022 
 
Version 7.0, Amendment 8 
COORDINATING INVESTIGATOR AGREEMENT 
Protocol Title:  
A Phase 3, Randomized, Double-Blind, Placebo Controlled, 
Parallel Arm, Multicenter Study Evaluating the Efficacy and 
Safety of Pridopidine in Patients with Early Stage of Huntington 
Disease (PROOF-HD) 
Protocol Number:  
PL101-HD301 
Version and Date: 
7.0,10 November 2022  
Amendment No.:  
8.0 
Regulatory Agency 
Identifier Number(s): 
IND: 77419 
EudraCT: 2020-002822-10 
As the coordinating Investigator, I have read this protocol and agree to personally supervise the 
conduct of this protocol in accordance with ethical principles as outlined in the International 
Council for Harmonisation (ICH) guidelines on Good Clinical Practice, any applicable laws and 
requirements (including Part 54: Financial Disclosure by Clinical Investigators) and any 
additional conditions mandated by a regulatory authority and/or Institutional Review 
Board/Independent Ethics Committee (IRB/IEC). 
I acknowledge that I am responsible for the overall study conduct; I approve of and will comply 
with all conditions, instructions and restrictions described in this protocol. I am aware that my 
adherence to the above protocol is mandatory and that any changes in the protocol or consent 
form, except those necessary to eliminate apparent immediate hazards to human subjects, must 
first be approved in writing by Prilenia Therapeutics and the respective IRB/IEC. 
I also agree that all information provided to me by the Sponsor, including this document, 
Investigator’s Brochure, case report form, and verbal and written information, will be kept strictly 
confidential and confined to the clinical personnel involved in conducting the study. It is 
recognized that this information may be related in confidence to the IRB/IEC. I also understand 
that reports of information about the study or its progress will not be provided to anyone not 
involved in the study other than to the Principal Investigator, or in confidence to the IRB/IEC or 
to the Food and Drug Administration (FDA) or other legally constituted authority. 
Coordinating Investigators Signatures 
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Prilenia Therapeutics 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
PROTOCOLAMENDMENTSUMMARYOFCHANGESTABLE 
DOCUMENT HISTORY 
Document 
Date 
Protocol V7 .0, Amendment 8 
10 November 2022 
Protocol V6.0, Amendment 7 
27 Januaiy 2022 
Protocol V5.0, Amendment 6 
13 May 2021 
Protocol V4.2, Amendment 5, France Countiy-
15 March 2021 
specific 
Protocol V4.1, Amendment 4, France Countiy-
15 Febrnaiy 2021 
specific 
Protocol V4, Amendment 3 
25 October 2020 
Protocol V3, Amendment 2 
29 September 2020 
Protocol V2, Amendment 1 
O1iginal Protocol Vl 
Amendment 8, 10 November 2022 
Overall Rationale for the Amendment: 
17 July 2020 
14 June 2020 
The Sponsor has introduced the following modifications to protocol V7.0; these changes are 
from V6.0 (Amendment 7) and are presented in order of appearance: 
Section # and Name 
1.1 Synopsis (Objectives 
and Endpoints) 
3 Objectives and Endpoints 
CONFIDENTIAL 
Description of Change 
• Hierai·chy of secondaiy endpoints 
changed (cUHDRS moved up to 
#1, propo1tion of pa1ticipants with 
improvement or no worsening in 
UHDRS-TFC moved to #2, TFC 
at Week 52 and 78 moved up to 
#3 and #4, Q-Motor lowered to 
#5, TMS lowered to #6) and 
change from Baseline to Week 65 
in SDMT added to #7 in the 
hierarchy 
5 
Brief Rationale 
• 
• Moved cUHDRS up in the 
hierarchy as it represents a global 
measure of HD progression 
including motor, function, and 
cognitive components 
• Moved Q-Motor above TMS to 
include an objective measure of 
motor function 
• Moved SDMT into multiplicity 
adjusted secondaiy endpoint in 
recognition of the impo1tance of 
cognition in HD 
10 November 2022 
Version 7.0, Amendment 8 


Prilenia Therapeutics 
  
Study drug: Pridopidine 
Protocol Number: PL101-HD301 
 
CONFIDENTIAL 
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10 November 2022 
 
Version 7.0, Amendment 8 
Section # and Name 
Description of Change 
Brief Rationale 
• TFC at Week 52 elevated in 
hierarchy to evaluate an earlier 
onset of response  
• TFC at Week 78 elevated in 
hierarchy to evaluate durability 
of response within the double-
blind period 
1.1 Synopsis (Objectives 
and Endpoints) 
3 Objectives and Endpoints 
• Change from Baseline to Week 26 
and 39 are added for some non-
multiplicity adjusted efficacy 
endpoints to better describe the 
change over time  
• Sub-scales for some efficacy 
endpoints as well as OLE and 
safety endpoints are clarified in 
endpoint section 
• Biomarker (NfL) endpoints are 
added to the OLE endpoints in 
Section 3 
• Pharmacodynamics assessments 
are not performed therefore 
removed from the protocol 
• Changes are made for clarity 
3.1.2 Primary Estimand  
 
• Estimand definitions are further 
elaborated   
• Additional details provided 
1.1 Synopsis (Overall 
Study Design) 
1.3.1 Schedule of Activities 
– Main Study 
4.1 Overall Design 
• Clarify timing of End of Study 
visit of the Main study 
• For clarity 
1.1 Synopsis (Study 
Duration) 
4.4 Study Duration 
4.5 End of Study Definition 
 
• Extending the OLE duration by 6 
months (to 12 months after the 
last participant completes the 
double-blind treatment period) 
• Ensuring pridopidine treatment 
continuity for participants  
6.1 Study Drug(s) 
Administered 
• Adding Patheon by Thermo 
Fisher Scientific as a 
manufacturer of pridopidine drug 
product 
• Adding a new manufacturing site 
for pridopidine drug product 
9 Statistical Considerations 
• Sensitivity analyses for 
multiplicity-adjusted secondary 
endpoints, the details of missing 
• To provide additional details  
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Study drug: Pridopidine 
Protocol Number: PL101-HD301 
 
CONFIDENTIAL 
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10 November 2022 
 
Version 7.0, Amendment 8 
Section # and Name 
Description of Change 
Brief Rationale 
data handling, and OLE analyses 
are added 
9.4.2 Analysis of Primary 
Endpoint 
• Only in-clinic UHDRS-TFC 
assessments will be used in the 
primary analysis and secondary 
analyses 
• To include only in clinic data as 
<2% of participants are missing 
in-clinic visits  
9.6 Safety Monitoring 
Committee 
• It was clarified that the SMC 
monitoring will only be 
performed during the double-
blind period of the Main Study 
• Clarification added 
General 
• Update version and date 
• Update table of contents 
• Update for consistency 
throughout protocol (including 
terminology) 
• Update cross reference / linking 
throughout 
• Minor corrections/updates 
throughout (punctuation, 
formatting, style, etc.) 
• For consistency and accuracy 
 
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Prilenia Therapeutics 
  
Study drug: Pridopidine 
Protocol Number: PL101-HD301 
 
CONFIDENTIAL 
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10 November 2022 
 
Version 7.0, Amendment 8 
TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
SPONSOR SIGNATURES ..............................................................................................................2 
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE ..........................................................3 
COORDINATING INVESTIGATOR AGREEMENT ...................................................................4 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................5 
1. 
PROTOCOL SUMMARY ..........................................................................................13 
1.1. 
Synopsis ......................................................................................................................13 
1.2. 
Study Scheme .............................................................................................................25 
1.3. 
Schedule of Activities (SoA) ......................................................................................27 
1.3.1. 
Schedule of Activities – Main Study – Double-blind, Placebo-Controlled................27 
1.3.2. 
Schedule of Activities – Open-label Extension (OLE) ...............................................32 
2. 
INTRODUCTION ......................................................................................................34 
2.1. 
Study Rationale ...........................................................................................................34 
2.2. 
Background .................................................................................................................37 
2.3. 
Benefit/Risk Assessment ............................................................................................37 
2.3.1. 
Risk Assessment .........................................................................................................38 
2.3.2. 
Benefit Assessment .....................................................................................................39 
2.3.3. 
Overall Benefit: Risk Conclusion ...............................................................................39 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................40 
3.1. 
Main Study Objectives, Endpoints and Primary Estimand ........................................40 
3.1.1. 
Main Study Objectives and Endpoints .......................................................................40 
3.1.2. 
Primary Estimand .......................................................................................................43 
3.2. 
OLE Objectives and Endpoints ..................................................................................44 
4. 
STUDY DESIGN .......................................................................................................47 
4.1. 
Overall Design ............................................................................................................47 
4.2. 
Scientific Rationale for Study Design ........................................................................48 
4.3. 
Justification for Dose ..................................................................................................48 
4.4. 
Study Duration ............................................................................................................49 
4.5. 
End of Study Definition ..............................................................................................49 
4.6. 
Coronavirus Disease 2019 (COVID-19) Mitigation Plan ..........................................49 
5. 
STUDY POPULATION .............................................................................................51 
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Study drug: Pridopidine 
Protocol Number: PL101-HD301 
 
CONFIDENTIAL 
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10 November 2022 
 
Version 7.0, Amendment 8 
5.1. 
Inclusion Criteria – Main Study .................................................................................51 
5.2. 
Inclusion Criteria – OLE ............................................................................................52 
5.3. 
Exclusion Criteria – Main Study ................................................................................52 
5.4. 
Screen Failures ............................................................................................................54 
6. 
STUDY DRUG ...........................................................................................................55 
6.1. 
Study Drug(s) Administered .......................................................................................55 
6.2. 
Handling Missed Doses ..............................................................................................56 
6.3. 
Preparation/Handling/Storage/Accountability ............................................................56 
6.4. 
Measures to Minimize Bias: Randomization and Blinding ........................................56 
6.5. 
Study Drug Compliance .............................................................................................57 
6.6. 
Dosing Regimen and Modifications ...........................................................................57 
6.7. 
Concomitant Therapy .................................................................................................57 
6.7.1. 
Permitted Medication ..................................................................................................58 
6.7.2. 
Prohibited Medication ................................................................................................58 
6.8. 
Treatment of Overdose ...............................................................................................58 
6.9. 
OLE .............................................................................................................................59 
7. 
DISCONTINUATION OF STUDY DRUG AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................60 
7.1. 
Individual Participant Stopping Rules from Study Drug ............................................60 
7.1.1. 
QT Stopping and Monitoring Rules ...........................................................................60 
7.1.2. 
Creatinine Clearance Stopping Rules .........................................................................60 
7.1.3. 
Psychiatric Stopping Rules .........................................................................................60 
7.1.4. 
Seizures .......................................................................................................................60 
7.1.5. 
Other Excluded Conditions during Study ...................................................................60 
7.1.6. 
Pregnancy ...................................................................................................................61 
7.2. 
Discontinuation of Study Drug ...................................................................................61 
7.3. 
Participant Withdrawal from the Study ......................................................................62 
7.4. 
Lost to Follow-up .......................................................................................................62 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................63 
8.1. 
Efficacy Assessments .................................................................................................63 
8.1.1. 
United Huntington Disease Rating Scale – Total Functional Capacity 
(UHDRS-TFC) ...........................................................................................................63 
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Study drug: Pridopidine 
Protocol Number: PL101-HD301 
 
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Version 7.0, Amendment 8 
8.1.2. 
United Huntington Disease Rating Scale – Total Motor Score (UHDRS-
TMS) ...........................................................................................................................64 
8.1.3. 
Quantitative Motor (Q-Motor) ....................................................................................64 
8.1.4. 
Clinical Global Impression .........................................................................................64 
8.1.4.1. 
Modified Clinical Global Impression of Severity (modified CGI-S) .........................64 
8.1.4.2. 
Clinical Global Impression - Change (CGI-C) ...........................................................65 
8.1.5. 
Exploratory Assessments ............................................................................................65 
8.1.5.1. 
Stroop Word Reading (SWR) .....................................................................................65 
8.1.5.2. 
Symbol Digit Modalities Test (SDMT) ...................................................................65 
8.1.5.3. 
Problem Behaviors Assessment – Short Form (including apathy sub-
item) ...........................................................................................................................66 
8.1.5.4. 
The Huntington Disease Quality of Life Questionnaire (HDQoL) .......................66 
8.2. 
Safety Assessments .....................................................................................................67 
8.2.1. 
Physical Examinations ................................................................................................67 
8.2.2. 
Vital Signs ..................................................................................................................67 
8.2.3. 
Electrocardiograms .....................................................................................................67 
8.2.4. 
Clinical Safety Laboratory Assessments ....................................................................68 
8.2.5. 
Suicidal Ideation and Behavior Risk Monitoring .......................................................68 
8.3. 
Adverse Events and Serious Adverse Events .............................................................69 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................69 
8.3.2. 
Method of Detecting AEs and SAEs ..........................................................................69 
8.3.3. 
Follow-up of AEs and SAEs .......................................................................................70 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...........................................................70 
8.3.5. 
Pregnancy ...................................................................................................................70 
8.3.6. 
Death Events ...............................................................................................................70 
8.4. 
Pharmacokinetics ........................................................................................................70 
8.5. 
Pharmacodynamic/Biomarkers ...................................................................................71 
8.6. 
Pharmacogenetics .......................................................................................................71 
9. 
STATISTICAL CONSIDERATIONS .......................................................................72 
9.1. 
Statistical Hypotheses .................................................................................................72 
9.2. 
Sample Size Determination ........................................................................................72 
9.3. 
Populations for Analyses ............................................................................................72 
9.3.1. 
Main Study..................................................................................................................73 
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Protocol Number: PL101-HD301 
 
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Version 7.0, Amendment 8 
9.3.2. 
OLE .............................................................................................................................74 
9.4. 
Statistical Analyses .....................................................................................................74 
9.4.1. 
General Considerations ...............................................................................................74 
9.4.2. 
Analysis of Primary Endpoint ....................................................................................74 
9.4.3. 
Analyses of Secondary Endpoints ..............................................................................76 
9.4.4. 
Exploratory Endpoints ................................................................................................77 
9.4.5. 
Safety Analyses ..........................................................................................................77 
9.4.6. 
OLE Analyses .............................................................................................................77 
9.4.7. 
PK Analysis ................................................................................................................78 
9.4.8. 
Biomarker (NfL) Analysis ..........................................................................................78 
9.5. 
Interim Analysis ..........................................................................................................78 
9.6. 
Safety Monitoring Committee ....................................................................................78 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................80 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................80 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................80 
10.1.2. 
Financial Disclosure ...................................................................................................80 
10.1.3. 
Informed Consent Process ..........................................................................................80 
10.1.4. 
Data Protection ...........................................................................................................81 
10.1.5. 
Dissemination of Clinical Study Data ........................................................................82 
10.1.6. 
Data Quality Assurance ..............................................................................................82 
10.1.7. 
Source Documents ......................................................................................................82 
10.1.8. 
Study and Site Start and Closure ................................................................................83 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................84 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting .........................................................................85 
10.3.1. 
Definition of AE .........................................................................................................85 
10.3.2. 
Definition of SAE .......................................................................................................86 
10.3.3. 
Definition of Suspected and Unsuspected Adverse Reaction .....................................87 
10.3.4. 
Recording and Follow-Up of AE and/or SAE ............................................................87 
10.3.5. 
Reporting of SAEs ......................................................................................................89 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................................91 
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Study drug: Pridopidine 
Protocol Number: PL101-HD301 
 
CONFIDENTIAL 
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10 November 2022 
 
Version 7.0, Amendment 8 
10.4.1. 
Definitions ..................................................................................................................91 
10.4.2. 
Contraception Guidance .............................................................................................91 
10.4.3. 
Collection of Pregnancy Information .........................................................................94 
10.5. 
Appendix 5: Genetics .................................................................................................95 
10.6. 
Appendix 6: Permitted Medications ...........................................................................96 
10.7. 
Appendix 7: Prohibited Medications and Substitution Alternatives ..........................98 
10.8. 
Appendix 8: ECG Monitoring Plan ..........................................................................100 
10.9. 
Appendix 9: QT Safety Data ....................................................................................102 
10.10. 
Appendix 10: Guidance to Address Global Health Emergencies and 
Potential Impact on the Clinical Study .....................................................................104 
10.11. 
Appendix 11: Abbreviations .....................................................................................110 
10.12. 
Appendix 12: Protocol Amendment History ............................................................113 
11. 
REFERENCES .........................................................................................................123 
 
LIST OF TABLES 
Table 1: 
Treatment Groups – Main Study ................................................................................23 
Table 2: 
Schedule of Activities – Main Study – Double-blind, Placebo-Controlled................27 
Table 3: 
Schedule of Activities – Open-label Extension ..........................................................32 
Table 4: 
UHDRS-TFC Annual Progression in Clinical Studies in HD Patients ......................36 
Table 5: 
UHDRS-TFC Progression in Clinical Studies >12 months ........................................36 
Table 6: 
Modified CGI-S Score ................................................................................................65 
Table 7: 
Protocol-Required Safety Laboratory Assessments ...................................................84 
Table 8: 
Study Visit Activities per Visit Type ........................................................................106 
 
LIST OF FIGURES 
Figure 1: 
Study Scheme – Main Study – Double-blind Placebo-controlled ..............................25 
Figure 2: 
Study Scheme – Open-label Extension .......................................................................26 
Figure 3: 
ECG Monitoring Flow ..............................................................................................101 
 
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Prilenia Therapeutics 
1. 
PROTOCOLSU1\1MARY 
1.1. 
Synopsis 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
Protocol Title: A Phase 3, Randomized, Double-Blind, Placebo-Contrnlled, Parallel Ann, 
Multicenter Study Evaluating the Efficacy and Safety of Pridopidine in Patients with Early Stage 
of Huntington Disease. 
Short Title: Pridopidine Outcome On Function in Huntington Disease (PROOF-HD) 
Rationale 
Huntington Disease (HD) is an autosomal dominant, progressive fatal neurodegenerative 
disorder characterized by motor, cognitive, and behavioral abnonnalities. While medications to 
treat chorea and some behavioral symptoms are available, no therapy has yet proven able to 
modify the progressive and inexorable functional decline of the disease. A therapy that maintains 
functional capacity and prevents or delays the development of disability represents a critically 
unmet clinical need. 
The pmpose of this Phase 3 study is to fmiher evaluate the effect of pridopidine 45 mg bid on 
functional capacity, as well as motor and behavioral features of HD in early-stage paiiicipants 
(TFC 7-13). 
CONFIDENTIAL 
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10 November 2022 
Version 7.0, Amendment 8 


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Prilenia Therapeutics 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
Objectives and Endpoints (Primary, Secondary and Safety) 
Main Stud 
Objectives 
Primaiy 
• To assess the effect of pridopidine on 
functional capacity in paiticipants with 
Stage 1-2 HD 
Multiplicity Adjusted Secondaiy Endpoints 
Endpoints 
• Change from Baseline to Week 65 in the 
UHDRS-TFC score 
Key Seconda1y (secondaiy endpoints ai·e listed by order ofhierai·chy) 
• To assess the effect of pridopidine on a 
composite measure of disease 
progression in participants with HD 
1. Change from Baseline to Week 65 in 
composite UHDRS ( cUHDRS) total 
score 
Seconda1y (secondaiy endpoints ai·e listed by order ofhierai·chy) 
• To evaluate the effect of pridopidine on 
functional capacity, motor function, 
cognition, and other measures of 
efficacy over time in paiticipants with 
HD 
CONFIDENTIAL 
14 
2. Propo11ion of paiiicipants with 
improvement or no worsening ( change 
from BaselineĆ 0 point) at Week 65 in 
UHDRS-TFC 
3. Change from Baseline to Week 52 in 
UHDRS-TFC score 
4. Change from Baseline to Week 78 in 
UHDRS-TFC score 
5. Change from Baseline to Week 65 in 
Quantitative motor (Q-Motor) 
6. Change from Baseline to Week 65 in 
UHDRS Total Motor Score (TMS) 
7. Change from Baseline to Week 65 in 
Symbol Digit Modalities Test (SDMT) 
8. Change from Baseline to Week 52 in 
UHDRS-TMS score 
9. Propo11ion of paiiicipants with 
im rovement or no worsenin in 
10 November 2022 
Version 7.0, Amendment 8 


Prilenia Therapeutics 
  
Study drug: Pridopidine 
Protocol Number: PL101-HD301 
 
CONFIDENTIAL 
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10 November 2022 
 
Version 7.0, Amendment 8 
Clinical Global Impression of Change 
(CGI-C) at Week 65 
Non-multiplicity Adjusted Secondary Endpoints 
• To evaluate the effects of pridopidine in 
participants with HD 
• Change from Baseline to Week 26 and 39 in 
the UHDRS-TFC  
• Proportion of participants with improvement 
or no worsening in UHDRS-TFC (change 
from Baseline ≥ 0) at Weeks 26, 39, 52 and 
78 
• Change from Baseline to Weeks 26, 39, 52 
and 78 in cUHDRS 
• Proportion of participants with change from 
Baseline ≥ -1 in cUHDRS at Weeks 26, 39, 
52, 65 and 78 
• Change from Baseline to Week 26, 39 and 
78 in the UHDRS-TMS score 
• Proportion of participants with improvement 
or no worsening in UHDRS-TMS (change 
from Baseline ≤ 0) at Weeks 26, 39, 52, 65 
and 78 
• Change from Baseline to Weeks 26, 39, 52, 
65 and 78 in: 
− UHDRS-TFC Scale sub-items 
(capacity to undertake domestic 
chores, activities of daily living, 
capacity to manage finances, care 
level and occupation) 
− UHDRS-TMS sub-scores for: 
o Gait and balance score (defined 
as the sum of UHDRS-TMS 
domains gait, tandem walking, 
and retropulsion pull test) 
o Eye movement 
o Dystonia 
• Change from Baseline to Weeks 26, 39, 52 
and 78 in SDMT 
• Change from Baseline to Weeks 26, 39, 52, 
65 and 78 in Stroop Word Reading (SWR) 
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Prilenia Therapeutics 
Safety and Tolerability 
• To evaluate the safety and tolerability of 
pridopidine in paiiicipants with HD 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
• 
Change from Baseline to Weeks 26, 39, 52 
and 78 in Q-Motor 
• Propo11ion of paiiicipants with improvement 
or no worsening ( change from Baseline :::: 0 
msec) in Q-Motor 
• 
Change from Baseline to Weeks 26, 39, 52, 
65 and 78 in Q-motor 
• 
Responder analyses on CGI-C using 
different thresholds at Weeks 26, 39, 52, 65 
and 78 
• Incidence ( count and rate) of adverse 
events (AEs) and serious AEs (SAEs) 
overall, by severity, by relationship to 
study diug, and those that led to 
discontinuation of study diug and/or 
withdi·awal from the study 
• Incidence and shifts of clinically 
significant abnonnalities in 
electrocardiogram (ECG)2, laborato1y tests, 
vital signs, and abno1malities in physical 
and neurological exam 
• Analysis of Columbia-Suicide Severity 
Rating Scale (C-SSRS) throughout the 
study 
• Tolerability: 
-
The number (%) of paiiicipants who 
complete the Treatment period 
-
The number (%) of paiiicipants who 
fail to complete the Treatment period 
due to AEs 
-
The number (%) of paiiicipants who 
fail to complete the Treatment period 
due to Fridericia-conected T 
2 QT Stopping Rules: QTcF >500 ms; QTcF >480 ms AND *QTcF >60 ms from baseline. 
QT Monitoring Rule: QTcF >480 ms OR *QTcF >60 ms from baseline. 
CONFIDENTIAL 
16 
10 November 2022 
Version 7.0, Amendment 8 


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Prilenia Therapeutics 
0 en-label Extension OLE 
Objectives 
Efficacy 
• To evaluate the long-tenn treatment 
effect of pridopidine in paiiicipants with 
HD who previously completed the Main 
Study 
Safety and Tolerability 
• To evaluate long-te1m safety and 
tolerability of pridopidine in 
CONFIDENTIAL 
17 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
inte1val (QTcF) change, Creatinine 
Clearance (CrCl) or Psychiatric 
Stopping Rules 
Endpoints 
• Propo1iion of paiiicipants with change 
from Baseline (Main Study) to each OLE 
visit in UHDRS-TFC -1 
• Propo1iion of paiiicipants with change 
from Baseline (Main Study) to each OLE 
visit in UHDRS-TFC Ć 0 
• Change from Baseline (Main Study) to 
OLE visits in: 
-
UHDRS-TFC 
-
cUHDRS 
-
UHDRS-TMS 
-
Quantitative motor (Q-Motor): 
I 
I 
-
SDMT 
-
SWR 
• Change from Baseline (Main Study) to 
OLE visits in: 
-
CGI-C 
-
PBA-s 
-
Huntington Disease Quality of Life 
Questionnaire (HDQoL) 
• Incidence ( count and rate) of AEs and 
SAEs overall, by severity, by relationship 
to stud drn , and those that led to 
10 November 2022 
Version 7.0, Amendment 8 


Prilenia Therapeutics 
  
Study drug: Pridopidine 
Protocol Number: PL101-HD301 
 
CONFIDENTIAL 
18 
10 November 2022 
 
Version 7.0, Amendment 8 
participants with HD who previously 
completed the Main Study 
discontinuation of study drug and/or 
withdrawal from the study  
• Incidence and shifts of clinically significant 
abnormalities in ECG (refer to 
Section 7.1.1), laboratory tests and vital 
signs 
• Analysis of C-SSRS throughout the study 
• Tolerability: 
− The number (%) of participants who 
complete the OLE treatment period 
− The number (%) of participants who 
fail to complete the OLE treatment 
period due to AEs 
Inclusion/Exclusion Criteria 
Inclusion Criteria – Main Study: 
1. Twenty-five years of age (inclusive) and older, at the time of signing the informed 
consent. 
2. Diagnosis of HD based on clinical features and the presence of ≥36 cytosine-adenine-
guanine (CAG) repeats in the huntingtin gene (HTT), confirmed by historical 
laboratory quantified results or by a diagnostic test at Screening. 
3. Diagnostic confidence level (DCL) of 4 (unequivocal motor signs, ≥ 99% confidence) 
on the standardized motor exam UHDRS-TMS. 
4. Adult-onset HD with onset of signs and symptoms ≥18 years of age. 
5. Stage 1 or Stage 2 HD, defined as a UHDRS-TFC score of ≥7, at Screening. 
6. UHDRS-Independence Scale (IS) score ≤90% at Screening. 
7. UHDRS-TMS ≥20 at Screening. 
8. Must meet all criteria required to move forward with the Randomization 
Authorization Flow (RAF) and be considered eligible by the RAF Reviewer. 
9. Male or female. 
10. Female participants of childbearing potential must have a negative β-human chorionic 
gonadotropin (β-HCG) test at Screening and Baseline, be sterile, or be 
postmenopausal. 
11. Female participants of childbearing potential whose male partners are potentially 
fertile (e.g., no vasectomy) must use highly effective birth control methods stable for 
at least 3 months prior to screening, for the duration of the study and for 30 days after 
discontinuation of the study drug. 
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Prilenia Therapeutics 
  
Study drug: Pridopidine 
Protocol Number: PL101-HD301 
 
CONFIDENTIAL 
19 
10 November 2022 
 
Version 7.0, Amendment 8 
12. Male participants must be sterile, or if they are potentially fertile/reproductively 
competent ((not surgically (e.g., vasectomy) or congenitally sterile)) and their female 
partners are of childbearing potential, they must use, together with their female 
partners, effective birth control methods for the duration of the study and for 90 days 
after study drug discontinuation. 
13. For participants taking allowed antipsychotic, antidepressant, or other psychotropic 
medication, the dosing of medication must be stable for at least 4 weeks before the 
Baseline visit and throughout the study (unless clinically necessary to change). 
14. For participants taking allowed concomitant medications, dosing of medications must 
be stable for a t least 4 weeks prior to the Baseline visit (note: Amiodarone is not 
allowed within 6 weeks of Baseline visit). 
15. Capable of providing signed informed consent. 
Inclusion criteria – OLE 
1. Completed the End of Study (EoS) visit of the Main Study on treatment without 
important protocol deviations impacting efficacy and safety assessments. 
2. Capable and willing to provide signed informed consent for the OLE. 
3. Must meet all criteria required to move forward with the OLE assessments. 
Exclusion Criteria – Main Study 
1. Prolonged QTcF interval (defined as a QTcF interval of >450 ms for male and 
>470 ms for female) at Screening3. 
2. Clinically significant heart disease within 12 weeks before randomization, defined as 
follows: 
a. Participants with clinically significant heart disease, a clinically significant 
history of arrhythmia, symptomatic or uncontrolled atrial fibrillation despite 
treatment, or confirmed ventricular tachycardia2, or presence of left bundle 
branch block 
b. Participants with a known history of congenital long QT syndrome or a first-
degree relative with this condition 
c. Clinically significant bradycardia, sick sinus syndrome, complete 
atrioventricular block, congestive heart failure, polymorphic ventricular 
tachycardia, clinically relevant hypocalcemia, hypokalemia or 
hypomagnesemia 
4. History of epilepsy or seizures within the last 5 years. 
5. Serious medical illness includes, but not limited to, uncontrolled hypertension; 
respiratory disease, including severe forms of asthma; severe hepatic disease 
(confirmed Hepatitis B virus [HBV], Hepatitis C virus [HCV]; confirmed human 
 
3 If there is evidence of a prolonged QTcF interval at screening from the initial (single) administration, then the ECG 
will be repeated twice, and the mean of the 3 screening administrations will be used to determine whether or not the 
participant is suitable for inclusion in the study. 
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Prilenia Therapeutics 
  
Study drug: Pridopidine 
Protocol Number: PL101-HD301 
 
CONFIDENTIAL 
20 
10 November 2022 
 
Version 7.0, Amendment 8 
immunodeficiency virus [HIV]); renal disease; acquired immune deficiency 
syndrome; and unstable psychiatric or other neurologic disorders) and metastatic 
cancer. 
For serious kidney and liver illnesses see also exclusion criterion 12 (laboratory test 
abnormalities). 
6. Known intracranial neoplasms, vascular malformations, history of cerebrovascular 
accident, or intracranial hemorrhage. 
7. Female participants who are pregnant, planning to become pregnant or breastfeeding. 
8. Medications that prolong QT interval, taken within 4 weeks of the Baseline visit 
(note, Amiodarone is not allowed within 6 weeks of the Baseline visit) or at any 
timepoint during the study, including non-allowed antipsychotic medications, 
tricyclic antidepressants, and/or Class I antiarrhythmics. 
9. Use of pridopidine within 12 months before the Baseline visit. 
10. Treatment with any investigational product within 6 weeks or 5 half-lives (whichever 
is longer) before the Screening visit or a plan to participate in another clinical study 
that assesses any investigational product during the study. 
11. Gene therapy at any time. 
12. Prior participation in studies with tominersen at any time. 
13. Laboratory values that fall outside of the central laboratory’s reference range at 
Screening and are considered clinically significantly abnormal by the Investigator, 
and affect the participant’s suitability to participate in the study or put the participant 
at risk if he/she enters the study in the Investigator’s opinion4. 
14. Have any of the following laboratory test abnormalities at Screening: 
a. Creatinine clearance (CrCl) <30 mL/min at Screening, calculated using the 
Cockcroft-Gault equation: (140–age) × mass (kg) × [0.85 if female] / 72 × serum 
creatinine (mg/dL)5 
b. Aspartate aminotransferase (AST) ≥2.5 × upper limit of normal (ULN) 
c. Alanine aminotransferase (ALT) ≥2.5 × ULN 
d. Gamma glutamyl transferase (GGT) ≥3.0 × ULN 
e. Total bilirubin >1.5 mg/dL, except participants with unconjugated 
hyperbilirubinemia without other liver function derangements or other 
explanations for the elevated bilirubin (consistent with diagnosis of Gilbert’s 
syndrome)  
15. Alcohol and/or substance use disorder within the 6 months prior to screening, as 
defined by the Diagnostic and Statistical Manual–Fifth Edition (DSM-5) Text 
Revision criteria for substance use. 
 
4 Repeat testing is allowed (up to a maximum of 3 tests) if required to establish whether values are within the normal 
range or clinically significantly abnormal. 
5 It is allowed to repeat the test once, if clinically appropriate. 
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Prilenia Therapeutics 
  
Study drug: Pridopidine 
Protocol Number: PL101-HD301 
 
CONFIDENTIAL 
21 
10 November 2022 
 
Version 7.0, Amendment 8 
16. Active suicidal ideation as measured by a most severe suicide ideation score of 4 
(Active Suicidal Ideation with Some Intent to Act, without Specific Plan) or 5 (Active 
Suicidal Ideation with Specific Plan and Intent) on the C-SSRS if the ideation 
occurred within 1 year of Screening, or participants who answered “Yes” on any of 
the 5 C-SSRS Suicidal Behavior Items (actual attempt, interrupted attempt, aborted 
attempt, preparatory acts, or behavior), if the attempt or acts were performed within 1 
year of Screening, or participants who, in the opinion of the Investigator, present a 
serious risk of suicide. 
17. Known allergy to any ingredient of the study drug (pridopidine, silicified 
microcrystalline cellulose, or magnesium stearate). 
18. Vulnerable participant (e.g., people kept in detention), or participant unfit to 
participate in a clinical study due to living circumstances (e.g., without sufficient 
family or social support, stable residence, sustainable financial and general healthcare 
and resources). 
19. An employee or a family member of an employee of the Sponsor, Investigator or 
Investigator study site, or otherwise dependent on the Sponsor, the Investigator or the 
Investigator study site. 
Overall Design 
This is a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety 
of pridopidine administered orally at a dose of 45 mg bid in participants with early HD defined 
as Stages 1 and 2 (based on Shoulson and Fahn (Shoulson, 1979)). The study will be conducted 
at approximately 60 sites in North America and Europe. 
The study will consist of a Screening period, a double-blind Treatment period (Main Study), and 
an optional OLE as described below. 
After signing informed consent, participants will undergo screening assessments to determine 
eligibility over a Screening period of up to 6 weeks6. 
The Screening period will be followed by a 65- to 78-week double-blind Treatment period, 
composed of a 2-week Titration period, a 63-week double-blind full-dose Maintenance 
Treatment period followed by a variable double-blind Treatment period of up to 13 weeks (total 
of up to 78 weeks; Main Study). 
On Day 1 (Baseline visit), eligible participants will be randomized in a 1:1 ratio to active 
(pridopidine 45 mg bid) or control (placebo) arm as shown in Table 1. Randomization will be 
stratified by Baseline HD stage (HD1 vs. HD2) and baseline Neuroleptic use (Yes/No). 
Starting on Day 1, during the Titration period, all participants will self-administer 1 capsule of 
study drug orally (PO), once daily (QD), in the morning for 2 weeks. Thereafter, the study drug 
will be taken PO bid in the morning and in the afternoon (7-10 hours apart) for 63 weeks 
(double-blind full-dose Maintenance Treatment period). Participants who complete the 
Maintenance period (63 weeks) will continue into a variable double-blind period of up to 13 
 
6 If there is no need for genetic tests or washout from prohibited medication, the screening period should be 
completed within 3 weeks. 
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Prilenia Therapeutics 
  
Study drug: Pridopidine 
Protocol Number: PL101-HD301 
 
CONFIDENTIAL 
22 
10 November 2022 
 
Version 7.0, Amendment 8 
weeks or until the last participant randomized completes 65 weeks of treatment (2-weeks 
Titration + 63-weeks full- dose), whichever comes first. Most participants will be followed for 
78 weeks. Participants entering the study within 90 days of the last randomized participant will 
be followed between 65 and 78 weeks. As soon as the last participant reaches Week 65, the Main 
study EoS visit for all remaining participants who are between Week 65 and Week 78 needs to 
be conducted within 4 weeks. 
For participants who complete their Week 65 visit within 4 weeks of the last participant 
completing Week 65, the Week 65 visit will be considered the EoS Visit. For participants who 
are beyond 4 weeks from their Week 65 visit when the last participant reaches Week 65, and 
have not had a Week 78 visit, the EoS visit will be conducted within 4 weeks.  
The double-blinding will be maintained for all participants and Investigators until that time.  
For each participant, the last visit will be the Main Study EoS visit scheduled between Week 65 
and Week 78, if the participant completes all study visits, or Early Termination (ET) visit if the 
participant withdraws from the study before Week 65 or Week 78, respectively. 
Eligible participants who complete the Main Study, 65- or 78-week double-blind Treatment 
period, will have the option to enroll into an OLE period, commencing at the Main Study EoS 
visit, and receive pridopidine. The OLE will consist of a 2-week Titration period and a 
Maintenance period. During the Titration period, participants will self-administer 1 capsule of 
pridopidine 45 mg PO, QD, in the morning, for 2 weeks. Thereafter, pridopidine will be taken 
PO, bid in the morning and in the afternoon (7-10 hours apart). 
Participants who are not continuing to the OLE study will be contacted by phone for a safety 
evaluation 2 weeks after the Main Study EoS/ET visit. AEs will be monitored for these 2 weeks 
until the safety telephone contact. 
Throughout the study, participants will be assessed through on-site clinic visits, virtual visits (via 
telephone), and safety telephone calls (TCs), as specified in the corresponding Schedule of 
Activities (SoA) (Table 2 – Main Study, and Table 3 – OLE) and study schema (Figure 1 – Main 
Study, and Figure 2 – OLE). 
During the double-blind Treatment period of the Main Study, an independent Safety Monitoring 
Committee will oversee the safety and tolerability based on participants’ data accrued in the 
electronic data capture (EDC) system, based on an ongoing review of SAEs and periodical 
review of the accumulating safety data. 
Disclosure Statement: The Main Study is a parallel-group treatment study with 2 arms that is 
participant- and Investigator-blinded. 
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Prilenia Therapeutics 
  
Study drug: Pridopidine 
Protocol Number: PL101-HD301 
 
CONFIDENTIAL 
23 
10 November 2022 
 
Version 7.0, Amendment 8 
Number of Participants and Treatment Groups 
Main Study 
Table 1: 
Treatment Groups – Main Study 
Treatment 
Dose and dose regimen 
Number of 
participants 
Titration Period  
(2 weeks) 
Maintenance Period 
(65 to 78 weeks) 
Active – pridopidine 
45 mg capsule PO, QD 
45 mg capsule PO, bid  
(total daily dose of 90 mg) 
240 
Control – matching 
placebo 
Capsule, PO, QD 
Capsule, PO, bid 
240 
Abbreviations: twice daily (bid); oral (PO); once daily (QD) 
OLE 
Pridopidine, 45 mg capsule PO, QD will be taken for the first 2 weeks (Titration period), 
followed by 45 mg capsule PO, bid (total daily dose of 90 mg, Full-dose period). The number of 
participants is to be determined, depending on the number of eligible participants. 
Study Duration 
The Main Study is expected to be conducted from Q3 2020 until Q1 2023. Participant 
recruitment period is planned from Q3 2020 until approximately Q4 2021 (end date can vary 
based on actual study performance and enrollment status). 
For each participant, the total duration of study participation in the Main Study (Screening and 
Double–blind period) will be up to 86 weeks. 
Main Study: 
 
Screening period: 
Up to 6 weeks 
Double-Blind Treatment 
period: 
Up to 78 weeks as follows: 
• 2 weeks Titration period 
• 63 weeks full-dose treatment 
• Up to 13 weeks variable double-blind period (until the 
last randomized participant completes 65 weeks of 
treatment = 2 weeks Titration + 63 weeks full-dose) 
Follow-up period: 
2 weeks (only for participants not continuing to OLE) 
OLE: 
• 2 weeks Titration period 
• Full dose treatment until 12 months after the last 
participant completes the double-blind Treatment 
period  
• OLE duration may be further extended pending 
emerging data from the double-blind portion of the 
study  
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Prilenia Therapeutics 
  
Study drug: Pridopidine 
Protocol Number: PL101-HD301 
 
CONFIDENTIAL 
24 
10 November 2022 
 
Version 7.0, Amendment 8 
Safety Monitoring Committee: Yes 
Coronavirus Disease 2019 (COVID-19) Mitigation Plan 
Proactive mitigation measures to ensure participants’ safety and study integrity during 
COVID-19 pandemic (or any Public Health Emergency) are included in this study. Four virtual 
visits are incorporated into the protocol to ensure participant safety and minimize the risk of 
missing data. In addition, every in-clinic visit, except Screening, Baseline and Week 65 visits, 
can be converted to a virtual visit if this will be required. 
Some of the efficacy and safety measures can be carried out by remote assessments, if required. 
Raters will be trained and ready to implement these remote safety and efficacy measures. Home 
visits by health care professionals for safety assessments may be conducted if in-clinic visits will 
not be possible (including safety laboratories, vital signs, and ECG administration). Drug 
accountability will also be conducted at home visits by health care professionals. 
 
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Prilenia Therapeutics 
  
Study drug: Pridopidine 
Protocol Number: PL101-HD301 
 
CONFIDENTIAL 
25 
10 November 2022 
 
Version 7.0, Amendment 8 
1.2. 
Study Scheme 
Figure 1: 
Study Scheme – Main Study – Double-blind Placebo-controlled 
 
Abbreviations: twice daily (bid); Baseline (BL); End of Study (EoS); Early Termination (ET); once daily (QD); Visit (V); Virtual Visit (VV); Week (W); Total Daily Dose 
(TDD). 
* For each participant, the last treatment visit will be the EoS at either Week 65 or Week 78 if the participant completes all study visits; or Early Termination (ET) visit if the 
participant withdraws from the study before Week 65. 
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Prilenia Therapeutics 
  
Study drug: Pridopidine 
Protocol Number: PL101-HD301 
 
CONFIDENTIAL 
26 
10 November 2022 
 
Version 7.0, Amendment 8 
 
Figure 2: 
Study Scheme – Open-label Extension 
 
 
Abbreviations: End of Study (EoS); EarlyTermination (ET); Open-label Extension (OLE); Visit (V); Week (Wk). 
 
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Prilenia Therapeutics 
1.3. 
1.3.1. 
Schedule of Activities (SoA) 
Schedule of Activities - Main Study - Double-blind, Placebo-Controlled 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
General note: eve1y clinic visit, except Screening VI, Baseline V2, and V7 can be conve1ied to viiiual visits 01V) (e.g., via telephone). Refer to 
Appendix 10 (Section 10.10) for guidance. 
Table 2: 
Schedule of Activities - Main Study - Double-blind, Placebo-Controlled 
Study Pe1iod 
Screening• 
Double-blind 
Double-blind, Placebo-controlled, Full-dose Maintenance Treatment 
Double-blind 
Follow-up 
Procedures and 
Titration 
Assessments 
Pe1iod 
Study Clinic Visit 
Vl 
V2 
V3 
V4 
BLd 
Vfrtual Visit (VV) 
VVl 
vv 
BL 
2 
Telephone Call Safety 
 
 
 
Visit 
Study Week 
Dayl 
2 
4 
8 
13 
19 
26 
Visit Windows (days) 
<42 
<7 
±5 
±5 ±14 ±14 ±14h 
Infonued consent 
X (Main Study) 
Check willingness to 
enter OLE 
Demography 
X 
Medical and psychiatric 
X 
histo1y (including 
smoking) 
Prior medication and 
X 
treatment histo1y 
Inclusion and exclusion 
Xi 
criteria 
CONFIDENTIAL 
27 
Peliod 
vs 
V6 
VV3 
vv 
4 
 
32 
39 
45 
52 
58 
±14 
±14h 
±14 
±14h ±14 
Variable Periodb 
Safety 
Assessment< 
v1• 
vs (Main 
F/U 
Study Eos•, r 
/ET') 
 
 
65 
72 
78 
80 (2 weeks afte1· 
Main Study 
EoS/ET) 
±14h 
±14 
±14h 
±5 
X 
X(OLE) if 
(OLE) 
not obtained 
atV7 
Xi 
IO November 2022 
Version 7.0, Amendment 8 


DocuSign Envelope ID: 79A0F46O-86E9-4200-BCF E -5435260803CF 
Prilenia Therapeutics 
Study Pe1iod 
Screening• 
Double-blind 
Procedures and 
Titration 
Assessments 
Pe1iod 
Study Clinic Visit 
Vl 
V2 
BLd 
Vfrtual Visit (VV) 
VVl 
BL 
Telephone Call Safety 
v 
Visit 
Study Week 
Dayl 
2 
Visit Windows (days) 
<42 
<7 
Clinical lab tests ( serum 
X 
X 
chemistry, hematology 
and urinalysis)1' 
Pregnancy test (for 
Semm 
Urine 
WOCBP)1 
(U) 
Full physical and 
X 
X 
neurological 
examination 
Brief physical 
examination 
12 leadECG 
xm 
xn.o 
Vital signs' 
X 
X 
C-SSRS (Baseline 
X 
version) 
C-S SRS ( since last visit 
X 
version) 
UHDRS-TFC 
X 
X 
X 
UHDRS-TMS 
X 
X 
UHDRS-IS 
X 
CONFIDENTIAL 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
Double-blind, Placebo-controlled, Full-dose Maintenance Treatment 
Double-blind 
Follow-up 
V3 
vv 
2 
v 
v 
4 
8 
13 
19 
±5 
±5 ±14 ±14 
X 
u 
X 
xo 
X 
X 
X 
X 
X 
28 
Peliod 
Variable Periodb 
Safety 
Assessment< 
V4 
vs 
V6 
v1• 
vs (Main 
F/U 
Study Eos•, r 
/ET') 
VV3 
vv 
4 
v 
v 
v 
26 
32 
39 
45 
52 
58 
65 
72 
78 
80 (2 weeks afte1· 
Main Study 
EoS/ET) 
±14h 
±14 
±14h 
±14 
±14h ±14 
±14h 
±14 
±14h 
±5 
X 
X 
X 
X 
X 
u 
u 
u 
u 
u 
Monthly urine pregnancy tests (at home) 
X 
X 
X 
xP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
xP 
XJl,4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IO November 2022 
Version 7.0, Amendment 8 
X 


DocuSign Envelope ID: 79A0F46O-86E9-4200-BCF E -5435260803CF 
Prilenia Therapeutics 
Study Pe1iod 
Screening• 
Double-blind 
Procedures and 
Titration 
Assessments 
Pe1iod 
Study Clinic Visit 
Vl 
V2 
BLd 
Vfrtual Visit (VV) 
VVl 
BL 
Telephone Call Safety 
J 
Visit 
Study Week 
Dayl 
2 
Visit Windows (days) 
<42 
<7 
SDMT 
X 
SWR 
X 
Q-Motor 
x• 
X 
PBA-S (Sho,t Fonu) 
X 
X 
CGI-S (modified) 
X 
X 
CGI-C 
HDQoL-P 
X 
Benzodiazepines and 
X 
X 
X 
X 
antidepressants inquiry' 
Alcohol/illicit drug use 
X 
X 
X 
X 
inqui.ty 
Review of tolerability to 
X 
study drug prior to dose 
escalation 
Randomization 
X 
Dispense/collect study 
X 
dmg 
(dispen 
se 
only) 
Review study 
X 
compliance and 
adherence 
CONFIDENTIAL 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
Double-blind, Placebo-controlled, Full-dose Maintenance Treatment 
Double-blind 
Follow-up 
Peliod 
V3 
V4 
vs 
vv 
VV3 
2 
J 
J 
J 
4 
8 
13 
19 
26 
32 
39 
45 
±5 
±5 ±14 ±14 ±14h 
±14 
±14h 
±14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
29 
V6 
vv 
4 
52 
58 
±14h ±14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Variable Periodb 
Safety 
Assessment< 
v1• 
vs (Main 
F/U 
Study Eos•, r 
/ET') 
J 
J 
65 
72 
78 
80 (2 weeks afte1· 
Main Study 
EoS/ET) 
±14h 
±14 
±14h 
±5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IO November 2022 
Version 7.0, Amendment 8 


DocuSign Envelope ID: 79A0F46O-86E9-4200-BCF E -5435260803CF 
Prilenia Therapeutics 
Study Pe1iod 
Procedures and 
Assessments 
Study Clinic Visit 
Vfrtual Visit (VV) 
Telephone Call Safety 
Visit 
Study Week 
Visit Windows (days) 
Study drug 
administration 
Adverse event inquiry 
Concomitant medication 
inquiiy 
Blood samples for PK 
analysis u 
Plasma sample for 
biomarkers analysisv 
Blood sample for genetic 
analysis v,x 
Blood sample for CAG 
repeat analysis v,y 
Screening• 
Vl 
VVl 
BL 
<42 
<7 
X 
X 
X 
X 
xw 
xw 
X 
Double-blind 
Titration 
Pe1iod 
V2 
BLd 
Þ 
Dayl 
2 
< 
X 
X 
X 
X 
xw 
xw 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
Double-blind, Placebo-controlled, Full-dose Maintenance Treatment 
Double-blind 
Follow-up 
Peliod 
Variable Periodb 
Safety 
Assessment< 
V3 
V4 
vs 
V6 
v1• 
vs (Main 
F/U 
Study Eos•, r 
/ET') 
vv 
VV3 
vv 
2 
4 
Þ 
Þ 
Þ 
Þ 
Þ 
4 
8 
13 
19 
26 
32 
39 
45 
52 
58 
65 
72 
78 
80 (2 weeks afte1· 
Main Study 
EoS/ET) 
±5 
±5 
±14 ±14 ±14h 
±14 
±14h 
±14 
±14h ±14 
±14h 
±14 
±14h 
±5 
X 
> 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: Baseline (BL); cytosine-adenosine-guanine (CAG); Clinical Global Impression of Change (CGI-C); Clinical Global Impression of Severity (CGI-S); Columbia-Suicide Severity 
Rating Scale (C-SSRS); electrocardiogram (ECG); End of Study (EoS); Early Tennination (ET); Follow-Up (F/U); Huntington Disease Quality of L ife Questionnaii·e-Participant (HDQoL -P); 
Independence Scale (IS); Problem Behaviors Assessment - Sho1t Fo1m (PBA-s); pha1macokinetic (PK); Quantitative motor (Q-Motor); Symbol Digit Modalities Test (SDMT); Stroop Word 
Reading (SWR); Total Functional Capacity (TFC); Total Motor Score (TMS); Unified Huntington Disease Rating Scale (UHDRS); Visit (V); Virtual Visit (VV); women of childbearing potential 
(WOCBP). 
Table Footnotes: 
a. A pa1ticipant not meeting all eligibility requirements may be rescreened only once. Screening assessments may be repeated during the screening period if approved and at the discretion of 
the study Medical Monitor (or designee). After the screening period all screening assessments must be repeated except for Cytosine Adenine Guanine (CAG) repeat (provided the results are 
available from a prior screening period). 
CONFIDENTIAL 
30 
IO November 2022 
Version 7.0, Amendment 8 


Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301 
 
CONFIDENTIAL 
31 
10 November 2022 
 
Version 7.0, Amendment 8 
b. This period is variable in duration up to 13 weeks. Participants will continue to receive treatment during the double-blind variable period until they reach Week 78 or until the last participant 
randomized completes 65 weeks of treatment (2 weeks titration + 63 weeks full-dose), whichever comes first. As soon as the last participant reaches Week 65, the Main Study EoS visit for 
all remaining participants who are 4 weeks beyond their respective Week 65 visit needs to be conducted within 4 weeks. 
c. Follow-up visit in Main Study is only applicable to participants who are not continuing to Open-label Extension. 
d. All Baseline assessments should be done pre-dose, except post-dose ECG. 
e 
For the last group of participants whose Week 65 visit is within 4 weeks of last participant’s Week 65 visit in the Main Study, the End of Study visit will be V7. 
f. After completing the Main Study EoS visit, eligible participants will have the option to continue for an Open-label Extension. 
g. When a participant discontinues study drug but continues to be followed in the study, they should first do ET visit and then continue with the follow-up off study treatment as scheduled.  
h. Visit window can be expanded any post Week 4 (V3) in-clinic visit window to ±28 days; this applies to V4-8). The expansion of the in-clinic visit window is only in case of a global 
pandemic. 
i. To be done once, as early as Main Study Week 58, or at V7 (Main Study Week 65)/Main Study Week 72 (depending on when the participant is anticipated to transition to OLE). 
j. Inclusion/exclusion criteria should be met before Baseline visit. 
k. Safety laboratories should not be collected for participants who are off drug and remain in the study, unless there are abnormalities requiring follow-up. 
l. Serum pregnancy test will be performed at Screening. At Baseline visit, urine pregnancy test will be performed before first dose. Both test results must be known before first dosing. Urine 
pregnancy test will be performed at subsequent timepoints. An indeterminate or positive reading for the urine pregnancy test should be followed-up by a serum pregnancy test and the 
participant should be referred to a gynecologist if required. During the Treatment period, urine pregnancy tests will be performed monthly. Refer to Appendix 4 Section 10.4. 
m. Single ECG to assess eligibility. 
n. Baseline pre-dose assessment will include triplicate ECG administrations. 
o. Single ECG 1-2 hours post-dose. 
p. Single ECG pre-dose. 
q. Only for participants not continuing to Open-label Extension (single ECG). Participants continuing to OLE, will have triplicate ECG (pre-dose) at V8. 
r. Vital signs (body temperature, systolic and diastolic blood pressure, and heart rate) will be measured in a supine position after 5 minutes rest; thereafter, blood pressure should be measured 
again after standing for 2 minutes. 
s.  For training purposes only. 
t. This information will be collected as part of the concomitant medication inquiry. 
u. Blood samples for plasma concentration of study drug will be collected 1-2 hours after dosing and after the ECG. PK samples should not be collected from participants who are off drug 
and remain in the study. 
v  Always collect blood after ECG is administered (not before). 
w. Sample analysis will be drawn at Screening or Baseline. 
x. Sampling analyses for DNA extraction will be performed only once during the study, at Screening or at Baseline, for future genetic analysis related to pridopidine response or HD. 
y. Sampling analyses for CAG, only if needed. 
 
 
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DocuSign Envelope ID: 79A0F46D-86E9-4200-BCFE-5435260803CF


DocuSign Envelope ID: 79A0F46O-86E9-4200-BCF E -5435260803CF 
Prilenia Therapeutics 
1.3.2. 
Schedule of Activities - Open-label Extension (OLE) 
Table 3: 
Schedule of Activities - Open-label Extension 
Study Pe1iod 
Open-Label Titration Period 
Open-Label Full-dose Treatment Period 
Procedures and assessments 
Study Clinic Visit 
OLE Vl • (same as 
OLE V2 
OLEV3 
Main Study VS) 
Telephone Call Safety Visit 
 
 
 
OLE Study Week 
OLE Day 1 (same as 
OLE Wk2 
OLE Wk4 
OLE Wk 
OLE Wk 
OLEWk 39 &  
Main Study Wk 
13 
26 
every 26 wks 
78/EoS) 
thereafter 
Visit Windows (days) 
±1 
±5 
±5 
±14 
±14 
OLE Info,med consent 
X (if not obtained at 
Main Study V7) 
Re-confinu eligibility to OLE 
X 
Clinical laborato,y tests ( serum 
chemistry, hematology) d 
X 
X 
X 
Urinalysis• 
X 
Pregnancy test (for WOCBP) 
u 
u 
u 
Monthly urine pregnancy test (at home) 
Brief physical examination 
X (full PE) 
X 
X 
12 lead ECG 
xr,g 
xg 
Xh 
Vital signs 
X 
X 
X 
C-SSRS (since last visit version) 
X 
X 
X 
X 
X 
UHDRS-TFC 
X 
X 
UHDRS-TMS 
X 
X 
SDMT 
X 
X 
SWR 
X 
X 
Q-Motor 
X 
X 
X 
PBA-S (Sho,t Fonu) 
X 
X 
X 
X 
CGI-C 
X 
X 
HDQoL 
X 
X 
CONFIDENTIAL 
32 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
Follow-up 
Safety Assessment 
OLEV4+ 
OLE 
OLEF/U 
EoS 
/ETb 
 
OLE Wk 52 &  
X 
+ 2 weeks afte1· 
eve1-y 26 wks 
OLEEoS/ET 
the1·eafte1· 
±14 
±14 
±5 
X 
X 
u 
u 
X 
X 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IO November 2022 
Version 7.0, Amendment 8 


DocuSign Envelope ID: 79A0F46O-86E9-4200-BCF E -5435260803CF 
Prilenia Therapeutics 
Study Pe1iod 
Open-Label Titration Period 
Procedures and assessments 
Study Clinic Visit 
OLE Vl • (same as 
Main Study VS) 
Telephone Call Safety Visit 
À 
OLE Study Week 
OLE Day 1 (same as 
OLE Wk2 
Main Study Wk 
78/EoS) 
Visit Windows (days) 
±1 
Benzodiazepines and 
X 
X 
antidepressants inquiry 
Alcohol/illicit drug use inquiry 
X 
X 
Dispense/collect study dmg 
X 
Review study compliance and 
X 
X 
adherence 
Study drug administration 
< 
Adverse event inquiry 
X 
X 
Concomitant medication inquiry 
X 
X 
Plasma sample for biomarkers 
analysis 
Open-Label Full-dose Treatment Period 
OLEV2 
OLE V3 
À 
À 
OLE Wk4 
OLE Wk 
OLE Wk 
OLE Wk39 & 
13 
26 
every 26wks 
the1·eafter 
±5 
±5 
±14 
±14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
> 
X 
X 
X 
X 
X 
X 
X 
X 
xc 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
Follow-up 
Safety Assessment 
OLEV4+ 
OLE 
OLEF/U 
EoS 
/ETb 
À 
OLE Wk52& 
X 
+ 2 weeks afte1· 
eve1-y 26 wks 
OLEEoS/ET 
the1·eafte1· 
±14 
±14 
±5 
X 
X 
X 
X 
X 
X 
X 
X(collec 
t only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
xc 
Abbreviations: Clinical Global Impression of Change (CGI-C); Columbia-Suicide Severity Rating Scale (C-SSRS); electrocardiogram (ECG); End of Study (EoS); Early Tenuination (ET); 
Follow-up (F/U); Huntington Disease Quality of Life Questionnaire (HDQoL ); Open-label Extension (OLE); Physical Examination (PE); Problem Behaviors Assessment-Sho1t Form (PBA-s); 
Symbol Digit Modalities Test (SDMT); Stroop Word Reading (SWR); Total Functional Capacity (TFC); Total Motor Score (TMS); Unified Huntington Disease Rating Scale (UHDRS); Visit (V); 
women of childbearing potential (WOCBP). 
Table Footnotes: 
a. The OLE VI is the same as Main Study V8 ( or V7 /W65 for the last group of pa1ticipants in the Main Study). Assessments do not need to be repeated if conducted as part of the Main Study. 
b. A pa1ticipant who discontinues study drug at any point during the OLE, must also be w-ithdrawn from the study and attend an EoS visit. 
c. In-clinic visit window can be expanded to ±28 days; th.is applies to all in-clinic visits including OLE Vl-4+ and OLE F/U. The expansion of the in-clinic visit window is only in case of a 
global pandemic. 
d 
Collect blood after ECG is administered (not before). 
e. U1-inalysis will be done as pait of Main Study V8, not as pait of OLE 
f. 
Triplicate ECG pre-dose. 
g. Single ECG 1-2 hom·s post-dose. 
h. Single ECG pre-dose. 
CONFIDENTIAL 
33 
IO November 2022 
Version 7.0, Amendment 8 


DocuSign Envelope ID: 79A0F46O-86E9-4200-BCF E -5435260803CF 
Prilenia Therapeutics 
2. 
INTRODUCTION 
2.1. 
Study Rationale 
Study chug: P1idopidine 
Protocol Number: PL101-HD301 
Huntington Disease (HD) is an autosomal dominant, progressive fatal neurodegenerative 
disorder characterized by motor, cognitive, and behavioral abno1malities. While medications to 
treat chorea and some behavioral symptoms are available, no therapy has yet proven able to 
modify the progressive and inexorable functional decline of the disease. A therapy that maintains 
functional capacity and prevents or delays the development of disability represents a critically 
unmet clinical need. 
Pridopidine, a novel small molecule under development for the treatment of HD has high affinity 
CONFIDENTIAL 
34 
10 November 2022 
Version 7.0, Amendment 8 


DocuSign Envelope ID: 79A0F46O-86E9-4200-BCF E -5435260803CF 
Prilenia Therapeutics 
CONFIDENTIAL 
35 
Study chug: P1idopidine 
Protocol Number: PL101-HD301 
10 November 2022 
Version 7.0, Amendment 8 


DocuSign Envelope ID: 79A0F46O-86E9-4200-BCF E -5435260803CF 
Prilenia Therapeutics 
--
■ -
--
I -
■ 
-
I 
I -
■ 
-
■ 
CONFIDENTIAL 
36 
-
• 
--
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
I 
I 
-
I 
I 
I 
■ 
I 
-
I 
- ■ 
I 
- -
I 
10 November 2022 
Version 7.0, Amendment 8 


DocuSign Envelope ID: 79A0F46O-86E9-4200-BCF E -5435260803CF 
Prilenia Therapeutics 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
The pmpose of this Phase 3 study is to fmiher evaluate the effect of pridopidine 45 mg bid on 
functional capacity, as well as motor and behavioral features of HD in early-stage paiiicipants 
(TFC 7-13). 
2.2. 
Background 
HD is a fatal neurodegenerative disorder chai·acterized by progressive deterioration of motor 
and cognitive functions, as well as behavioral and psychiatric disturbances. The disease has an 
autosomal dominant inheritance and is caused by an expanded cytosine-adenine-guanine 
(CAG) repeat in the huntingtin gene (HTT) on chromosome 4, encoding the mutant protein 
huntingtin (Huntington's Disease Collaborative Research Group, 1993). 
The estimated prevalence of HD in No1ih America, No1ih-Westem Emope, and Australia ranges 
from 5.96 to 13.7 cases per 100,000 people (Fisher, 2014; Rawlins, 2016). The age of onset of 
the signs and symptoms of HD and the rate of disease progression can va1y greatly. Adult-onset 
HD most often begins between 30 and 40 years of age. The illness generally lasts 15 to 20 years 
and is fatal. Following diagnosis, motor and cognitive functions steadily decline, ultimately 
leading to a state of immobility, dementia, and prematme death (Ross, 2014). 
fu HD to date, only 2 diugs, tetrabenazine and deutetrabenazine, have been approved for the 
management of chorea. A number of medications are used off-label to control motor and 
psychiatric symptoms arising from HD. 
A detailed description of the chemistiy, phannacology, efficacy, and safety of pridopidine is 
provided in the fuvestigator's Brochme (IB). 
2.3. 
Benefit/Risk Assessment 
More detailed infonnation about the known and expected benefits and risks and reasonably 
expected AEs of pridopidine may be found in the IB. 
CONFIDENTIAL 
37 
10 November 2022 
Version 7.0, Amendment 8 


Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
38 
10 November 2022 
 
Version 7.0, Amendment 8 
2.3.1. 
Risk Assessment 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
Study drug Pridopidine  
QT Prolongation 
Known risk identified in pre-
clinical and clinical studies as a 
result of Ikr potassium channel 
block in ventricular 
myocardium. Excessive QT 
prolongation is a recognized 
surrogate marker for a specific 
type of ventricular tachycardia, 
Torsade de Pointes. Exposure-
response modeling based on 
dosing of pridopidine up to 
112.5 mg bid suggests a linear 
response of QTcF to increasing 
drug exposure (refer to 
Appendix 9 Section 10.9). At 
45 mg bid, the dose evaluated in 
this trial, the estimated QTcF 
prolongation is 6.6 ms and not 
considered clinically 
meaningful. 
Participants will be excluded if 
they have a clinically significant 
heart disease, a clinically 
significant history of 
arrhythmia, symptomatic or 
uncontrolled atrial fibrillation 
despite treatment, or 
asymptomatic sustained 
ventricular tachycardia, or 
presence of left bundle branch 
block. 
Participants with known history 
of congenital long QT syndrome 
or a first degree relative with 
this condition will be excluded. 
Participants with clinically 
significant bradycardia, sick 
sinus syndrome, complete 
atrioventricular block, 
congestive heart failure, 
polymorphic ventricular 
tachycardia, clinically relevant 
hypocalcemia, hypokalemia or 
hypomagnesemia will be 
excluded. 
ECG parameters will be closely 
monitored throughout the study 
(refer to Appendix 8, 
Section 10.8). 
Participants will be required to 
discontinue study drug during 
the study if they have 
symptomatic or uncontrolled 
atrial fibrillation, confirmed 
ventricular tachycardia, 
presence of left bundle branch 
block 
Decreased creatinine renal 
clearance  
Identified risk in clinical studies. 
There have been no serious 
outcomes relating to the 
decrease, and discontinuation of 
the pridopidine treatment results 
Participants with a creatinine 
clearance (CrCl) <30 mL/min 
will be excluded. 
Creatinine values will be 
monitored throughout the study. 
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Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
39 
10 November 2022 
 
Version 7.0, Amendment 8 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
in the return of creatinine to 
normal values. 
Participants will be discontinued 
from the study if their CrCl 
reaches <30 mL/min during the 
study. 
2.3.2. 
Benefit Assessment 
There are currently no disease-modifying drugs for the treatment of HD. The results from 
completed studies with pridopidine suggest a potential benefit of pridopidine to fulfill a 
critical unmet need in the treatment of patients with HD, and support further clinical 
development. 
Participants in the study may experience symptomatic improvement and, possibly, the rate of 
disease progression may be reduced. However, there is no guarantee that participation in the 
current study will help the participant; the participant may receive a placebo treatment during the 
Main Study. During the OLE, all participants will receive pridopidine. 
2.3.3. 
Overall Benefit: Risk Conclusion 
Taking into account the measures taken to minimize risk to participants taking part in this study, 
the potential risks identified in association with pridopidine are justified by the anticipated 
benefits that may be afforded to participants with HD. 
 
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DocuSign Envelope ID: 79A0F46O-86E9-4200-BCF E -5435260803CF 
Prilenia Therapeutics 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
3. 
OBJECTIVES AND ENDPOINTS 
3.1. 
Main Study Objectives, Endpoints and Primary Estimand 
3.1.1. 
Main Stud Ob· ectives and End oints 
Objectives 
Primaiy 
• To assess the effect of pridopidine on 
functional capacity in paiticipants with 
Stage 1-2 HD 
Multiplicity Adjusted Secondaiy Endpoints 
Endpoints 
• Change from Baseline to Week 65 in the 
UHDRS-TFC score 
Key Seconda1y (seconda1y endpoints are listed by order ofhierai·chy) 
• To assess the effect of pridopidine on a 
composite measure of disease 
progression in pa1ticipants with HD 
1. Change from Baseline to Week 65 in 
composite UHDRS ( cUHDRS) total 
score 
Seconda1y (secondaiy endpoints ai·e listed by order ofhierai·chy) 
• To evaluate the effect of pridopidine on 
functional capacity, motor function, and 
other measures of efficacy over time in 
paiticipants with HD 
CONFIDENTIAL 
40 
2. Propo11ion of paiiicipants with 
improvement or no worsening ( change 
from BaselineĆ 0 point) at Week 65 in 
UHDRS-TFC 
3. Change from Baseline to Week 52 in 
UHDRS-TFC score 
4. Change from Baseline to Week 78 in 
UHDRS-TFC score 
5. Change from Baseline to Week 65 in 
Quantitative motor (Q-Motor) 
6. Change from Baseline to Week 65 in 
UHDRS Total Motor Score (TMS) 
7. Change from Baseline to Week 65 in 
Symbol Digit Modalities Test (SDMT) 
8. Change from Baseline to Week 52 in 
UHDRS-TMS score 
10 November 2022 
Version 7.0, Amendment 8 


Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
41 
10 November 2022 
 
Version 7.0, Amendment 8 
9. Proportion of participants with 
improvement or no worsening in 
Clinical Global Impression of Change 
(CGI-C) at Week 65 
Non-multiplicity Adjusted Secondary Endpoints 
• To evaluate the effects of pridopidine in 
participants with HD 
• Change from Baseline to Week 26 and 39 
in the UHDRS-TFC  
 
 
 
• Proportion of participants with 
improvement or no worsening in UHDRS-
TFC (change from Baseline ≥ 0) at Weeks 
26, 39, 52 and 78 
• Change from Baseline to Weeks 26, 39, 52 
and 78 in cUHDRS 
• Proportion of participants with change 
from Baseline ≥ -1 in cUHDRS at Weeks 
26, 39, 52, 65 and 78 
• Change from Baseline to Week 26, 39 and 
78 in the UHDRS-TMS score 
• Proportion of participants with 
improvement or no worsening in UHDRS-
TMS (change from Baseline ≤ 0) at Weeks 
26, 39, 52, 65 and 78 
• Change from Baseline to Weeks 26, 39, 52, 
65 and 78 in: 
− UHDRS-TFC Scale sub-items 
(capacity to undertake domestic 
chores, activities of daily living, 
capacity to manage finances, care 
level and occupation) 
− UHDRS-TMS sub-scores for: 
o Gait and balance score (defined 
as the sum of UHDRS-TMS 
domains gait, tandem walking, 
and retropulsion pull test) 
o Eye movement 
o Dystonia 
• Change from Baseline to Weeks 26, 39, 52 
and 78 in SDMT 
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Prilenia Therapeutics 
Safety and Tolerability 
• To evaluate the safety and tolerability of 
pridopidine in paiticipants with HD 
CONFIDENTIAL 
42 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
• Change from Baseline to Weeks 26, 39, 52, 
65 and 78 in Stroop Word Reading (SWR) 
• Change from Baseline to Weeks 26, 39, 52 
and 78 in O-Motor 
• Propo1tion of paiticipants with 
improvement or no worsening ( chan e 
from Baseline ƈ 0 msec) in O-Moto 
Weeks 26, 39, 52, 65 and 78 
• Change from Baseline to Weeks 26, 39, 52, 
65 and 78 in Q-motor 
• Responder analyses on CGI-C using 
different thresholds at Weeks 26, 39, 52, 
65 and 78 
• Incidence ( count and rate) of AEs and 
serious AEs (SAEs) overall, by severity, by 
relationship to study diug, and those that 
led to discontinuation of study diug and/or 
withdi·awal from the study 
• 
Incidence and shifts of clinically significant 
abnonnalities in electrocai·diogram (ECG) 
(refer to Section 7 .1.1 ), laborato1y tests, 
vital signs, and abnonnalities in physical 
and neurological exam 
• Analysis of Columbia-Suicide Severity 
Rating Scale (C-SSRS) throughout the 
study 
• Tolerability: 
-
The number (%) of participants who 
complete the Treatment period 
-
The number (%) of pa1ticipants who 
fail to complete the Treatment period 
due to AEs 
-
The number (%) of participants who 
fail to complete the Treatment period 
due to meeting the Fridericia-conected 
QT interval (QTcF) change, CrCl or 
Psychiatric Stopping Rules 
10 November 2022 
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Prilenia Therapeutics 
Explorato1y 
• To evaluate the explorato1y efficacy 
effects of pridopidine in participants 
with HD 
• To evaluate changes in disease 
biomarker plasma neurofilament light 
chain (NfL) following treatment with 
pridopidine in pa1iicipants with HD 
• To evaluate the phaimacokinetics (PK) 
of pridopidine and its main metabolite 
in paiiicipants with HD 
3.1.2. 
Primary Estimand 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
• Change from Baseline to Weeks 26, 52, 65 
and 78 in: 
-
Problem Behaviors Assessment -
Sho1i Fonn (PBA-s) total score 
o PBA-s sub-score for apathy 
-
Measurement of quality of life using 
HDQoL 
• Change from Baseline to Weeks 26, 52, 65 
and 78 in plasma NfL protein 
• Relationship between Baseline NfL and 
changes from Baseline in select efficacy 
endpoints 
• Relationship between changes from 
Baseline to Weeks 26, 52, 65 and 78 in 
NfL and selected efficacy endpoints 
• Propo1iion of paiiicipants with different 
thresholds for change from Baseline in 
plasma NFL levels to Weeks 26, 52, 65 
and 78 
• Plasma concentrations of pridopidine and 
its main metabolite at Weeks 26, 52, 65, 
and 78 and at last pa1iicipants' visit 
• Relationship between plasma concentration 
of pridopidine and clinical outcome 
measures 
The primaiy estimand will answer the clinical question of "Whether the intent-to-treat (ITT) 
population of eai·ly HD patients (HDl and HD2) have a clinically meaningful and statistically 
significant mean change from Baseline to Week 65 in UHDRS-TFC." 
The 5 components of the primaiy estimand for this study based on the futemational Council for 
Haimonization (ICH) E9 R(l) guidance which defines the scientific question of interest ai·e listed 
below. 
The hypothesis testing will be based on the main estimand sepai·ately defined for European 
Medicines Agency (EMA) and non-EMA regions.: 
For non-EMA regions, the main estimand is defined as non-EMA-Estimand: 
• Treatment of interest: Pridopidine 45 mg bid vs placebo ( on background of standai·d 
of care) that participants ai·e randomized to 
CONFIDENTIAL 
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DocuSign Envelope ID: 79A0F46O-86E9-4200-BCF E -5435260803CF 
Prilenia Therapeutics 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
• Population of interest: Early HD Paiiicipants (HD 1 & HD2) defined through the 
study inclusion/exclusion criteria. The modified intent to treat (mITT) dataset will be 
used in analyzing this estimand 
• V ai·iable of interest measured on each pa1iicipant: Change from Baseline to Week 65 
in UHDRS-TFC 
• Population level summaiy: Least squai·es (LS) mean difference between pridopidine 
and placebo from Mixed Model for Repeated Measurements (MMRM) in change of 
UHDRS-TFC from Baseline to Week 65 
• 
Handling of IntercmTent Events (ICEs): ICE include treatment discontinuation or 
death. Treatment policy strategy will be used to handle the ICE, where occmTence of 
an ICE is inelevant. All observed values will be used regardless of occmTence of an 
ICE. No imputation is perfonned. 
For EMA regions, the main estimand is defined as EMA-Estimand: 
• 
Treatment: Pridopidine 45 mg bid or placebo (on background of standard of cai·e) that 
paiiicipants ai·e randomized to 
• Population: Early HD Pa1iicipants (HD 1 & HD2) defined through the study 
inclusion/exclusion criteria. The ITT population will be used in analyzing this 
estimand 
• V ai·iable: Change from Baseline to Week 65 in UHDRS-TFC 
• Population Level Summaiy: LS-Mean difference between pridopidine 45 mg bid and 
placebo from MMRM model in change of UHDRS-TFC from Baseline to Week 65 
• 
ICE and Strategies for Addressing ICE: 
ICE include treatment discontinuation or death and will be handled by a composite of 
treatment policy and hypothetical strategies. 
o Treatment policy strategy will apply to all observed values including those 
collected after treatment discontinuation as these values reflect the remaining off­
drng treatment effect in reality 
o Hypothetical strategy will apply to missing values after the last observed values. 
The method of multiple imputation will be applied to impute the missing data. 
using Pattern Mixture Model (PMM) with control-based pattern imputation under 
Missing Not at Random (MNAR) assumptions 
Additional details ai·e included in Statistical Section of this protocol (Section 9) and in the 
statistical analysis plan. 
3.2. 
OLE Objectives and Endpoints 
I 
Objectives 
Endpoints 
Efficacy 
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DocuSign Envelope ID: 79A0F46O-86E9-4200-BCF E -5435260803CF 
Prilenia Therapeutics 
• To evaluate the long-tenn treatment 
effect of pridopidine in paiiicipants with 
HD who previously completed the Main 
Study 
Safety and Tolerability 
• To evaluate long-te1m safety and 
tolerability of pridopidine in 
paiiicipants with HD who previously 
completed the Main Study 
CONFIDENTIAL 
45 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
• Propo1iion of paiiicipants with change 
from Baseline (Main Study) to each OLE 
visit in UHDRS-TFC Ć -1 
• Propo1iion of paiiicipants with change 
from Baseline (Main Study) to each OLE 
visit in UHDRS-TFC Ć 0 
• Change from Baseline (Main Study) to 
OLE visits in: 
-
UHDRS-TFC 
-
cUHDRS 
-
UHDRS-TMS 
-
Quantitative motor (Q-Motor): 
I 
I 
-
SDMT 
-
SWR 
• Change from Baseline (Main Study) to 
OLE visits in: 
-
CGI-C 
-
PBA-s 
-
HDQoL 
• Incidence ( count and rate) of AEs and 
SAEs overall, by severity, by relationship 
to study diug, and those that led to 
discontinuation of study diug and/or 
withdi·awal from the study 
• 
Incidence and shifts of clinically significant 
abno1malities in ECG (refer to Section 
7.1.1), laborato1y tests, and vital signs 
• Analysis of C-SSRS throughout the study 
• Tolerability: 
-
The number (%) of paiticipants who 
complete the OLE treatment period 
10 November 2022 
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Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
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10 November 2022 
 
Version 7.0, Amendment 8 
− The number (%) of participants who 
fail to complete the OLE treatment 
period due to AEs 
Biomarker 
• To evaluate long-term efficacy effects 
of pridopidine on NfL in participants 
with HD who previously completed the 
Main Study 
• Change from Baseline (Main Study) in 
NfL protein level to each OLE visit 
• Relationship between changes from 
baseline in NfL and selected efficacy 
endpoints in the OLE period 
 
 
DocuSign Envelope ID: 
DocuSign Envelope ID: 79A0F46D-86E9-4200-BCFE-5435260803CF


Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
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10 November 2022 
 
Version 7.0, Amendment 8 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety 
of pridopidine administered orally at a dose of 45 mg bid in participants with early HD defined 
as Stages 1 and 2 (based on Shoulson and Fahn (Shoulson, 1979)). Approximately 480 
participants will be enrolled (240 per arm) at approximately 60 sites in North America and 
Europe. 
The study will consist of a Screening period, a double-blind Treatment period (Main Study), and 
an OLE as described below. 
After signing informed consent, participants will undergo screening assessments to determine 
eligibility over a Screening period of up to 6 weeks7. 
The Screening period will be followed by a 65- to 78-week double-blind Treatment period, 
composed of a 2-week Titration period, a 63-week double-blind full-dose Maintenance 
Treatment period followed by a variable double-blind Treatment period of up to 13 weeks (total 
of up to 78 weeks: Main Study). 
On Day 1 (Baseline visit), eligible participants will be randomized in a 1:1 ratio to active 
(pridopidine 45 mg bid) or control (placebo) arm as shown in Table 1. Randomization will be 
stratified by Baseline HD stage (HD1 vs. HD2) and Baseline Neuroleptic use (Yes/No). 
Starting on Day 1, during the Titration period, all participants will self-administer 1 capsule of 
study drug orally (PO), once daily (QD), in the morning for 2 weeks. Thereafter, the study drug 
will be taken PO, bid in the morning and in the afternoon (7-10 hours apart) for 63 weeks 
(double-blind full-dose Maintenance Treatment period). Participants who complete the 
Maintenance period (63 weeks) will continue into a variable double-blind period of up to 13 
weeks or until the last participant randomized completes 65 weeks of treatment (2 weeks titration 
+ 63 weeks full-dose), whichever comes first. Most participants will be followed for 78 weeks. 
Participants entering the study within 90 days of the last randomized participant will be followed 
between 65 and 78 weeks. As soon as the last participant reaches Week 65, the Main Study EoS 
visits for the remaining participants who are between Week 65 and Week 78 needs to be 
conducted within 4 weeks. For the group of participants who will not be able to reach Week 78 
within these 4 weeks, Week 65 will be considered their EoS visit. The double-blinding will be 
maintained for all participants and Investigators until that time. 
For each participant, the last visit will be the Main Study EoS or Early Termination (ET) visit. 
For participants who stay on study drug and complete all scheduled visits during the double-
blind study period, their EoS visit will be either Week 65 visit or Week 78. Participants who 
discontinue early from study drug will be encouraged to remain in the study and complete 
all other visits as scheduled for the full course of the study. Participants who withdraw from 
the study before Week 65 visit and are not willing to continue with the study visits and 
procedures for the full course of the study, will be asked to undergo an ET visit that will 
include evaluations as specified in the SoA (Table 2 – Main Study). Participants withdrawing 
from the Main Study will be encouraged to complete the same final evaluations as participants 
 
7 If there is no need for genetic tests or washout from prohibited medication, the screening period should be 
completed within 3 weeks. 
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DocuSign Envelope ID: 79A0F46O-86E9-4200-BCF E -5435260803CF 
Prilenia Therapeutics 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
completing the study according to this protocol (EoS visit of the Main Study), pa1ticularly safety 
and primaiy and seconda1y efficacy evaluations. 
Eligible paiticipants who complete the Main Study, 65- or 78-week double-blind Treatment 
period, will have the option to emoll into an OLE period, commencing at the Main Study EoS 
visit, and receive pridopidine. The OLE will consist of a 2-week Titration period and a 
Maintenance period. During the Titration period, pa1ticipants will self-administer 1 capsule of 
pridopidine 45 mg PO, QD, in the morning for 2 weeks. Thereafter, pridopidine will be taken 
PO, bid, in the morning and in the afternoon (7-10 hours apait) until 12 months after the last 
paiticipant completes the double-blind Treatment period. 
Paiticipants who are not continuing to the OLE study will be contacted by phone for a safety 
evaluation 2 weeks after the Main Study EoS/ET visit. AEs will be monitored for these 2 weeks 
until the safety telephone contact. 
Throughout the study, pa1ticipants will be assessed through on-site clinic visits, virtual visits (via 
telephone), and safety telephone calls (TCs), as specified in the conesponding SoAs (Table 2 -
Main Study, and Table 3 - OLE) and study schemas (Figure 1 - Main Study, and Figure 2 -
OLE). 
During the double-blind Treatment period of the Main Study, an independent Safety Monitoring 
Committee will oversee the safety and tolerability based on paiticipants' data accmed in the 
electronic data capture (EDC) system, based on an ongoing review of SAEs and periodical 
review of the accumulating safety data. Fmther details ai·e provided in Section 9.6. 
4.2. 
Scientific Rationale for Study Design 
There are cunently no available HD therapies that maintain function capacity or core clinical 
features of the disease. Tetrabenazine and deutetrabenazine are the only cunently approved 
treatments for HD, but they are indicated for symptomatic treatment of chorea, and not for 
maintenance of functional capacity (Shen, 2013; Frank, 2016). 
4.3. 
Justification for Dose 
CONFIDENTIAL 
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DocuSign Envelope ID: 79A0F46O-86E9-4200-BCF E -5435260803CF 
Prilenia Therapeutics 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
4.4. 
Study Duration 
The Main Study is expected to be conducted from Q3 2020 until Ql 2023. Paiiicipant 
recrnitment period is planned from Q3 2020 until approximately Q4 2021 (end date can vaiy 
based on actual study perfonnance and enrollment status). 
For each paiiicipant, the total duration of study paiiicipation in the Main Study (Screening and 
Double-blind period) will be up to 86 weeks. 
Main Study: 
Screening period: 
Up to 6 weeks 
Double-blind Treatment 
Up to 78 weeks as follows: 
Period: 
k 
• 
• 
• d 
• 2 wee s T1trat10n per10 
• 63 weeks full-dose treatment 
• Up to 13 weeks vai·iable double-blind period (until the 
last randomized paiiicipant completes 65 weeks of 
treatment = 2 weeks titration + 63 weeks full-dose) 
Follow-up period: 
2 weeks 
OLE: 
• 2 weeks Titration period 
• Full dose treatment until 12 months after the last 
pa11icipant completes the double-blind Treatment 
period. OLE duration may be further extended pending 
emerging data from the double-blind po11ion of the 
study. 
4.5. 
End of Study Definition 
A paiiicipant is considered to have completed the Main Study if he/she has completed the Week 
65 assessments without discontinuing early. The Main Study will be considered completed when 
all paiiicipants either complete the study through Week 65 (EoS visit) or discontinue eai·lier (ET 
visit). 
The OLE study will be considered completed 12 months after the last paiiicipant completes the 
double-blind Treatment period. OLE duration may be fmiher extended pending emerging data 
from the double-blind po11ion of the study. The Sponsor intends to submit a substantial protocol 
amendment for the extension of the OLE after ensuring a remaining positive benefit-risk ratio 
after analysis of the data from the Main Study. 
4.6. 
Coronavirus Disease 2019 (COVID-19) Mitigation Plan 
Proactive mitigation measures to ensure pa11icipant•s safety and study integrity during 
COVID-19 pandemic (or any Public Health Emergency) ai·e included in this study. Four virtual 
visits are incmporated into the protocol to ensure paiiicipant safety and minimize the risk of 
CONFIDENTIAL 
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Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
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10 November 2022 
 
Version 7.0, Amendment 8 
missing data. In addition, every in-clinic visit, except Screening, Baseline and Week 65 visits, 
can be converted to a virtual visit if this will be required. 
Some of the efficacy and safety measures can be carried out by remote assessments, if required. 
Raters will be trained and ready to implement these remote safety and efficacy measures. Home 
visits by health care professionals for safety assessments may be provided if in-clinic visits will 
not be possible (including safety laboratories, vital signs and ECG administration). Drug 
accountability will also be conducted at home visits by health care professionals. For additional 
information refer to Appendix 10 (Section 10.10). 
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Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
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10 November 2022 
 
Version 7.0, Amendment 8 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria – Main Study 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Twenty-five years of age (inclusive) and older, at the time of signing the informed 
consent. 
Type of Participant and Disease Characteristics 
2. Diagnosis of HD based on clinical features and the presence of ≥36 CAG repeats in the 
HTT, confirmed by historical laboratory quantified results or by a diagnostic test at 
Screening. 
2. Diagnostic confidence level (DCL) of 4 (unequivocal motor signs, ≥99% confidence) on 
the standardized motor exam UHDRS-TMS. 
3. Adult-onset HD with onset of signs and symptoms ≥18 years of age. 
4. Stage 1 or Stage 2 HD, defined as a UHDRS-TFC score of ≥7, at Screening. 
5. UHDRS-Independence Scale (IS) score ≤90% at Screening. 
6. UHDRS-TMS ≥20 at Screening. 
7. Must meet all criteria required to move forward with the Randomization Authorization 
Flow (RAF) and be considered eligible by the RAF Reviewer. 
Sex 
8.  Male or female. 
Pregnancy and Contraception 
Contraceptive use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies (refer to Appendix 4, 
Section 10.4). 
9. Female participants of childbearing potential must have a negative β-human chorionic 
gonadotropin (β-HCG) test at Screening and Baseline, be sterile, or be postmenopausal. 
10.  Female participants of childbearing potential whose male partners are potentially fertile 
(i.e., no vasectomy) must use highly effective birth control methods stable for at least 3 
months prior to Screening, for the duration of the study and for 30 days after 
discontinuation of the study drug. 
11. Male participants must be sterile, or if they are potentially fertile/reproductively 
competent (not surgically [e.g., vasectomy] or congenitally sterile) and their female 
partners are of childbearing potential, they must use, together with their female partners, 
effective birth control methods for the duration of the study and for 90 days after study 
drug discontinuation. 
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Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
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10 November 2022 
 
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Concomitant Therapy 
12. For participants taking allowed antipsychotic, antidepressant, or other psychotropic 
medication, the dosing of medication as listed in Appendix 6 (Section 10.6), must be 
stable for at least 4 weeks before the Baseline visit. and throughout the study (unless 
clinically necessary to change). 
13. For participants taking allowed concomitant medications, dosing of medications must be 
stable for a t least 4 weeks prior to the Baseline visit (note: Amiodarone is not allowed 
within 6 weeks of Baseline visit). 
Informed Consent 
14. Capable of providing signed informed consent for the Main Study as described in 
Appendix 1 (Section 10.1) which includes compliance with the requirements and 
restrictions listed in the informed consent form (ICF) and in this protocol. 
5.2. 
Inclusion Criteria – OLE 
1. Completed the EoS visit of the Main Study on treatment without important protocol 
deviations impacting efficacy and safety assessments. 
2. Capable and willing to provide signed informed consent for the OLE. 
3. Must meet all criteria required to move forward with the OLE assessments. 
5.3. 
Exclusion Criteria – Main Study 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Prolonged QTcF interval (defined as a QTcF interval of >450 ms for male and >470 ms 
for female) at Screening8. 
2. Clinically significant heart disease within 12 weeks before randomization, defined as 
follows: 
a. Participants with clinically significant heart disease, a clinically significant history 
of arrhythmia, symptomatic or uncontrolled atrial fibrillation despite treatment, or 
confirmed ventricular tachycardia, or presence of left bundle branch block. 
b. Participants with a known history of congenital long QT syndrome or a first 
degree relative with this condition. 
c. Clinically significant bradycardia, sick sinus syndrome, complete atrioventricular 
block, congestive heart failure, polymorphic ventricular tachycardia, clinically 
relevant hypocalcemia, hypokalemia or hypomagnesemia. 
2. History of epilepsy or seizures within the last 5 years. 
3. Serious medical illness includes, but not limited to, uncontrolled hypertension; 
respiratory disease, including severe forms of asthma; severe hepatic disease (confirmed 
Hepatitis B virus [HBV], Hepatitis C virus [HCV]; confirmed human immunodeficiency 
 
8 If there is evidence of a prolonged QTcF interval at screening from the initial (single) administration, then the ECG 
will be repeated twice, and the mean of the 3 screening administrations will be used to determine whether or not the 
participant is suitable for inclusion in the study. 
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Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
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Version 7.0, Amendment 8 
virus [HIV]); renal disease; acquired immune deficiency syndrome; and unstable 
psychiatric or other neurologic disorders) and metastatic cancer. 
For serious kidney and liver and liver illnesses see also exclusion criterion 12 (laboratory 
test abnormalities). 
4. Known intracranial neoplasms, vascular malformations, history of cerebrovascular 
accident, or intracranial hemorrhage. 
5. Female participants who are pregnant, planning to become pregnant or breastfeeding. 
Prior/Concomitant Prohibited Therapy 
6. Medications that prolong QT interval, taken within 4 weeks of the Baseline visit (note, 
Amiodarone is not allowed within 6 weeks of the Baseline visit) or at any timepoint 
during the study, including non-allowed antipsychotic medications, tricyclic 
antidepressants, and/or Class I antiarrhythmics as listed in Appendix 7 (Section 10.7). 
7. Use of pridopidine within 12 months before the Baseline visit. 
8. Treatment with any investigational product within 6 weeks or 5 half-lives (whichever is 
longer) before the Screening visit or a plan to participate in another clinical study that 
assesses any investigational product during the study. 
9. Gene therapy at any time. 
10. Prior participation in studies with tominersen at any time. 
Diagnostic Assessments 
11. Laboratory values that fall outside of the central laboratory’s reference range at Screening 
and are considered clinically significantly abnormal by the Investigator and affect the 
participant's suitability to participate in the study or put the participant at risk if he/she 
enters the study in the Investigator’s opinion9. 
12. Have any of the following laboratory test abnormalities at Screening: 
a. CrCl <30 mL/min at Screening, calculated using the Cockcroft-Gault equation: (140–
age) × mass (kg) × [0.85 if female] / 72 × serum creatinine (mg/dL)10 
b. Aspartate aminotransferase (AST) ≥2.5 × upper limit of normal (ULN) 
c. Alanine aminotransferase (ALT) ≥2.5 × ULN 
d. Gamma-glutamyl transferase (GGT) ≥3.0 × ULN 
e. Total bilirubin >1.5 mg/dL, except participants with unconjugated hyperbilirubinemia 
without other liver function derangements or other explanations for the elevated 
bilirubin (consistent with diagnosis of Gilbert’s syndrome) 
Other Exclusions 
13. Alcohol and/or substance use disorder within the 6 months prior to Screening, as defined 
by the Diagnostic and Statistical Manual–Fifth Edition (DSM-5) Text Revision criteria 
for substance use. 
 
9 Repeat testing is allowed (up to a maximum of 3 tests) if required to establish whether values are within the normal 
range or clinically significantly abnormal. 
10 It is allowed to repeat the test once, if clinically appropriate. 
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Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
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14. Active suicidal ideation as measured by a most severe suicide ideation score of 4 (Active 
Suicidal Ideation with Some Intent to Act, without Specific Plan) or 5 (Active Suicidal 
Ideation with Specific Plan and Intent) on the C-SSRS if the ideation occurred within 1 
year of Screening, or participants who answered “Yes” on any of the 5 C-SSRS Suicidal 
Behavior Items (actual attempt, interrupted attempt, aborted attempt, preparatory acts, or 
behavior), if the attempt or acts were performed within 1 year of Screening, or 
participants who, in the opinion of the Investigator, present a serious risk of suicide. 
15. Known allergy to any ingredient of the study drug (pridopidine, silicified microcrystalline 
cellulose, or magnesium stearate). 
16. Vulnerable participant (e.g., people kept in detention), or participant unfit to participate in 
a clinical study due to living circumstances (e.g., without sufficient family or social 
support, stable residence, sustainable financial and general healthcare and resources). 
17. An employee or a family member of an employee of the Sponsor, Investigator or 
Investigator study site, or otherwise dependent on the Sponsor, the Investigator or the 
Investigator study site. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study drug. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria 
not met, and any serious adverse event (SAE). 
Potential candidates who do not meet the criteria for participation in this study (screen failure) 
may be rescreened only once. 
Screening assessments may be repeated during the screening period if approved and at the 
discretion of the study Medical Monitor (or designee). After the screening period, all screening 
assessments must be repeated except for Cytosine Adenine Guanine (CAG) repeat (providing the 
results are available from a prior screening period). 
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Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
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6. 
STUDY DRUG 
The study drug is defined as investigational intervention(s) and intended to be administered to a 
study participant according to the study protocol. 
6.1. 
Study Drug(s) Administered 
ARM Name 
Active 
Control 
Study Part 
Main Study and OLE 
Main Study only 
Study Drug Name (INN) 
Pridopidine 
Placebo 
Type  
Drug (small molecule) 
- 
Dose Formulation 
Hard gelatin capsules 
Hard gelatin capsules 
Unit Dose Strength(s) 
45 mg 
NA 
Dosage Level(s) 
 
 
Titration period 
45 mg capsule QD (morning 
dose) for 2 weeks 
Placebo capsule QD (morning dose) 
for 2 weeks 
Main full-dose 
Treatment period 
45 mg capsule bid (1 capsule in 
the morning and 1 capsule in the 
afternoon, 7 to 10 hours after 
morning dose); total daily dose of 
90 mg  
Placebo capsule bid (1 capsule in the 
morning and 1 capsule in the 
afternoon, 7 to 10 hours after 
morning dose) 
Route of Administration 
Oral 
Oral 
Use 
Experimental  
Placebo-comparator  
Sourcing 
Pridopidine drug product, 
manufactured by Teva 
Pharmaceutical Industries, Ltd or 
by Apotek Production & 
Laboratories AB (APL) or  
Patheon, by Thermo Fisher 
Scientific and provided centrally 
by the Sponsor or subsidiary, or 
designee 
Placebo, manufactured by Teva 
Pharmaceutical Industries, Ltd or by 
Apotek Production & Laboratories 
AB (APL) and provided centrally by 
the Sponsor or subsidiary, or 
designee 
Packaging and Labeling 
Study drug will be provided in high-density polyethylene bottle with a 
child-resistant cap, labeled as required per country requirement. 
The secondary packaging and labeling of the study drug will be performed 
by Fisher Clinical Services. All packaging and labeling operations for the 
study drug will be performed according to current Good Manufacturing 
Practice for Medicinal Products and the relevant regulatory requirements. 
Prior Code Name 
PL101 (formerly TV7820, 
ACR16 and ASP2314) 
- 
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Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
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10 November 2022 
 
Version 7.0, Amendment 8 
6.2. 
Handling Missed Doses 
If a participant misses the morning dose, he/she can still take the missed morning dose as long as 
there is a minimum of 7 hours before the planned afternoon dose. 
If there are less than 7 hours until the planned afternoon dose, the participant should skip the 
morning dose and administer only the afternoon dose. 
If a participant misses the afternoon dose, he/she can take that dose until 7:00 pm. 
After 7:00 pm the participant should skip the dose and continue the next day with the planned 
morning dose. 
6.3. 
Preparation/Handling/Storage/Accountability 
• Capsules will be swallowed whole with water. The study drug can be taken irrespective of 
meals. 
• The Investigator or designee must confirm that appropriate temperature conditions have 
been maintained during transit for all the study drug received and that any discrepancies are 
reported and resolved before the use of the study drug. 
• Only participants enrolled in the study may receive study drug and only authorized site staff 
may supply or administer study drug. All study drug must be stored in a secure, 
environmentally controlled (15 to 25 ºC), and monitored (manual or automated) area in 
accordance with the labeled storage conditions, with access limited to the Investigator and 
authorized site staff. 
• The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study drug accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
• Study drug will be dispensed at the study visits summarized in SoA (Table 2 – Main Study, 
and Table 3 – OLE). Returned study drug (which was previously dispensed) should not be 
re-dispensed to participants. 
• Further guidance and information for the final disposition of unused study drugs are 
provided in the Study Reference Manual. 
6.4. 
Measures to Minimize Bias: Randomization and Blinding 
All participants will be centrally randomized on a 1:1 basis to receive either pridopidine or 
placebo using an Interactive Response Technology (IRT), based upon the stratification variables 
of whether they are HD1 or HD2 and whether they are taking neuroleptics or not. 
All participants, site staff, Sponsor, CRO and vendors involved with the study will remain 
blinded to treatment assignments until the database is locked and the study unblinded. The 
CRO(s) creating the randomization assignments, implementing the IRT and drug packaging 
groups will follow their standard operating procedures to ensure no one, involved in the conduct 
of the study or review and analysis of data, is unblinded except as indicated below for emergency 
unblinding. Drug concentration information that would unblind the study will not be reported 
to investigative sites or blinded personnel until the study has been unblinded. 
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The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
Investigator has the sole responsibility for determining if unblinding of a participant’s study drug 
assignment is warranted. Participant safety must always be the first consideration in making such 
a determination. If a participant’s study drug assignment is unblinded, the Sponsor must be 
notified within 24 hours after breaking the blinding. The date and reason that the blinding was 
broken must be recorded in the source documentation and case report form, as applicable. 
Appropriate personnel at the Sponsor or sponsor designee will unblind suspected unexpected 
serious adverse reactions (SUSARs) for the purpose of regulatory reporting. The Sponsor will 
submit SUSARs to regulatory agencies in blinded or unblinded fashion according to local law. 
The Sponsor will submit SUSARs to Investigators in a blinded fashion. 
6.5. 
Study Drug Compliance 
When participants self-administer study drug(s) at home, compliance with study drug will be 
assessed at each visit. Participants will be instructed to bring the used and unused study drug 
bottles at every site visit. Compliance will be assessed by counting returned unused capsules 
during the site visits and documented in the source documents and electronic case report form 
(eCRF). Deviation(s) from the prescribed dosage regimen should be recorded in the eCRF. 
Compliance for each clinic visit and overall for the Main Study period and for the OLE period 
will be calculated using the following formulation: 
   Compliance (%) = [Total number of administered doses/Total number of scheduled  
      doses] x 100 
 
The total number of scheduled doses will be calculated based on the extent (days) of exposure 
of each participant. A range between 80% to 120% will be taken as reference limits for a 
satisfactory level of compliance.  
A record of the number of pridopidine capsules dispensed to and taken by each participant must 
be maintained and reconciled with study drug and compliance records. Study drug start and stop 
dates, including dates for study drug delays and/or dose reductions, will also be recorded in the 
eCRF. 
6.6. 
Dosing Regimen and Modifications 
All participants receiving the study drug are intended to receive the same fixed-dose regimen, in 
terms of dose and daily (bid) frequency, according to the study schedule. 
After the Titration period, participants who are unable to tolerate bid schedule will be allowed to 
stay in the study at the lower study drug dose QD schedule for 1 week. After 1 week of study 
drug at QD schedule, the dose will be increased to bid dose schedule. If participants cannot 
tolerate the second increase to bid dose schedule, they will be discontinued from treatment with 
the study drug (refer to Section 7.2). 
6.7. 
Concomitant Therapy 
Any medication or vaccine including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
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• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
The study Medical Monitor (or designee) should be contacted if there are any questions 
regarding concomitant or prior therapy. 
6.7.1. 
Permitted Medication 
For participants taking allowed antipsychotic, antidepressant, antiarrhythmic, or other 
medication, the dosing of medication must be stable for at least 4 weeks before the Baseline visit 
and must be kept constant during the study (unless clinically indicated to change the dose). 
Please refer to Appendix 6, Section 10.6 for the list of permitted medications. 
6.7.2. 
Prohibited Medication 
Medications specifically prohibited in the exclusion criteria are not allowed during the study. If 
there is a clinical indication for any medication specifically prohibited during the study, 
discontinuation from the investigational product may be required. The Investigator should 
discuss any questions regarding this with the study Medical Monitor (or designee), prior, if 
possible, to the administration of prohibited medications and treatments. The final decision on 
any supportive therapy rests with the Investigator and/or the participant's primary physician. 
However, the decision to continue the participant on investigational product requires the mutual 
agreement of the Investigator and the study Medical Monitor (or designee). 
Please refer to Appendix 7, Section 10.7 for a summary of prohibited medications and 
substitution alternatives (note, the list of medications in Appendix 7 is not exhaustive). Any 
investigational agent, other than study drug, is also prohibited. 
Caution should be exercised with medications that are mainly eliminated via the 
CYP2D6 -dependent pathway. 
6.8. 
Treatment of Overdose 
For this study, any dose of pridopidine greater than 180 mg within a 24-hour time period will be 
considered an overdose. 
The Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator/treating physician should: 
1. Contact the study Medical Monitor (or designee) immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities (at least 3 
days). 
2. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the study Medical Monitor (or designee) based on the clinical evaluation of the 
participant. 
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6.9. 
OLE 
Eligible participants who complete the Main Study will have the option to enroll into an OLE 
study and receive pridopidine 45 mg orally bid (total daily dose of 90 mg) for 12 months after 
the last participant completes the double-blind Treatment period. OLE duration may be extended 
pending emerging data from the double-blind portion of the study. 
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7. 
DISCONTINUATION OF STUDY DRUG AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1. 
Individual Participant Stopping Rules from Study Drug 
7.1.1. 
QT Stopping and Monitoring Rules 
Refer to Appendix 8, Section 10.8 for ECG Monitoring Plan during the study. 
QT Stopping Rules: 
• QTcF >500 ms 
• QTcF >480 ms AND ΔQTcF >60 ms from Baseline 
If the local ECG reading results at the site match the above Stopping Rules, the participant will 
discontinue study drug until the central ECG reader’s report is received. If the central reader does 
not report a QTcF interval that leads to discontinuation according to the above, then the 
participant can restart the study drug. 
QT Monitoring Rule: 
• QTcF >480 ms OR ΔQTcF >60 ms from Baseline 
If the local ECG reading results at the site meet the Monitoring Rule, the participant can continue 
the study drug per protocol until the central ECG reader’s report is received. If the central reader 
confirms meeting Monitoring Rule, the participant will stay on study drug (per protocol) and will 
return for a follow-up ECG after 3-14 days. 
If after 3 days QTcF change is confirmed (meets Monitoring Rule) then the participant will be 
discontinued from study drug. 
7.1.2. 
Creatinine Clearance Stopping Rules 
Participants with CrCl <30 mL/min, calculated using the Cockcroft-Gault equation [(140 - age) × 
mass (kg) × [0.85 if female] / 72 × serum creatinine (mg/dL)], at any timepoint after the Baseline 
visit 2 will be requested to return to the clinic for an unscheduled visit 1 week later, to repeat the 
CrCl test one more time for confirmation. If the repeated CrCl value is confirmed to be <30 
mL/min, the participant will be discontinued from the study drug. 
7.1.3. 
Psychiatric Stopping Rules 
Participants with C-SSRS suicidal ideation ≥4 or PBA-s suicidal ideation >3 will be 
discontinued from treatment with study drug.  
7.1.4. 
Seizures 
Participants will discontinue study drug if they experience a seizure or convulsions. 
7.1.5. 
Other Excluded Conditions during Study 
Participants will discontinue study drug in case of occurrence of the following exclusion criteria 
after initiation of treatment: 
• Symptomatic or uncontrolled atrial fibrillation, confirmed ventricular tachycardia, 
presence of left bundle branch block 
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• Intracranial neoplasms, vascular malformations, history of cerebrovascular accident, 
or intracranial hemorrhage 
• Alcohol and/or substance use disorder per DSM-5 
7.1.6. 
Pregnancy 
A participant must permanently discontinue the investigational product if she becomes pregnant. 
See Appendix 4 (Section 10.4.3) and Section 8.3.5 for additional details. 
7.2. 
Discontinuation of Study Drug 
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study drug. A participant may discontinue study drug for reasons including but 
not limited to: 
• AE 
• Death 
• Lost to follow-up 
• Non-compliance with study drug 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Study terminated by Sponsor 
• Withdrawal of consent by participant 
• Loss of capability to consent 
The reason for participant discontinuation from the study drug will be recorded in the eCRF. 
Participants who are discontinued from study drug during the Main Study will be 
encouraged to continue their participation in the study and perform all the scheduled visits 
and assessments, while off study drug. If participants are unable/unwilling to attend in-clinic 
visits, these visits can be replaced with virtual phone visits except for the following: Main Study 
Week 65, Week 78/EoS and ET visits. If a clinic visit is replaced by a virtual visit at Week 4, 
Week 26, Week 39, and Week 52, the UHDRS-TFC, clinical laboratories, and vital signs should 
not be assessed (refer to Appendix 10, Section 10.10). They will continue to be closely 
monitored by the Investigator and will be referred for psychiatric evaluation per the 
Investigator's medical judgment. Participants who are discontinued from study drug during the 
OLE will be withdrawn from the study and will be requested to return to an EoS visit.  
See the SoA (Table 2 – Main Study, and Table 3 – OLE) for data to be collected at the time of 
study drug discontinuation and follow-up and for any further evaluations that need to be 
completed. 
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7.3. 
Participant Withdrawal from the Study 
A participant may withdraw from the study at any time at his/her own request or may be 
discontinued by the Investigator. Participants may be withdrawn from the study for any of the 
following reasons: 
• Death 
• Withdrawal by participant 
• Lost to follow-up 
• Study terminated by Sponsor 
The reason for participant withdrawal from the study will be recorded on the eCRF. At the time 
of withdrawal, ET visit procedures outlined in the SoA (Table 2 – Main Study, and Table 3 – 
OLE) should be completed, if possible. 
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected, based on local regulations, before such a withdrawal of 
consent. Participants withdrawing consent may request destruction of any samples taken and not 
tested, and the Investigator must document this request and proof of destruction in the site study 
records. 
If a participant withdraws from the study, he/she may request the destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
7.4. 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to engage for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit (for exceptions refer to Appendix 10 in Section 10.10): 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 
• Before a participant is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 TCs and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the 
participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole is handled as part of Appendix 1 
(Section 10.1.8). 
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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA (Table 2 – Main Study, 
and Table 3 – OLE). Protocol waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the study Medical Monitor (or 
designee) immediately upon occurrence or awareness to determine if the participant 
should continue or discontinue study drug. 
• Adherence to the study design requirements, including those specified in the relevant 
SoA, 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. 
• Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and 
were performed within the time frame defined in the SoA (Table 2 – Main Study, and 
Table 3 – OLE). 
8.1. 
Efficacy Assessments 
Planned timepoints for efficacy assessments are provided in the SoA (Table 2 – Main Study, 
and Table 3 – OLE). Some efficacy measures can be done by remote assessments, if required. 
Study personnel will be trained to implement these measures remotely by virtual visit (via 
telephone): UHDRS-TFC, PBA-s, and CGI-C. Completion of the applicable eCRF pages should 
be performed at each visit. 
All effort should be made to ensure that the same rater conducts a given rating scale for a given 
participant at all study visits, including virtual visits, to ensure consistency across the study. 
8.1.1. 
United Huntington Disease Rating Scale – Total Functional Capacity 
(UHDRS-TFC) 
The UHDRS-TFC is the standard and well-accepted clinical scale for staging and tracking 
the progression of HD using functional capacity (Shoulson, 1979; Marder, 2000). Scores 
range from 0 to 13, with 13 as the least affected and 0 as complete incapacity. The scale 
assesses the participant's capacity to maintain their domestic chores, activities of daily living, 
finances, care level (home, chronic care, skilled nursing required) and occupation. As 
described below, the scale is designed to detect changes in the early stages of HD (HD1 and 
HD2), and it has an obvious floor effect in advanced HD. 
Functional capacity declines inexorably throughout the course of the disease, but the steepest 
rate of decline occurs in the earlier stages of HD manifestation, corresponding to TFC scores 
of 7 to 13, or HD Stages 1 and 2. Functional decline, as measured by TFC, correlates with 
advancing pathology (as assessed by computerized tomography and more recently, with 
magnetic resonance volumes in TRACK-HD) (Tabrizi, 2012). Natural history studies 
demonstrate that TFC decline parallels the progressive disability in other measures, 
including motor, cognitive, neuropsychiatric, and functional (Tabrizi, 2012; Dorsey, 2013). 
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As paiticipants advance beyond Stage 2 into Stage 3, the annual rate of functional decline in 
TFC lessens, consistent with the known floor effect of this widely used HD assessment tool. 
Observational studies demonstrate an annual decline of approximately 0.8 to 1.2 units per 
year for paiticipants with TFC scores 7 to 13 (Stages 1 and 2), compared to only 0.2 to 0.3 
units per year for participants with TFC scores of 3 to 6 (Stage 3), and less than 0.1 units per 
year for paiticipants with a TFC score under 3 (Stages 4 and 5) (Marder, 2000). 
8.1.2. 
United Huntington Disease Rating Scale - Total Motor Score (UHDRS-TMS) 
The UHDRS comprises a broad assessment of features associated with HD. It is a research 
tool which has been developed to provide a unifo1m assessment of the clinical features and 
course of HD (HSG, 1996). 
The UHDRS-TMS is the standard and well-accepted clinical tool for tracking the 
progression of motor symptoms in patients with HD (HSG, 1996). The motor section of the 
UHDRS assesses motor features of HD with standardized ratings of oculomotor function, 
dysarthria, chorea, dystonia, gait, and postural stability. 
The UHDRS-TMS is the sum of 31 individual motor ratings from the 15 items of the 
UHDRS, with each assessment rated on a 5-point scale from O (normal) to 4 (maximally 
abno1mal). Higher scores indicate more severe motor impairment. 
8.1.3. 
Quantitative Motor (Q-Motor) 
8.1.4. 
Clinical Global Impression 
8.1.4.1. 
Modified Clinical Global Impression of Severity (modified CGI-S) 
The Clinical Global Impression of Severity (CGI-S) is a modified 7-point scale that requires the 
clinician to rate the overall severity of the paiticipant's HD symptoms at the time of assessment, 
relative to the clinician's past experience with paiticipants who have the same diagnosis. 
Considering total clinical experience, a paiticipant is assessed on the severity of illness at the 
time ofrating (Table 6). 
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Table 6: 
Modified CGI-S Score 
Description 
Score 
Normal, not at all ill 
1 
Borderline ill 
2 
Mildly ill 
3 
Moderately ill 
4 
Markedly ill 
5 
Severely ill 
6 
Extremely ill 
7 
8.1.4.2. 
Clinical Global Impression - Change (CGI-C) 
Global improvement will also be rated by the Investigator or designee separately using the 
CGI-C. 
CGI-C Score: 
0 = Not assessed 
1 = Very much improved 
2 = Much improved 
3 = Minimally improved 
4 = No change 
5 = Minimally worse 
6 = Much worse 
7 = Very much worse 
8.1.5.Exploratory Assessments 
8.1.5.1. 
Stroop Word Reading (SWR) 
The SWR is a neuropsychological test commonly used to measure the participant’s attention and 
mental flexibility. It takes advantage of the Stroop effect to assess the ability to inhibit cognitive 
interference that occurs when the processing of a specific stimulus feature impedes the 
simultaneous processing of a second, conflicting stimulus attribute (Stroop, 1935; Scarpina, 
2017). The words in the Stroop Word Reading are in Black print. The participants read the name 
of the colors ("red" "green" "blue”) that appear in black ink/print ("participants are required to 
read names of colors (henceforth referred to as color-words) printed in black ink"). The 
participant’s accuracy and speed at the SWR can be recorded and used to track the progression of 
cognitive deterioration. Scores reflect the number of correct responses in 45 seconds. Higher 
scores indicate better performance. 
8.1.5.2. 
Symbol Digit Modalities Test (SDMT) 
The SDMT is a paper-and-pencil test of psychomotor speed and working memory. 
Participants view a ‘key’ at the top of the page containing symbols paired with numbers. 
The remainder of the page displays rows of symbols, and the participant has 90 seconds to 
write the corresponding number that matches each symbol. 
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8.1.5.3. 
Problem Behaviors Assessment – Short Form (including apathy sub-item) 
Because of the prominence of psychiatric symptoms in HD, it is recommended that the 
PBA-s form be used in all HD studies with any need for behavioral assessment as a 
comprehensive screen for the most common psychiatric symptoms in HD (Craufurd, 2001; 
Kingma, 2008). The PBA-s also includes questions concerning suicidal behavior, a 
particular concern in HD. The PBA-s is based on the same set of core behavioral symptoms 
as the UHDRS behavioral questions, which were used previously as the global psychiatric 
measure in most HD studies. The PBA-s has more detailed questions and more specific 
guidance on administration and scoring. 
The PBA-s is a brief semi-structured interview covering the most common behavioral and 
psychiatric manifestations of HD. The interview is not restricted to a single construct, but 
rather covers several broad symptom domains relevant to HD, comprising 11 items: low 
mood, suicidal ideation, anxiety, irritability, anger/aggressive behavior, loss of motivation, 
perseverative thinking or behavior, obsessive-compulsive behaviors, paranoid thinking, 
hallucinations, behavior suggestive of disorientation. Each symptom is rated for severity on 
a 5-point scale according to detailed scoring criteria which roughly correspond to the 
following: 0 = “not at all”; 1 = trivial; 2 = mild; 3 = moderate (disrupting everyday 
activities) and 4 = severe or intolerable. Each symptom is also scored for frequency on a 5-
point scale as follows: 0 = symptom absent; 1= less than once weekly; 2 = at least once a 
week; 3 = most days (up to and including some part of each day); and 4 = all day, every day. 
Severity and frequency scores are multiplied to produce an overall ‘PBA score’ for each 
symptom. 
If the participant has a positive score 1 and 2 on the suicidal ideation item or depressed 
mood item of the PBA-s, the participant will be monitored more closely and treated 
according to the Investigator's medical judgment. Participants’ PBA-s suicidality scores 1 
and 2 may be handled by study Investigator/neurologist with a consultancy with 
psychiatrists, where necessary, per Investigator’s medical judgment. 
Appropriate clinical care is required for AE/SAE of suicidal ideation/suicidal attempt or a 
significant increase in the suicidality scale from Baseline (e.g., 2-point increase or higher) or 
C-SSRS or PBA-s suicidality score 3 and above. All participants with PBA-s suicidal 
ideation item score >3 will be discontinued from treatment with study drug. Participants 
who are discontinued from treatment may continue their participation in the study and 
perform the scheduled visits and assessments, while off study drug. They will continue to be 
closely monitored by the Investigator and will be referred for psychiatric evaluation per the 
Investigator's medical judgment. 
Assessment can be done by virtual visits or phone calls (via telephone), if required. 
8.1.5.4. 
The Huntington Disease Quality of Life Questionnaire (HDQoL) 
The HD-QoL is a standardized instrument for measuring health-related QoL (Hocaoglu, 
2012). It is a validated disease-specific measure designed for HD, and can provide a 
summary score of overall health-related QoL, as well as scores on several discrete scales. 
HD-QoL is for people who are living with HD; this includes people who are at risk for HD, 
people who have tested positive for the HTT but do not have symptoms, and also for people 
at early to late stages of disease. HD-QoL can be used across the full spectrum of HD. 
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HD-QoL will be completed by the participant. 
8.2. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA (Table 2 – Main Study, 
and Table 3 – OLE). Safety evaluations can be done by remote assessments, if required. Study 
personnel will be trained to perform remote safety assessments of C-SSRS, AE, and concomitant 
medication inquiry by virtual visits (via telephone), and safety TCs. Home visits by health care 
professionals for safety assessment may be provided if in-clinic visits are not possible, including 
safety laboratories, vital signs, and ECG administration. Study procedures should be completed 
within the windows provided in the corresponding SoA and as specified in this section. 
8.2.1. 
Physical Examinations 
• A complete physical examination will include, at a minimum, assessment of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and 
weight will also be measured and recorded. 
• A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen). 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.2.2. 
Vital Signs 
• Vital signs will be measured in a supine position after 5 minutes rest in a quiet setting 
without distractions (e.g., television, cell phones) and will include body temperature, 
systolic and diastolic blood pressure, and heart rate. Thereafter, blood pressure should 
be measured again after standing for 2 minutes. 
• Vital signs will be measured prior to any blood draw that occurs at the same 
timepoint. 
• Home health care professionals may be used to measure vital signs for safety if clinic 
visits will not be possible. Note, this will only occur if the nursing service is activated 
during COVID-19 and the participant is on treatment. 
8.2.3. 
Electrocardiograms 
• 12-lead ECG will be obtained as outlined in the SoA (Table 2 – Main Study, and 
Table 3 – OLE) using an ECG machine that automatically calculates the heart rate 
and measures PR, QRS, QT, and QTc intervals. Home ECG administration may be 
carried out by health care professionals, if in-clinic visits are not possible. 
• In case QTcF prolongation is observed, monitoring procedures and criteria for 
discontinuation of individual participants from treatment with the study drug are 
outlined in Section 7.1 and Appendix 8 (Section 10.8). 
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8.2.4. 
Clinical Safety Laboratory Assessments 
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed 
and the SoA (Table 2 – Main Study, and Table 3 – OLE) for the timing and 
frequency. 
• The Investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
eCRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the Investigator to be more severe than expected 
for the participant's condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or 
baseline or are no longer considered clinically significant by the Investigator or study 
Medical Monitor (or designee). 
− If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, and the Medical 
Monitor notified. 
− All protocol-required laboratory assessments, as defined in Appendix 2 
(Section 10.2), must be conducted in accordance with the Laboratory Manual and 
the SoA. 
− If laboratory values from non-protocol specified laboratory assessments, 
performed at the institution’s local laboratory, require a change in participant 
management or are considered clinically significant by the Investigator (e.g., SAE 
or AE or dose modification), then the results must be recorded in the eCRF. 
• Home visits by health care professionals may be provided for safety blood draws if 
clinic visits will not be possible. Note, this will only occur if the nursing service is 
activated during COVID-19 and the participant is on treatment. 
8.2.5. 
Suicidal Ideation and Behavior Risk Monitoring 
The study population should be monitored appropriately and observed closely for suicidal 
ideation and behavior or any other unusual changes in behavior. Consideration should be 
given to discontinuing study drug in participants who experience signs of suicidal ideation or 
behavior. 
Families and caregivers of participants should be instructed to monitor participants for the 
emergence of unusual changes in behavior, as well as the emergence of suicidal ideation and 
behavior, and to report such symptoms immediately to the study Investigator. 
Baseline assessment of suicidal ideation and behavior and/or treatment-emergent suicidal 
ideation and behavior will be assessed during the study using the PBA-s (see Section 8.1.4.2) 
and the C-SSRS. 
The C-SSRS will be used to rate the participant’s degree of suicidal ideation on a scale 
ranging from “no suicidal ideation” to “active suicidal ideation with specific plan and 
intent” (Posner, 2011). The C-SSRS Baseline version will be completed at Screening (Visit 
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0), while the C-SSRS Since Last Visit version will be completed at all other visits as 
specified in the SoA. Participants with active suicidal ideation, as measured by a score of 4 
or 5 on the C-SSRS at the Screening visit, will not be eligible for the study. 
Assessment should be done through on-site clinic visits, virtual visits (via telephone), and safety 
TCs. Rater consistency should be maintained in all visits, including virtual visits. As much as 
possible, there should be one rater for a participant throughout the study in-clinic, safety TCs, 
and virtual visits. 
In any event of suspected active suicidality (e.g., active suicidal ideation or intent, significant 
suicidal behavior) or clinical findings suggesting that the participant is dangerous to himself 
or herself, the participant should be referred for immediate psychiatric evaluation. 
Participants with a positive C-SSRS suicidal ideation score of 1 and 2 will be monitored 
more closely and treated according to the Investigator's medical judgment. Participants with 
C-SSRS or PBA-s suicidality scores 1 and 2 may be handled by study Investigator/ 
neurologist with a consultancy with psychiatrists, where necessary per Investigator’s medical 
judgment. 
8.3. 
Adverse Events and Serious Adverse Events 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, etc.). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study drug or study procedures, or that caused 
the participant to discontinue the study drug (see Section 7). 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AE and SAEs will be collected from the signing of the ICF until the last Follow-up visit at 
the timepoints specified in the SoA (Table 2 – Main Study, and Table 3 – OLE). Assessment 
should be done through on-site clinic visits, safety TCs, and virtual visits (via telephone). 
An event that emerged during or after treatment or worsened relative to the pretreatment state 
will be recorded as a treatment-emergent adverse event (TEAE). 
All SAEs will be recorded and reported to the Sponsor or designee immediately upon any site 
study staff becoming aware and under no circumstance should this exceed 24 hours, as indicated 
in Appendix 3 (Section 10.3). The Investigator will submit any updated SAE data to the Sponsor 
within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including death, at any time after a 
participant has been discharged from the hospital, and he/she considers the event to be 
reasonably related to the study drug or study participation, the Investigator must promptly notify 
the Sponsor. 
8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
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Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, 
the event is otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.4). Further information on follow-up procedures is provided in Appendix 3 
(Section 10.3). 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the Investigator to the Sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study drug under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study drug under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• For all studies of therapeutic agents, Investigator safety reports must be prepared for 
SUSARs according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
8.3.5. 
Pregnancy 
• Details of all pregnancies in female participants and female partners of male 
participants will be collected as outlined in Appendix 4 (Section 10.4). 
• If pregnancy is reported, the Investigator should inform the Sponsor within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6. 
Death Events 
Timelines for reporting of death events are identical to the requirements for SAE reporting. 
(Appendix 3, Section 10.3). 
8.4. 
Pharmacokinetics 
Blood samples will be collected at the timepoints detailed in the SoA (Table 2 – Main Study) 
for measurements of plasma concentration of pridopidine and its main metabolite (TV45065). 
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In case of an SAE, the aim will be to collect an additional PK sample at the closest time 
possible to the event. Instructions for the collection and handling of the plasma samples will 
be provided in the Laboratory Manual. The dates and times of pridopidine administration 
and the date and timepoint (24-hour clock time) of each pharmacokinetic sample will be 
recorded both on the source documentation and the eCRF. 
Samples will be analyzed for the concentration of pridopidine and its main metabolite 
TV45065 using an appropriate validated method. Incurred sample reanalysis may be 
performed. 
Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 
8.5. 
Pharmacodynamic/Biomarkers 
Potential exploratory assessments include at least plasma NfL protein. 
For biomarkers, blood will be drawn and processed at the timepoints detailed in the SoA 
(Table 2 – Main Study and Table 3 – OLE). 
Details on specimen collection, processing, and handling requirements are provided in the 
Laboratory Manual. 
8.6. 
Pharmacogenetics 
Blood sample will be collected at Screening to examine CAG repeats in the HTT, if historical 
laboratory quantified results or diagnostic test are not available. 
Blood sample for remnant deoxyribonucleic acid (DNA) will also be collected at Screening 
and saved for future exploratory analysis to examine association of genetic variation with 
emergent safety or efficacy findings of pridopidine. 
See Appendix 5 (Section 10.5) for information regarding genetic research. Details on 
processes for collection and shipment and destruction of these samples can be found in the 
Laboratory Manual. 
 
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9. 
STATISTICAL CONSIDERATIONS 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
This protocol section summarizes the planned statistical analyses. A separate SAP will be 
finalized prior to database lock and unblinding the data. The SAP will serve as a complement to 
the study protocol and will supersede the protocol in case of differences. In case of major 
differences between the study protocol and SAP (e.g., changes in the analysis related to the 
primaiy endpoint), a protocol amendment will be considered. 
9.1. 
Statistical Hypotheses 
The null hypothesis represents no difference between the therapeutic efficacy response in the 
active treatment group compai·ed to the placebo group: 
Ho: µA= µp 
HA: µA#: µp 
Where µAis the mean change from Baseline to Week 65 in UHDRS-TFC for paiticipants 
randomized to pridopidine (Active) and µpis the mean change from Baseline to Week 65 in 
UHDRS-TFC for paiticipants randomized to the placebo group. 
Under the alternative hypothesis, there exists a difference between the therapeutic efficacy 
response in the pridopidine (Active) group compared to the placebo group. 
Testing of the statistical hypothesis will be conducted hierai·chically for the prima1y and 
seconda1y endpoints as indicated in Sections 9.4.2 and 9.4.3. Each test will be at a type I enor 
level :'.S 0.05, two-sided to preserve the overall Type I error. As soon as a test yields a p-value 
>0.05 no fmther tests following it will be considered statistically significant. 
9 .2. 
Sample Size Determination 
Under this assumption, a total sample size of 372 paiticipants will provide 94% power using a 
two-tailed t-test at a significance level of 0.05. Assuming a dropout rate of22.5%, a total of 480 
paiticipants needs to be randomized. 
For analysis ofUHDRS-TFC under assumption of Missing Not at Random (MNAR) with 
imputed values for all discontinued participants estimated based on the trajecto1y of placebo 
paiticipants with available data, a treatment difference in change from Baseline for imputed 
values at Week 65 is anticipated to be 0.1 points. The overall difference would then be 0.565 
(0. 7*0. 775+0.1 *0.225) or 0. 7 points for the 77 .5% completers and 0.1 points for the 22.5 % 
paiticipants who discontinue and have imputed data at Week 65. A difference of 0.565 points 
with SD of 1.9 with a sample size of 480 participants would provide 90% power (SAS V 9.4 
PROC POWER). 
9.3. 
Populations for Analyses 
The ITT population is the main analysis population of primaiy endpoint for EMA region. The 
mITT population is the main analysis population for primaiy endpoint in non-EMA regions. For 
all other efficacy analyses, the mITT population is the main analysis population in both EMA 
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and non-EMA regions. The ITT and PP populations will also be used as sensitivity analyses to 
show robustness of results for select secondary endpoints. 
9.3.1. 
Main Study 
Population 
Description 
Intent-to-Treat (ITT) population 
The ITT population will include all randomized 
participants. The participants will be grouped as 
randomized.  
Modified Intent-to-Treat (mITT) 
population 
The mITT set is a subset of the ITT population and will 
include all randomized participants who receive a dose 
of study drug and have valid TFC efficacy assessments 
both at the Baseline visit and at least one post-baseline 
in-clinic timepoint. The participants will be grouped as 
randomized.  
Per Protocol Week 65 (W65PP) 
population 
The per protocol Week 65 set is a subset of the mITT set 
and includes all participants who have a valid in-clinic 
UHDRS-TFC at Week 65, were on study drug with 
compliance > 80% during the study, and did not have 
any important protocol deviations impacting efficacy 
assessment. Per protocol variations will be defined prior 
to unblinding the data and participants subsequently 
grouped as treated. The per protocol set will be used for 
supplementary analysis of the primary and select 
secondary endpoints. 
Per Protocol Week 78 (W78PP) 
population 
The per protocol Week 78 set is a subset of the mITT set 
and includes all participants who have a valid in-clinic 
UHDRS-TFC at Week 78, were on study drug with 
compliance > 80% during the study, and did not have 
any important protocol deviations impacting efficacy 
assessment. Per protocol variations will be defined prior 
to unblinding the data and participants subsequently 
grouped as treated. The per protocol set will be used for 
supplementary analysis of the primary and select 
secondary endpoints. 
Safety population 
The safety set will include all participants receiving at 
least one dose of study drug. The participants will be 
grouped according to the treatment regimen actually 
received. The safety set will be used for safety analyses. 
PK population 
The PK population will include all randomized 
participants who received at least 1 dose of pridopidine 
and have at least 1 valid PK assessment. The 
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Population 
Description 
participants will be grouped according to the treatment 
regimen actually received. 
9.3.2. 
OLE 
 
Population 
Description 
OLE mITT population 
The OLE mITT population will include all participants 
who received at least 1 dose of pridopidine during the 
OLE period, and have at least 1 valid in-clinic UHDRS-
TFC score during the OLE period. 
OLE Safety population 
The OLE safety population will include all participants 
who received at least one dose of pridopidine during the 
OLE period.  
 
9.4. 
Statistical Analyses 
9.4.1. 
General Considerations 
Statistical analysis will be performed using SAS software Version 9.4 or higher. Continuous 
variables will be summarized using the number of participants with available and missing data, 
the mean, the standard deviation, first quartile, median, third quartile, minimum value, and 
maximum value. Categorical variables will be summarized using frequency counts and 
percentages. All collected data will be listed in data listings unless agreed to otherwise with 
regulatory agencies. 
Unless otherwise specified, for all efficacy and safety analyses in Main Study (double-blind) 
Treatment Period, the Baseline will be defined as the last non-missing assessment prior to the 
first dose of study drug. All analyses of Main Study and OLE data will be fully described in the 
SAP. 
9.4.2. 
Analysis of Primary Endpoint 
The primary endpoint is the change from Baseline to Week 65 in the UHDRS-TFC score. Due 
to <2% missing in-clinic visits during COVID-19 pandemic and lack of validation of virtual 
UHDRS-TFC assessments, the analyses of primary endpoint and UHDRS-TFC-related 
secondary endpoints will include only in-clinic UHDRS-TFC assessments. 
Based on the feedback from regulatory agencies, the primary analysis is specified separately for 
the EMA and non-EMA regions based on the primary estimands defined in Section 3.1.2. 
For the EMA, the following is considered the primary analysis: 
The primary endpoint will be compared between the treatment groups using the MMRM. Before 
conducting the MMRM analysis, missing data will be imputed using Multiple Imputation (MI) 
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methods under the assumption of MNAR. For this purpose, Copy-Reference imputation will be 
used, i.e., the trajectories of the participants are assumed to follow the placebo group after the 
discontinuation. The Copy-Reference procedure for imputing the missing data is summarized 
below. 
• First, the ITT dataset will be used to generate monotone missing data. For participants 
with intermittent missing values, before performing MI, a monotone missingness pattern 
will be generated. After this, intermittent missing values will be imputed using the 
Markov Chain Monte Carlo (MCMC) methodology, by repeating the MI procedure 100 
times. This imputation step is based on the Missing at Random (MAR) assumption. 
• After this, the remaining missing data will be imputed sequentially for each in-clinic visit 
(virtual visits are not included in the analysis) (first Week 26, followed by Week 39, etc.). 
Only data from the placebo group will be used for the imputation. Patients with the first 
missing value occurring at Week 26 will have their missing Week 26 value replaced by 
an imputed value from a regression model with treatment group, stratification variables 
(baseline HD stage and baseline neuroleptic use) and the baseline UHDRS-TFC value as 
explanatory variables. In the next step, participants with their Week 39 value missing will 
have their missing Week 39 value replaced by an imputed value from a regression model 
with treatment group, stratification variable (baseline HD stage and baseline neuroleptic 
use), region, baseline UHDRS-TFC value and the Week 26 value as explanatory 
variables. Similar procedure will be used to replace the missing values at the subsequent 
in-clinic visits and each regression model includes the data from all previous in-clinic 
visits as explanatory variables, in addition to the treatment group, stratification variables 
(baseline HD stage and baseline neuroleptic use), region and baseline UHDRS-TFC 
value. 
• Finally, the imputed datasets generated with the approach described above do contain 
only non-missing values and are used as input in the model for the primary analysis of the 
primary endpoint. MMRMs (as described above) will thus be run on each of the 100 
generated imputed datasets. The results from these analyses will be combined to derive 
an overall estimate of the treatment difference at Week 65. 
• MMRM on observed data will be performed as a sensitivity analysis in addition to other 
sensitivity analyses under assumptions of MAR or MNAR. 
For non-EMA regions, the following is considered the primary analysis: 
The primary endpoint will be compared between the treatment groups using MMRM with 
observed cases in the mITT population. All scheduled post-Baseline UHDRS-TFC values from 
in-clinic visits obtained at Weeks 26, 39, 52, and 65 will be used as dependent variables in the 
MMRM. The variables used to stratify the randomization (baseline HD stage and baseline 
neuroleptic use), treatment group, region, visit and the interaction between the treatment group 
and visit will be included as fixed factors and the Baseline UHDRS-TFC value as a covariate in 
the model. The treatment difference at Week 65 will be estimated from the model using 
contrasts. 
An unstructured covariance structure will be applied for MMRM. In case the model will not 
converge with the unstructured covariance structure, the heterogeneous autoregressive (1), 
heterogeneous compound symmetry or the heterogeneous Toeplitz structure, autoregressive (1) 
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or compound symmetry without heterogenous variances (1) will be used instead. The 
denominator degrees of freedom will be computed using the Kenward-Roger method. 
The method of MI under different assumptions of MAR and MNAR will be used as sensitivity 
analyses. 
Further sensitivity analyses, including sensitivity analyses assessing the impact of the COVID-19 
pandemic on study data will be defined in the SAP. 
9.4.3. 
Analyses of Secondary Endpoints 
All secondary and exploratory efficacy analyses on endpoints evaluated as change from 
Baseline, for both EMA and non-EMA regions, will follow treatment policy strategy regardless 
of treatment discontinuation or death. Binary endpoints indicated for responder analyses will 
follow an estimand elaborated below for UHDRS-TFC response. 
Multiplicity Adjusted Secondary Endpoints: 
The key secondary efficacy variable is change from Baseline to Week 65 in cUHDRS and the 
main estimand is defined similarly to non-EMA-Estimand for primary endpoint as described in 
Section 3.1.2. Change from Baseline to Week 65 in cUHDRS will be analyzed using the MMRM 
in mITT population under treatment policy strategy, as described for the primary endpoint in 
Section 9.4.2. Other multiplicity adjusted secondary endpoints (UHDRS-TMS, Q-Motor 
 
 and SDMT), evaluated as change from Baseline to post-baseline visits, will also 
be analyzed similarly to cUHDRS.  
The binary UHDRS-TFC response at Week 65 is defined as achieving improvement or no 
worsening in UHDRS-TFC score, i.e., change from Baseline to Week 65 ≥ 0 points. The 
hypothesis testing is based on the main estimand as follows: 
• Treatment: Pridopidine 45 mg bid or placebo (on background of standard of care) that 
participants are randomized to 
• Population: Early HD Participants (HD1 & HD2) defined through the study 
inclusion/exclusion criteria. The mITT population will be used in analyzing this estimand 
• Variable: Improvement or no worsening (change from Baseline ≥ 0 point) at Week 65 in 
UHDRS-TFC (Defined as responders to treatment) 
• Population Level Summary: Proportion of responders, defined as the proportion of 
participants achieving improvement or no worsening in UHDRS-TFC (change from 
Baseline ≥ 0 point) at Week 65  
• ICEs and Strategies for Addressing ICEs: 
ICEs include treatment discontinuation and will be handled by combining composite 
strategy and hypothetical strategy as follows: 
o Composite strategy: Observed UHDRS-TFC values will be used to determine if a 
participant is a responder or not. For treatment discontinuation due to disease-
progression-related death, or meeting Stopping Rules, the participant will be 
considered a non-responder.   
Hypothetical strategy: For treatment discontinuation due to other reasons not included in 
composite strategy and no TFC data collected afterward, all values after ICEs will be imputed 
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under MAR as if the participants had continued receiving the study treatment. The MAR 
imputation model will include UHDRS-TFC as a continuous response variable as described in 
Section 9.4.2. The UHDRS-TFC response at Week 65 (change from Baseline in UHDRS-TFC ≥ 
0) will then be derived using the imputed UHDRS-TFC score as well as the non-missing 
UHDRS-TFC scores.   
The proportion of participants with improvement or no worsening based on CGI-C (assessed as ≥ 
1 and ≤ 4), will be analyzed using a logistic regression in the mITT population, as described 
above for binary UHDRS-TFC response.  
Non-Multiplicity Adjusted Secondary Efficacy Endpoints: 
The continuous non-multiplicity adjusted secondary endpoints (change from Baseline to post-
baseline visits in UHDRS-TMS, Q-Motor 
 and cUHDRS total score) will be 
analyzed similarly as described in non-EMA-Estimand for the primary endpoint. 
Q-Motor endpoints 
 
The binary non-multiplicity adjusted secondary endpoints, evaluated as proportion of 
participants meeting a given threshold, will be analyzed similarly to UHDRS-TFC response. 
Different thresholds that are clinically meaningful may be used for the responder analyses. 
Further details for secondary analyses will be included in the SAP. 
9.4.4. 
Exploratory Endpoints 
The exploratory endpoints will be analyzed with methods similar to the primary and secondary 
endpoints. Additional details will be provided in the SAP. 
9.4.5. 
Safety Analyses 
The safety analysis will be conducted on the safety dataset. The AEs will be coded according to 
the Medical Dictionary for Regulatory Activities (MedDRA) dictionary. The TEAEs will be 
summarized by treatment group, system organ class and preferred term. Further summaries will 
be done by seriousness, severity and relationship to study drug. 
Vital signs, ECG data and laboratory tests at Baseline at each post-baseline visit, and changes 
from Baseline to each of the post-baseline visits will be summarized with descriptive statistics. 
Shift tables for the laboratory tests based on a classification of values as low, normal, or high 
with respect to the reference range will be summarized. 
For ECG data, absolute QTcF of > 450 ms, > 480 ms, and > 500 ms, changes from Baseline in 
QTcF > 30 ms and ≤ 60 ms, and changes in QTcF > 60 ms throughout the study will be 
summarized. 
All other safety data will be summarized with descriptive statistics. 
9.4.6. 
OLE Analyses 
The final analyses of OLE data will be performed at the End of OLE when all participants 
complete the OLE EoS visit. Interim analyses may be performed as needed.  
Proportion of participants with change of UHDRS-TFC ≥ -1 from Baseline by treatment group 
and the difference between treatment groups at each OLE visit will be provided along with a 2-
sided 95% CIs using normal approximation and p-values from a logistic regression similar to that 
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described for TFC response. This analysis will be repeated using a threshold of O for propo1tion 
of paiticipants with change ofUHDRS-TFC from BaselineĆ 0. 
Sumrnaiy statistics will be presented for UHDRS-TFC, cUHDRS, UHDRS-TMS, Q-Motor 
and Q-Motor 
by treatment group and visit during the OLE period. An MMRM analysis will be 
perfonned on change from Baseline in UHDRS-TFC through the entire study for patients 
switching from placebo in Main Study to pridopidine in OLE, with fixed effects of treatment at 
each period, visit, randomization stratification factors, interaction of treatment and visit within 
the period, and Baseline UHDRS-TFC. The covariance stmcture for the MMRM model will be 
used similarly as described in Section 9.4.2. 
9.4.7. 
PK Analysis 
Descriptive statistics of plasma concentrations of pridopidine and TV 45065 as continuous 
variables additionally with geometric mean and coefficient of variation will be presented by 
treatment groups, scheduled visit and timepoint. 
An exposure-response con-elation between pridopidine plasma concentrations vs change from 
Baseline in efficacy (e.g., UHDRS-TFC) and safety measures (including QTcF), and additional 
covariate analysis may be perfo1med and repo1ted separately as applicable. 
9.4.8. 
Biomarker (N11,) Analysis 
Descriptive statistics of plasma NfL levels and log2 transfo1med NfL levels will be presented by 
treatment group and visit. 
An MMRM will be used to analyze treatment and covai·iate effects on the change from Baseline 
in log2 transfo1med NfL levels. 
The impact oflog2 transfo1med Baseline NfL on change from Baseline to post-baseline visits in 
UHDRS-TFC, cUHDRS, Q-Motor 
UHDRS-TMS, SDMT, and SWR 
accounting for treatment effect and other covariates will also be analyzed using an MMRM. 
Fmthennore, the change from Baseline to post-baseline visits in above efficacy endpoints in 
response to change from Baseline in log2 transfo1med NfL levels will be analyzed using an 
MMRM model accounting for treatment effects and other covai·iates. 
The propo1tion of pa1ticipants with change from Baseline ƈ 0 in log2 NfL levels to post-baseline 
visits will be presented by treatment group with 95% CI with n01mal approximation. Other 
thresholds to dichotomize log2 NfL change will also be explored, and the resulting propo1tions 
by treatment group and the difference between treatment groups in the propo1tions will be 
presented along with 95% CI. 
9.5. 
Interim Analysis 
No interim analyses are planned for this study. 
9.6. 
Safety Monitoring Committee 
During the double-blind treatment period of the Main Study, an independent, unblinded Safety 
Monitoring Committee will assess the safety and if requested efficacy. 
It will be composed of an independent neurologist, cardiologist, and a biostatistician. 
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The conduct and specific details regarding the committee will be outlined in the Safety 
Monitoring Committee Charter which will be finalized prior to the first participant being 
randomized. 
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
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 Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
− Applicable ICH Good Clinical Practice (GCP) Guidelines 
− Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
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. 
• 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 
− 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, and all other applicable 
local regulations 
10.1.2. 
Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate 
financial information as requested to allow the Sponsor to submit a complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
• The Investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study. 
• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 
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Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
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CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or 
study center. 
• The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study. 
• In case of doubt if a participant is able to sign the ICF, it should be confirmed and 
documented by an independent specialist that the affected person is in the position to 
understand the nature, significance, and scope of the interventions in the clinical trial 
and to express their wishes accordingly. 
• A copy of the ICF(s) must be provided to the participant. 
• If a participant withdraws consent for the study, no additional data will be collected, 
and the data processed until the withdrawal of the consent will be used in accordance 
with the applicable data protection laws. 
A participant who is rescreened is not required to sign another ICF if the rescreening occurs 
within 30 days from the previous ICF signature date. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research. The Investigator or authorized designee will explain to each 
participant the objectives of the exploratory research. Participants will be told that they are free 
to refuse to participate and may withdraw their consent at any time and for any reason during the 
storage period. A separate signature will be required to document a participant's agreement to 
allow any remaining specimens to be used for exploratory research. Participants who decline to 
participate in this optional research will not provide this separate signature. 
10.1.4. 
Data Protection 
• Participants will be assigned a unique identifier by the Sponsor. Any participant 
records or datasets that are transferred to the Sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred. Any personal data processing and transfer from European 
Economic Area (EEA) to a non-EEA country will comply with Chapter V General 
Data Protection Regulation in the EU. 
• The participant must be informed that his/her personal study-related data will be used 
by the Sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant who will be required to give consent for 
their data to be used 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. 
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Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
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10.1.5. 
Dissemination of Clinical Study Data 
• A CSR will be developed by the Sponsor at the completion of data analysis. This 
report will be a clinical and statistical integrated report, according to the ICH E3 
guidelines. 
• Sponsor will register the study and post-study results regardless of the outcome on a 
publicly accessible website (e.g., clinicaltrials.gov) in accordance with the applicable 
laws and regulations. 
10.1.6. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic 
eCRF unless transmitted to the Sponsor or designee electronically (e.g., laboratory 
data). The Investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the eCRF. 
• The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-
Based Monitoring), methods, responsibilities and requirements, including handling of 
non-compliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan. 
• The Sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations). 
• Study monitors will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH-GCP, and all applicable 
regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator per ICH-GCP and local regulations or 
institutional policies. 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. 
10.1.7. 
Source Documents 
• Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
Investigator’s site. 
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Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
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• Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• Source documents are original documents, data, and records from which the 
participant’s eCRF data are obtained. These include but are not limited to hospital 
records, clinical and office charts, laboratory and pharmacy records, diaries, 
microfiches, radiographs, and correspondence. 
10.1.8. 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for the recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for reasons related to safety and/or tolerability issues, inability to recruit and retain the target 
population, inability to perform the study due to pandemic related circumstances, decision to 
discontinue development of the product or insolvency of the sponsor. Study sites will be closed 
upon study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• Discontinuation of further study drug development 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the participant and 
should assure appropriate participant therapy and/or follow-up. 
 
 
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Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
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10.2. 
Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 7 will be performed by the central laboratory (unless 
otherwise indicated). 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations. 
• Investigators must document their review of each laboratory safety report in 
participant’s source records. 
Table 7: 
Protocol-Required Safety Laboratory Assessments  
Laboratory 
Parameters – Main Study  
Parameters - OLE 
Serum 
Chemistry 
Calcium, phosphorus, sodium, potassium, 
chloride, magnesium, bicarbonate, 
creatinine, blood urea nitrogen (BUN), 
creatine kinase, uric acid, glucose, 
cholesterol, triglycerides, lactate 
dehydrogenase (LDH), alkaline 
phosphatase, ALT, AST, indirect bilirubin, 
total bilirubin and direct bilirubin, GGT, 
globulin, total protein, albumin 
Calcium, phosphorus, sodium, 
potassium, chloride, magnesium, 
bicarbonate, creatinine, BUN, glucose, 
LDH, alkaline phosphatase, ALT, AST, 
indirect bilirubin, total bilirubin, direct 
bilirubin, GGT, total protein, albumin  
Hematology  
Hemoglobin, hematocrit, RBC, MCH, 
MCHC, MCV, RDW, RBC morphology, 
platelet, WBC (neutrophils, lymphocytes, 
eosinophils, monocytes, basophil) 
Hemoglobin, hematocrit, RBC, MCH, 
MCHC, MCV, RDW, RBC 
morphology, platelet, WBC 
(neutrophils, lymphocytes, eosinophils, 
monocytes, basophil) 
Urinalysis 
Protein, glucose, ketones, bilirubin, 
urobilinogen, hemoglobin, pH, specific 
gravity, appearance, color, leukocyte 
esterase, nitrite, microscopic tests 
(bacteria, erythrocytes, leucocytes, 
crystals, casts, epithelial cells, yeast, 
oval fat bodies, fat, mucous, sperm, 
trichomonas) 
None 
Other 
laboratory 
assessments 
β-HCG pregnancy test (as needed for 
women of childbearing potential) 
Urine pregnancy  
β-HCG pregnancy test (as needed for 
women of childbearing potential) 
Urine pregnancy 
 
 
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Prilenia Therapeutics 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
10.3. 
10.3.1. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting 
Definition of AE 
AE Definition 
• An AE is any untoward medical occmTence in a paiiicipant or clinical study 
paiiicipant, temporally associated with the use of study drng, whether or not 
considered related to the study drng. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnonnal laborato1y finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study diug. 
Events Meeting the AE Definition 
• Any abno1mal laborato1y test results (hematology, clinical chemistiy, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from Baseline, considered clinically 
significant in the medical and scientific judgment of the Investigator (i.e., not 
related to the progression of underlying disease). 
• Exacerbation of a chronic or inte1mit tent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study diug adininisti·ation even though 
it may have been present before the staii of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected di11g-diug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either the 
study di11g or a concomitant medication. Overdose per se will not be repo1ied as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self­
haiming intent. Such overdoses should be repo1ied regardless of sequelae. 
• 
"Lack of efficacy" or "failure of expected pha1macological action" per se will not 
be repo1ied as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be repo1ied as AE or SAE if they folfill the definition of an AE 
or SAE. 
Events NOT Meeting the AE Definition 
• Any clinically significant abnonnal laborato1y findings or other abno1mal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the paiiicipant's condition. 
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DocuSign Envelope ID: 79A0F46O-86E9-4200-BCF E -5435260803CF 
Prilenia Therapeutics 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
10.3.2. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
paiiicipant's condition. 
• 
Medical or surgical procedure ( e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
Situations in which an untowai·d medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the staii of the study that do not worsen. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
ai·e met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
Results in death 
Is life-threatening 
The te1m 'life-threatening' in the definition of 'serious' refers to an event in which the 
paiiicipant 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 
• fu general, hospitalization signifies that the paiticipant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician's office or outpatient setting. Complications that occur during 
hospitalization ai·e AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
"hospitalization" occmTed or was necessaiy, the AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from Baseline is not considered an AE. 
Results in persistent disability/incapacity 
• The te1m disability means a substantial dismption of a person's ability to conduct 
n01mal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diaiThea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with or 
prevent eve1yday life functions but do not constitute a substantial dismption. 
Is a con2enital anomaly/birth defect 
Other situations (Medically important): 
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Prilenia Therapeutics 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
10.3.3. 
• Medical or scientific judgment should be exercised in deciding whether SAE 
repo1iing is appropriate in other situations such as impo1iant medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the pa1iicipant or may require medical or smgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
• Examples of such events include invasive or malignant cancers, 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 dmg 
dependency or dmg abuse. 
Definition of Suspected and Unsuspected Adverse Reaction 
Suspected adverse reactions are defined as: 
• Any AE for which there is a reasonable possibility that the investigational product 
caused the AE. For the pmposes of Sponsor regulato1y safety repo1iing, 
"reasonable possibility" means there is evidence to suggest a causal relationship 
between the investigational product and the AE. A suspected adverse reaction 
implies a lesser degree of ce1iainty about causality than adverse reaction, which 
means any AE caused by the investigational product(s). 
Unexpected adverse events are defined as: 
• AE which is not listed in the 1B or approved label of the investigational product or 
is not listed at the specificity or severity that has been observed. 
10.3.4. 
Recordin2 and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• When an AE/SAE occms, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laborato1y repo1is, and diagnostics 
repo1is) related to the event. 
• 
The Investigator will then record all relevant AE/SAE info1mation in the eCRF 
within 24 homs of Investigator/site awareness of the event. 
• 
It is not acceptable for the Investigator to send photocopies of the paiiicipant's 
medical records to the Sponsor in lieu of completion of the AE/SAE eCRF page. 
• 
There may be instances when copies of medical records for ce1iain cases are 
requested by the Sponsor. In this case, all paiiicipant identifiers, with the exception 
of the paiiicipant number, will be redacted on the copies of the medical records 
before submission to the Sponsor. 
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DocuSign Envelope ID: 79A0F46O-86E9-4200-BCF E -5435260803CF 
Prilenia Therapeutics 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical infonnation. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE repo1ied during 
the study and assign it to 1 of the following categories: 
• 
Mild: An event that is easily tolerated by the paiiicipant, causing minimal discomfort 
and not interfering with eve1yday activities. 
• 
Moderate: An event that causes sufficient discomfo1i and interferes with nonnal 
eve1yday activities. 
• 
Severe: An event that intenupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. An AE that is 
assessed as severe should not be confused with an SAE. Severe is a catego1y utilized 
for rating the intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as 'serious' when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between study drng and each 
occunence of each AE/SAE. 
-
Related - The AE is known to occur with the study diug, there is a reasonable 
possibility that the study diug caused the AE, or there is a temporal relationship 
between the study di11g and event. Reasonable possibility means that there is 
evidence to suggest a causal relationship between the study di11g and the AE. 
-
Not Related - There is not a reasonable possibility that the adininistration of 
the study di11g caused the event, there is no temporal relationship between the 
study diug and event onset, or an alternate etiology has been established. 
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or ai·guments to suggest a causal relationship, rather than a relationship cannot 
be rnled out. 
• 
The Investigator will use clinical judgment to detennine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study diug 
adininistration will be considered and investigated. 
• 
The Investigator will also consult the IB and/or Product Infonnation, for marketed 
products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
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DocuSign Envelope ID: 79A0F46O-86E9-4200-BCF E -5435260803CF 
Prilenia Therapeutics 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
• 
There may be situations in which an SAE has occmTed and the Investigator has 
minimal info1mation to include in the initial report to the Sponsor. However, it is 
very important that the Investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the Sponsor. 
• 
The Investigator may change his/her opinion of causality in light of follow-up 
info1mation and send an SAE follow-up repo1i with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when dete1mining regulato1y 
repo1iing requirements. 
Follow-up of AEs and SAEs 
10.3.5. 
• 
The Investigator is obligated to peifo1m or aiTange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
Sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laborato1y tests or investigations, 
histopathological examinations, or consultation with other health care 
professionals. 
• 
If a paiticipant dies during paiticipation in the study or during a recognized follow­
up period, the Investigator will provide the Sponsor with a copy of any 
post-m01iem findings including histopathology, if available. 
• New or updated info1mation will be recorded in the originally completed eCRF. 
• 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours 
of receipt of the info1mation. 
Reportine of SAEs 
SAE Reporting to the Sponsor via an Electronic Data Collection Tool 
• 
The primaiy mechanism for reporting an SAE to the Sponsor will be the electronic 
data collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool in order to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available and within 24 hours of Investigator/site awareness. 
• After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entiy of new data or changes to existing data. 
• 
If a site receives a repo1i of a new SAE from a study paiiicipant or receives updated 
data on a previously repo1ied SAE after the electi·onic data collection tool has been 
taken off-line, then the site can repo1i this info1mation on a paper SAE fo1m (see 
next section) or to the study Medical Monitor ( or designee) by telephone. 
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Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
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• Contacts for SAE reporting are: 
− When the electronic system is not available please submit paper SAE forms to 
TFS Drug Safety at: safety.tfs@tfscro.com  
 
 
 
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Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
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Version 7.0, Amendment 8 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
10.4.1. 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal, unless 
permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before the first dose of study drug, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
− Documented hysterectomy 
− Documented bilateral salpingectomy 
− Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(e.g., mullerian agenesis, androgen insensitivity), Investigator discretion should be applied to 
determining study entry. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
 
Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
− A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with more than one FSH measurement 
is required. FSH may be repeated twice, separated by at least a month if the result 
of the first instance is more than 30 IU/L. 
• Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
10.4.2. 
Contraception Guidance 
Male Participants 
Male participants are eligible to participate if they agree to the following from informed consent 
through 90 days after the last dose of study drug: 
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Protocol Number: PL101-HD301  
 
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• Refrain from donating sperm, except for the purpose of fertility analysis as part of 
this protocol 
PLUS, either: 
− Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent 
OR 
− Must agree to use contraception/barrier (a male condom) 
Female Participants 
• A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies: 
− Is not a WOCBP 
OR 
− Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of < 1% per year), preferably with low user dependency (see table 
below), from consent through 30 days after the last dose of study drug, and agrees 
not to donate eggs (ova, oocytes) for the purpose of reproduction during this 
period. The Investigator should evaluate the effectiveness of the contraceptive 
method in relation to the first dose of study drug. 
− A WOCBP must have a negative serum pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of β-HCG] at Screening and a negative urine 
pregnancy test before the first administration of study drug. During the Treatment 
period, urine pregnancy tests will be performed monthly. If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test is required, 
and results must be negative. 
Contraceptive use by men or women should be consistent with local regulations regarding the 
use of contraceptive methods for those participating in clinical studies. 
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Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
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Highly Effective Methodsa That Have Low User Dependency  
• Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationb 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS)b 
• Bilateral tubal occlusion 
• Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed. If not, an additional highly effective method 
of contraception should be used. Spermatogenesis cycle is approximately 90 days.) 
Highly Effective Methodsa That Are User Dependent  
• Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation 
− oral 
− intravaginal 
− transdermal 
− injectable 
• Progestogen-only hormone contraception associated with inhibition of ovulationb 
− oral 
− injectable 
• Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the investigational 
product. The reliability of sexual abstinence needs to be evaluated in relation to the duration 
of the study and the preferred and usual lifestyle of the participant.) 
a Failure rate of < 1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
b If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method are not acceptable methods of contraception for this study. 
Male condom and female condom should not be used together (due to risk of failure with friction). 
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Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
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10 November 2022 
 
Version 7.0, Amendment 8 
10.4.3. 
Collection of Pregnancy Information 
Male participants with partners who become pregnant 
• The Investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study. This applies only to male participants who receive pridopidine. 
• After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the Investigator will record pregnancy information on the appropriate 
form and submit it to the Sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
Sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure. 
Female participants who become pregnant 
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the Sponsor within 24 hours of 
learning of a participant's pregnancy. 
• The participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the participant and the neonate, and 
the information will be forwarded to the Sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 
• A spontaneous abortion (occurring at <22 weeks gestational age) or still birth 
(occurring at >22 weeks gestational age) is always considered to be an SAE 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 as described in Section 8.3.5. 
While the Investigator is not obligated to actively seek this information in former 
study participants, he or she may learn of an SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study drug or be withdrawn from the study. 
 
 
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Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
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10 November 2022 
 
Version 7.0, Amendment 8 
10.5. 
Appendix 5: Genetics 
Use/Analysis of DNA 
• Genetic variation may impact a participant’s response to study drug, susceptibility to, 
and severity and progression of the disease. Variable response to study drug may be 
due to genetic determinants that impact drug absorption, distribution, metabolism, 
and excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis from consenting 
participants. 
• DNA samples will be used for research related to Pridopidine or HD and related 
diseases. They may also be used to develop tests/assays including diagnostic tests 
related to study drug and/or interventions of this drug class and HD. Genetic research 
may consist of the analysis of one or more candidate genes or the analysis of genetic 
markers throughout the genome (as appropriate). 
• DNA samples will be analyzed for CAG repeat. Additional analysis related to 
pridopidine response or HD may be conducted if it is hypothesized that this may help 
further understand the clinical data. The Sponsor will adhere to the National 
legislation, including on genetic counselling and processing of health and genetic 
data. 
• Remnant DNA will be saved for future exploratory analysis to examine the 
association of genetic variation with emergent safety or efficacy findings of 
pridopidine. 
• The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to study drug or study drugs of this class to understand study 
disease or related conditions. 
• The results of genetic analyses may be reported in the clinical study report (CSR) or 
in a separate study summary. 
• The Sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
• The samples will be retained while research on study drug continues but no longer 
than 8 years or other period as per local requirements. 
 
 
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Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
96 
10 November 2022 
 
Version 7.0, Amendment 8 
10.6. 
Appendix 6: Permitted Medications 
Note: The list of medications below is not exhaustive; please contact the study Medical Monitor 
(or designee) for any questions. 
Medication Class 
Permitted Medications 
Comments 
Antipsychotic  
Olanzapine, fluphenazine, 
clotiapine, quetiapine, 
thiothixene, acetophenazine, 
triflupromazine, loxapine, 
tiapride, chlorprothixene, 
bromperidol, tiapride and 
amilsupride.  
Aripiprazole, risperidone and 
perphenazine 
Permitted, at no more than 
usual recommended doses in 
the approved labeling. If, 
according to Investigator 
judgment, a change of usage 
or dosage of antipsychotic 
medication is required during 
the study, this should be 
recorded in the eCRF and 
discussed with the study 
Medical Monitor (or 
designee). 
Antidepressants 
SSRIs/SNRIs including 
fluvoxamine*, venlafaxine, 
paroxetine, duloxetine, 
sertraline, as well as 
omipramol (opipramol), 
moclobemide,  
tranylcypromine, buspirone, 
bupropion#, reboxetine and 
dibenzepin 
*Fluvoxamine is permitted, at 
no more than usual 
recommended doses in the 
approved labeling. 
#Bupropion dose should not 
exceed total daily dose of 
450 mg where the daily dose 
is administered 3 times daily 
(with each single dose not to 
exceed 150 mg, and the rate 
of incrementation of dose is 
very gradual) (Wellbutrin®, 
2017). 
Antiarrhythmic 
Mexiletine and tocainide 
Permitted, at no more than 
usual recommended doses in 
the approved labeling. 
Management of Chorea 
Tetrabenazine and 
deutetrabenazine 
Permitted, at no more than 
usual recommended doses in 
the approved labeling. 
Antiviral  
COVID-19 Vaccines 
Vaccination (including 
boosters) should preferably 
not occur within 1 week of a 
study visit to ensure possible 
side effects do not affect the 
assessments  
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Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
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10 November 2022 
 
Version 7.0, Amendment 8 
Medication Class 
Permitted Medications 
Comments 
Other 
Baclofen, bupropion*, 
ciprofloxacin, cyclosporine, 
isoniazid, lindane, 
methylphenidate, 
metronidazole, penicillins, 
theophylline, amantadine, 
morphine, buprenorphine, 
diphenoxylate, alfentanil, 
fentanyl, remifentanil, 
meptazinol and pethidine 
Only if no PK interactions are 
expected. 
*See comment above for 
bupropion 
 
 
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Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
98 
10 November 2022 
 
Version 7.0, Amendment 8 
10.7. 
Appendix 7: Prohibited Medications and Substitution Alternatives 
Note: The list of medications below is not exhaustive. Prohibited medications may include 
different salts, esters, ethers, isomers, complexes, or derivatives of the medications listed below. 
In addition, there may be medications which have the potential to prolong the QT interval which 
are not currently on the list and are not a derivative of a listed medication. In such instances, a 
decision to exclude such a medication will be taken following a discussion with the study 
Medical Monitor (or designee) who will provide the final decision as to whether to allow the 
medication.  
Medication Class 
Excluded Medications Within 4 
Weeks of the Baseline Visit 
(unless otherwise noted) 
Substitution Alternatives 
(dosing of alternative medications 
must have been stable for at least 
4 weeks before the Baseline visit and 
must be kept constant during the 
study) 
Antipsychotics 
Haloperidol, mesoridazine, 
thioridazine, pimozide, 
chlorpromazine, sulpiride and 
levomepromazine 
 
Olanzapine, fluphenazine, clotiapine, 
quetiapine, thiothixene, 
acetophenazine, triflupromazine, 
loxapine, tiapride, chlorprothixene, 
bromperidol, tiapride and amilsupride. 
Aripiprazole, risperidone, and 
perphenazine are permitted, at no 
more than usual recommended doses 
in the approved labelling. 
If, according to Investigator judgment, 
a change of usage or dosage of 
antipsychotic medication is required 
during the study, this should be 
recorded in the eCRF and discussed 
with the study Medical Monitor (or 
designee). 
Antidepressants 
Citalopram >20 mg/day, 
escitalopram >10 mg/day and 
fluoxetine 
 
Allowed and carefully monitored: 
amitriptyline, nortriptyline, 
imipramine, desipramine, doxepin, 
clomipramine, protriptyline, and 
amoxapine, the serotonin –
norepinephrine reuptake inhibitors, 
and trazodone (allowed up to 100 
mg/day). 
SSRIs/SNRIs including venlafaxine, 
paroxetine, duloxetine, sertraline, as 
well as omipramol (opipramol), 
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Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
99 
10 November 2022 
 
Version 7.0, Amendment 8 
Medication Class 
Excluded Medications Within 4 
Weeks of the Baseline Visit 
(unless otherwise noted) 
Substitution Alternatives 
(dosing of alternative medications 
must have been stable for at least 
4 weeks before the Baseline visit and 
must be kept constant during the 
study) 
moclobemide, tranylcypromine, 
buspiron, reboxetine, and dibenzepin.  
Fluvoxamine is permitted, at no more 
than usual recommended doses in the 
approved labelling. 
Bupropion dose should not exceed 
total daily dose of 450 mg where the 
daily dose is administered 3 times 
daily (with each single dose not to 
exceed 150 mg, and the rate of 
incrementation of dose is very 
gradual) (Wellbutrin®, 2017). 
Antiarrhythmics 
Disopyramide, procainamide, 
flecainide, propafenone, 
amiodarone (within 6 weeks of 
Baseline visit), dofetilide, ibutilide 
and sotalol 
Mexiletine and tocainide 
At no more than usual recommended 
doses in the approved labelling. 
Other 
Astemizole, terfenadine, 
azithromycin, erythromycin, 
moxifloxacin, pentamidine, 
sparfloxacin, clarithromycin, 
chloroquine, hydroxychloroquine, 
halofantrine, bepridil, cisapride, 
domperidone, droperidol, 
levomethadyl, sevoflurane, 
anagrelide, budipine, fluconazole, 
levofloxacin, lidoflazine, 
ondansetron, probucol, terodiline 
and vandetanib 
Allowed medications with lowering 
seizure thresholds but for which no 
PK interactions are expected are 
baclofen, bupropion, ciprofloxacin, 
cyclosporine, isoniazid, lindane, 
methylphenidate, metronidazole, 
penicillins, theophylline, 
amantadine, morphine, 
buprenorphine, diphenoxylate, 
alfentanil, fentanyl, remifentanil, 
meptazinol, and pethidine. 
 
 
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Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
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10 November 2022 
 
Version 7.0, Amendment 8 
10.8. 
Appendix 8: ECG Monitoring Plan 
ECG Monitoring Flow 
During in-clinic visits: 
For all participants, ECG will be administered at Screening, Baseline, Week 4 (V3), Week 26 
(V4) and Week 65 (V7). 
At Screening, a single 12-lead ECG will be administered to assess eligibility. 
At Baseline (V2) Visit:  
• A triplicate 12-lead ECG will be administered BEFORE 1st drug administration to 
determine the participant baseline QTcF. 
• A single 12-lead ECG will also be administered 1-2 hours POST 1st drug administration. 
At Week 4 (V3), a single 12-lead ECG will be administered 1-2 hours post-study drug 
administration. 
At Week 26 (V4) and Week 65 (V7), and Week 78 (V8/EoS/ET) for participants not continuing 
to OLE a single 12-lead ECG will be administered before study-drug administration. 
1. Screening Visit (V1) 
• QTcF will be measured by a single12-lead ECG administration 
• If the QTcF is >450 ms for men and >470 ms for women, then ECG will be repeated 
twice11 and the QTcF will be determined by the average of the 3 ECGs 
• If mean QTcF is >450 ms for men and >470 ms for women, then the participant will 
screen fail and will not be randomized 
2. Baseline Visit (V2) ECG will be administered before first study drug administration: 
• QTcF will be measured by a mean of 3 12-lead ECG administrations (triplicate) 
2. Baseline Visit (V2) and Week 4 (V3), single 12-lead ECG will be administered 1-2 hours 
post-study drug administration (Figure 3) 
3. Week 26 and 65 visits or ET, single 12 lead ECG will be administered before study drug 
administration (Figure 3) 
 
11 Standard ECG administration for abnormal QTcF readings will be for the ECG to be repeated twice (at least 5 
minutes after the 1st ECG, and with an interval of at least 1 minute between each of the 2 additional 10-second 
recordings), and the mean of the 3 screening administrations will be used to determine final QTcF. 
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Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
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10 November 2022 
 
Version 7.0, Amendment 8 
Figure 3: 
ECG Monitoring Flow 
 
 
• QTcF will be measured by a single 12-lead ECG 
• If QTcF meets Stopping/Monitoring Rules, then ECG will be repeated twice12 and the 
QTcF will be determined by the average of the 3 ECGs 
• If the average QTcF meets Stopping Rules (confirmed by central read ECG), then the 
participant is withdrawn from study drug and a follow-up ECG will be performed as 
soon as practicable (after 2 days) to ensure recovery from QT prolongation 
• If the average QTcF meets Monitoring Rule (confirmed by central read ECG), the 
participant will continue with the study drug per protocol, and will be followed as 
detailed under Monitoring Rule procedure 
Home ECG monitoring 
• Home visits by health care professionals for ECG administration may be provided if in-
clinic visits are not possible. 
Study personnel will confirm that the remote recordings are of sufficient quality to allow for 
interpretation (participant can record trace without artifact that would impair the ability to measure 
and interpret the trace). 
 
12 ECG will be repeated twice (at least 5 minutes after the 1st ECG, and with an interval of at least 1 minute between 
each of the 2 additional 10-second recordings), and the mean of the 3 screening administrations will be used to 
determine final QTcF. 
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Prilenia Therapeutics 
10.9. 
Appendix 9: QT Safety Data 
AEs Indicating Proarrhythmic Potential 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
fu accordance with the ICH E14 Guideline, Clinical Evaluation of QT/QTc futerval Prolongation 
and Proanhythinic Potential for Non-Antianhythinic Dmgs, the safety database was analyzed for 
rates of clinical events indicating a proanhythinic potential, and the rates observed in treated and 
control paiiicipants were compared. An analysis of the full safety database that includes all 
paiiicipants treated with at least one dose of pridopidine found no events of torsade de pointes 
following treatment with pridopidine at doses of up to 112.5 mg bid. One AE of ventricular 
anhythmia was repo1ied. 
Exposure-response analysis of OT Proloneation 
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Prilenia Therapeutics 
-
CONFIDENTIAL 
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Study drng: P1idopidine 
Protocol Number: PL101-HD301 
10 November 2022 
Version 7.0, Amendment 8 


Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
104 
10 November 2022 
 
Version 7.0, Amendment 8 
10.10. 
Appendix 10: Guidance to Address Global Health Emergencies and 
Potential Impact on the Clinical Study 
As of March 12, 2020, a Coronavirus Disease 2019 (COVID-19) pandemic has been declared by 
the World Health Organization, leading to the implementation of extensive measures by 
healthcare systems globally to limit the viral spread, with potential impact on the conduct of 
clinical studies (because participants/healthcare workers are in self-isolation/quarantine, there is 
limited access to public places, including hospitals, and health care professionals are committed to 
critical tasks). 
Based on guidelines issued by global regulatory authorities (Health Canada, April 7, 2020; 
Australian Government, April 9, 2020; EMA, April 2020; MHRA, March 19, 2020; FDA, March 
2020), the actions listed below are being implemented in this protocol to address potential 
disruptions to study conduct secondary to COVID-19 infection or control measures. These 
actions are to assure the safety of study participants, maintain compliance with good GCP, and 
minimize the risks to study integrity. Member states within the National Competent Authorities 
may issue their own guidance requiring country-specific recommendations to be followed. 
To the extent feasible, the Sponsor should ensure that the methods and conduct of remote 
assessments are consistent across sites, participants, and visits. 
Informed Consent 
• If written consent by the study participant is not possible (for example because of 
physical isolation due to COVID-19 infection), consent could be given orally by the 
study participant. Site would record the date and time of discussion. 
• Study participants and the person obtaining consent could sign and date separate 
ICFs. 
• In case a written informed consent cannot be obtained at the clinical site informed 
consent can be obtained remotely. Alternatively, the consent form may be sent to the 
participant by facsimile or e-mail, and the consent interview may then be conducted 
remotely by telephone when the participant can read the consent form during the 
discussion; the participant will be requested to sign and date a blank piece of paper 
with a written statement affirming that they agree to participate in the study. 
• If re-consent is necessary for the implementation of new urgent changes in study 
conduct (mainly expected for reasons related to COVID-19 or important safety issues 
for other trials), alternative ways of obtaining may include contacting the study 
participant via telephone and obtaining oral consents, to be documented in the study 
participants’ medical records, supplemented with e-mail confirmation. 
• The informed consent procedures to remain compliant with the study protocol as well 
as local regulatory requirements should be followed. All relevant records should be 
archived in the Investigator’s site master file. A correctly signed and dated ICF 
should be obtained from the study participants later, as soon as possible. 
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Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
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10 November 2022 
 
Version 7.0, Amendment 8 
Study Visits and Procedures 
• COVID-19 screening procedures that may be mandated by the health care system in 
which a clinical study is being conducted do not need to be reported as an amendment 
to the protocol even if done during clinical study visits. The Investigator in 
consultation with the Sponsor will decide if it is in the best interest of 
COVID-positive participants to remain in the study. 
• In the case of missed visits due to COVID-19 (or other health/pandemic) related 
reasons: 
− The site should make every effort to contact the study participant to confirm and 
document the reason for the missed visit, and at minimum evaluate AEs/SAEs, 
and concomitant medications in order to assess participant safety. 
• To maintain the integrity of the study, alternative methods of collecting study 
procedures may be considered where possible and in certain situations, with Sponsor 
approval: 
− Four Virtual visits have been incorporated as part of the study in addition to on 
site clinic visits and safety phone visits. Remote study assessments can be 
completed virtually (via telephone). 
− If on site clinic visits are not possible the visits can be converted to virtual visits 
(except Screening, Baseline and Week 65) (via telephone). 
− Study assessments will only be conducted in a remote manner if they can be done 
without affecting the wellbeing of the participant during the study and with the 
same level of scientific integrity as assessments conducted in a physical study 
center. 
− According to site operations during public health pandemics, home visits by a 
health care professional may be used to collect laboratory samples, obtain an 
ECG, and perform assessments as required by the protocol. 
− A local laboratory may be used to collect laboratory samples as required by the 
protocol. Local analysis can be used for safety decisions. In addition, a local 
laboratory can be used for study endpoints if samples drawn at the local 
laboratory cannot be shipped to the central laboratory. If a local laboratory is 
used, applicable lab ranges and laboratory certification should be provided to the 
Sponsor. 
− Data collected from participants participating in remote visits/assessments may be 
collected electronically using purpose-built technology, or via traditional paper-
based methods. AE/SAE (reporting, assessing and follow-ups) will be handled 
similarly to a traditional model, with the participant contacting study personnel or 
engaging local care for public health emergencies. 
− In cases where a participant is continuing to receive study drug but COVID-19 
pandemic-related circumstances preclude a visit to the investigative site, remote 
visits (e.g., virtual visits via telephone) will be allowed for relevant study 
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Prilenia Therapeutics 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
procedures while maintaining paiiicipant's privacy, as would be done for a clinic 
visit. 
-
For missed assessments for primaiy and secondaiy endpoints, please discuss these 
situations with the Sponsor for approval. In ce1iain situations, with prior approval, 
other options or delayed visits, can be considered. 
• 
The PROOF-HD study is being conducted during the COVID-19 global pandemic 
and inco1porates several mitigation strategies that ai·e included in the protocol and 
study plans. Table 8 sUilllnai·izes the Visit Activities according to the Visit Types (in­
clinic visits, pre-planned virtual visits and conve1ied viiiual visits (home/phone). 
Table 8: 
Study Visit Activities per Visit Type 
Study Period 
In-Clinic 
Procedures and Assessments 
Visit 
Infonned consent 
✓ 
Demography 
✓ 
Medical and psychiatric histo1y 
✓ 
Prior medication and treatment 
✓ 
hist01y 
Inclusion and exclusion criteria 
✓ 
Clinical laborato1y tests ( senun 
chemistry, hematology, and 
✓ 
urinalysis)* 
Pregnancy test (for WOCBP)* 
✓ 
Full physical and neurological 
✓ 
examination 
Brief physical exainination 
✓ 
12 lead ECG 
✓ 
Vital signs* 
✓ 
C-SSRS (baseline version) 
✓ 
C-SSRS (since last visit version) 
✓ 
UHDRS-TFC* 
✓ 
UHDRS-TMS 
✓ 
UHDRS-IS 
✓ 
SDMT 
✓ 
CONFIDENTIAL 
106 
Pre-
planned 
Virtual 
Visits 
(Phone) 
✓ 
✓ 
Converted VV 
(Home/Phone) 
✓ (Home Nursing Service) 
✓ (Home Nursing Service) 
✓ (Home Nursing Service) 
✓ (Phone) 
✓ (Phone) 
10 November 2022 
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Prilenia Therapeu tics 
Study Period 
In-Clinic 
Procedures and Assessments 
Visit 
SWR 
✓ 
Q-Motor 
✓ 
PBA-S (Sho1i Fo1m) 
✓ 
CGI-S (modified) 
✓ 
CGI-C 
✓ 
HDQoL-P 
✓ 
Benzodiazepines and 
✓ 
antidepressants inquiiy 
Alcohol/illicit dmg use inquiiy 
✓ 
Review of tolerability to study 
✓ 
dmg prior to dose escalation 
Randomization 
✓ 
Dispense/collect study diug* 
✓ 
Review study compliance and 
✓ 
adherence* 
Adverse event inqui1y 
✓ 
Concomitant medication inquiiy 
✓ 
Blood samples for PK analysis 
✓ 
Plasma sample for biomarkers 
✓ 
analysis 
Blood sample for genetic 
✓ 
analysis 
ECG 
✓ 
✓-Yes, assessment done 
Pre-
planned 
Virtual 
Visits 
(Phone) 
✓ 
✓ 
✓ 
✓ 
✓ 
S tudy drng: P1idopidine 
Protocol Number: PL101-HD301 
Converted VV 
(Home/Phone) 
✓ (Phone) 
✓ (Phone) 
✓ 
✓ (Phone) 
✓ (Phone) 
✓ (Qualified provider) 
✓ (Home Nursing Service) 
✓ (Phone) 
✓ (Phone) 
* Participants who are off study dmg and continue to participate in the study and have their clinic visits converted to virtual visits 
(by phone) will not be required to undergo UHDRS-TFC assessment or get home nursing services during the conve1ted virtual 
visits. 
Study Drug Supply 
• Alternative methods of supplying s tudy di11g to emolled s tudy paiiicipants (e.g., 
direct-to-paiiicipant shipment from site) may be considered where possible. 
• Additional study diug will not be released to the paiiicipant without an evaluation of 
paiiicipant safety, including protocol-required laborato1y results (at minimum 
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Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
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hematology, clinical chemistries, pregnancy for WOCBP measurements, and ECG 
administration), and clearance communicated to the participant. 
• In case a participant is unable to attend in-clinic visits or study personnel is not 
available at the site, where study drug compliance is assessed, accountability for 
compliance purposes can be done by a home health care professional. In both cases, 
when possible, the study drug will be return to the site for accountability. 
• Drug accountability will also be conducted at home visits by health care 
professionals. 
Monitoring and Audits 
• Certain Sponsor oversight responsibilities, such as monitoring and quality assurance 
activities need to be re-assessed and temporarily, alternative proportionate 
mechanisms of oversight may be required. On-site audits will be avoided or 
postponed, and if permitted under local regulations, social distancing restrictions 
should apply. 
• Cancelling or postponing of on-site monitoring visits and extending the period 
between monitoring visits will be allowed. 
• To the extent on-site monitoring remains feasible, it should take into account national, 
local and/or organizational social distancing restrictions. 
• Centralized monitoring can be considered for data acquired by EDC systems (e.g., 
eCRFs, central laboratory or ECG / imaging data, ePROs etc.) that are in place or 
could be put in place provides additional monitoring capabilities that can supplement 
and temporarily replace on-site monitoring through a remote evaluation of ongoing 
and/or cumulative data collected from trial sites, in a timely manner. 
• Off-site monitoring can be conducted and will include phone calls, video visits, 
e-mails or other online tools in order to discuss the study with the Investigator and 
site staff. Remote monitoring should be focused on the review of critical study-site 
documentation and source data; source documents and ICF with PHI redacted will be 
sent to the monitor for review. These activities could be used to get information on 
the clinical study progress, to exchange information on the resolution of problems, 
review of procedures, study participant status as well as to facilitate remote site 
selection and Investigator training for critical study procedures. 
COVID-19 Vaccination 
• Several vaccines for COVID-19 have been approved worldwide. 
• The Sponsor does not have specific data regarding any possible interaction between 
the COVID-19 vaccines and study drug and has no evidence or rationale to suggest 
that study drug alters the vaccine’s efficacy or increases the vaccine’s toxicity. 
• In the current study COVID-19 vaccines (and boosters) are allowed as concomitant 
medication per the discretion of the Investigator, based on current standard of care 
and published guidelines, institutional policies and the participant’s values and 
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Version 7.0, Amendment 8 
preference. The investigator must document participant’s receipt of the COVID-19 
vaccine as part of concomitant medicine in the eCRF. 
• Vaccination should preferably not occur within 1 week of a study visit to ensure 
possible side effects do not affect the assessments 
Risk Mitigation 
• The Sponsor will continually assess whether the limitations imposed by the COVID-
19 public health emergency on protocol implementation pose new safety risks to the 
study participants, and whether it is feasible to mitigate these risks by amending study 
processes and/or procedures. 
 
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Version 7.0, Amendment 8 
10.11. 
Appendix 11: Abbreviations 
Abbreviation Term 
Description 
AE 
Adverse event 
ALT 
Alanine aminotransferase  
AST 
Aspartate aminotransferase  
BDNF 
Brain-derived neurotrophic factor  
bid 
Twice daily  
CAG 
Cytosine-adenine-guanine  
CGI-C 
Clinical Global Impression of Change 
CGI-S 
Clinical Global Impression of Severity (modified) 
CIOMS 
Council for International Organizations of Medical Sciences  
COVID-19 
Coronavirus Disease 2019 
CrCl 
Creatinine clearance 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
cUHDRS 
Composite Unified Huntington’s Disease Rating Scale 
CYP2D6 
Cytochrome P450 2D6 
D2 
Dopamine 2  
D3 
Dopamine 3 
DCL 
Diagnostic confidence level  
DNA 
Deoxyribonucleic acid 
DSM-5 
Diagnostic and Statistical Manual–Fifth Edition 
ECG 
Electrocardiogram  
eCRF 
Electronic case report form  
EDC 
Electronic Data Capture 
EEA 
European Economic Area 
EMA 
European Medicines Agency 
EoS 
End of Study  
ER 
Endoplasmic reticulum  
ERK 
Extracellular-signal-regulated kinase 
ET 
Early termination 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone  
GCP 
Good Clinical Practice 
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Protocol Number: PL101-HD301  
 
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Version 7.0, Amendment 8 
Abbreviation Term 
Description 
GGT 
Gamma-glutamyl transferase 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HD 
Huntington disease  
HDQoL 
Huntington Disease Quality of Life Questionnaire 
HIPAA 
Health Insurance Portability and Accountability Act  
HIV 
Human immunodeficiency virus 
HRT 
Hormone replacement therapy  
HTT 
Huntingtin gene 
IB 
Investigator’s Brochure  
ICE 
Intercurrent event 
ICF 
Informed consent form  
ICH 
International Council for Harmonisation  
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug Application 
IOI 
Inter-onset interval 
iPSC 
Induced pluripotent stem cells  
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IS 
Independence Scale  
ITT 
Intent-to-treat  
LDH 
Lactate dehydrogenase  
LS 
Least squares 
MAM 
Mitochondria-associated membrane 
MAR 
Missing at Random 
MedDRA 
Medical Dictionary for Regulatory Activities  
mHTT 
Mutant huntingtin 
MI 
Multiple Imputation 
mITT 
Modified intent-to-treat  
MMRM 
Mixed Model for Repeated Measurements 
MNAR 
Missing Not at Random 
NfL 
Neurofilament light chain 
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Version 7.0, Amendment 8 
Abbreviation Term 
Description 
OLE 
Open-label Extension 
PBA-s 
Problem Behaviors Assessment – Short Form 
PET  
Positron emission tomography 
PK 
Pharmacokinetics 
PMM 
Pattern-mixture model 
PO 
Oral, per os 
QD 
Once daily  
Q-Motor 
Quantitative motor 
QoL 
Quality of life  
QTcF 
Fridericia-corrected QT interval  
RAF 
Randomization Authorization Flow 
S1R 
Sigma-1 receptor 
SAE 
Serious adverse event  
SAP 
Statistical analysis plan  
SDMT 
Symbol Digit Modalities Test  
SoA 
Schedule of Activities  
SUSAR 
Suspected unexpected serious adverse reaction 
SWR 
Stroop word reading 
TC 
Telephone call  
TEAE 
Treatment-emergent adverse events  
TFC 
Total functional capacity 
TMS 
Total Motor Score 
UHDRS 
Unified Huntington Disease Rating Scale 
ULN 
Upper limit of normal 
V 
Visit 
VV 
Virtual Visit(s) 
W65PP 
Per Protocol Week 65 Population 
W78PP 
Per Protocol Week 78 Population 
Wk 
Week 
WOCBP 
Woman of childbearing potential  
β-HCG 
β-human chorionic gonadotropin 
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Prilenia Therapeutics 
10.12. 
Appendix 12: Protocol Amendment History 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
The Protocol Amendment Summaiy of Changes Table for the cmrnnt amendment is located 
directly before the Table of Contents (TOC). 
Below are summai·ies of prior amendment(s) in reverse chronological order. 
Amendment 7, 27 January 2022 
Overall Rationale for the Amendment: 
The Sponsor has introduced the following modifications to protocol V6.0; these changes ai·e 
from V5.0 (Amendment 6.0) and are presented in order of appearance: 
Section # and Name 
1.1 Synopsis 
(Overall Design) 
1.3.1 Schedule of Activities 
-Main study 
4.1 Overall Design 
1.1 Synopsis (Objectives 
and Endpoints) for Open­
label Extension (OLE) 
3.2 OLE Objectives and 
Endpoints 
1.2 Study Scheme Figure 2 
1.3.2 Schedule of Activities 
- Open-label Extension 
1.3.1 Schedule of Activities 
-Main study 
CONFIDENTIAL 
Description of Change 
• Cla1ify timing of End of Study 
(EoS) visits after last participant 
reaches Week 65 
• Add Q-Motor to efficacy 
endpoints 
• Renumber and rename OLE visits 
• Reduce number of phone visits 
• Add info1med consent for OLE 
and willingness to enter OLE 
• Cla1ify that at V8, single ECG 
will be conducted for pruticipants 
not continuing to OLE, and 
triplicate ECG for pruticipants 
continuing to OLE 
• Update to conduct C-SSRS (since 
last visit) at each visit and delete 
footnote 'p' 
113 
Brief Rationale 
• For clruity 
• 
• For clruity, especially as 
pruticipants may roll over 
between Week 65 and 78 
• Pridopidine appears to be safe 
and tolerable, and therefore 
acceptable to decrease visit 
frequency and reduce pa1ticipant 
burden 
• To ensure study drng availability 
for pruticipants ente1ing OLE 
• For clruity; Safety measure for 
pruticipants who continue on 
study drng through the OLE 
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Section # and Name 
1.3.2 Schedule of Activities 
Open-label Extension 
6.5 Study Drng Compliance 
7.2 Discontinuation of 
Study Drng 
10.10 Appendix 10 
Guidance to Address 
Global Emergencies and 
Potential hnpact on the 
Clinical Study 
7.2 Discontinuation of 
Study Drng 
Appendix 2 Clinical 
Laborato1y Tests 
10.6 Appendix 6 Pe1mitted 
Medications 
10. 7 Appendix 7 
Prohibited Medications and 
Substitution Alternatives 
General 
CONFIDENTIAL 
Description of Change 
• Add vital signs at OLE EoS 
• Update to conduct C-SSRS (since 
last visit) at each visit and delete 
footnote 'f 
• Add Q-Motor assessment at each 
in-clinic visit 
• Cla1ify procedures for calculating 
study drng compliance 
• Cla1ify that pruticipants who 
discontinue study drng during the 
Main study can have phone 
virtual visits (instead of in-clinic 
visits), except for ET visit, Week 
65 and Week 78/EoS. If clinic 
visits ru·e conve1ted to virtual 
visits (by phone), UHDRS-TFC, 
clinical laboratodes, and vital 
signs will not be assessed 
• Cla1ify that pruticipants who 
discontinue study drng during the 
OLE will also be withdrawn from 
the study and attend OLE EoS 
visit 
• Update laborato1y pru·ameters to 
be done in OLE 
• Align pe1mitted medications 
(Appendix 6) and Substitution 
alternatives (Appendix 7) 
• Update version and date 
• Update table of contents 
• Update for consistency 
throughout protocol (including 
te1minology) 
• Update cross reference / linking 
throughout 
• Minor corrections/updates 
throughout (punctuation, 
fo1matting, style, etc.) 
114 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
Brief Rationale 
• Omitted by enor 
• For clruity 
• To reduce the burden on 
pruticipants who ru·e not on study 
drng 
• For clruity 
• Pridopidine appears to be safe 
and tolerable and therefore 
acceptable to optimize the 
laborato1y tests and reduce 
pruticipant burden 
• For consistency and accuracy 
10 November 2022 
Version 7.0, Amendment 8 


Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
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10 November 2022 
 
Version 7.0, Amendment 8 
Amendment 6, 13 May 2021 
Overall Rationale for the Amendment: 
The Sponsor has introduced the following modifications to protocol V5.0; these changes are 
from V4 (Amendment 3) and are presented in order of appearance:  
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
(Objectives/Endpoints) 
3.2 OLE Objectives and 
Endpoints 
• Add objectives and endpoints for 
OLE 
• Per feedback from ANSM, the 
French competent authority (this 
was incorporated in V4.2 
Amendment 5.0 – French 
Country-specific Amendment) 
1.1 Synopsis  
(Overall Design) 
4.1 Overall Design 
• Add number of clinical sites 
included in the study 
• Per feedback from French Ethics 
Committee (this was 
incorporated in V4.1 Amendment 
4.0 -French Country-specific 
Amendment) 
1.1 Synopsis 
(Inclusion/Exclusion 
Criteria) 
5.2 Inclusion Criteria-Main 
Study 
• Add inclusion criterion 14 on 
concomitant medication use 
• For safety purposes, participants 
should be on stable dosages of 
concomitant medications at the 
start of the baseline visit 
1.1 Synopsis 
(Inclusion/Exclusion 
Criteria) 
5.3 Exclusion Criteria-
Main Study  
• Update exclusion criterion no. 2c 
(based on clinically significant 
bradycardia) 
• To allow inclusion of participants 
with heart rate lower than 50 
bpm if not clinically significant 
• Add exclusion criterion no. 11 to 
exclude participation in studies 
with tominersen 
• Avoid interfering with the 
important ongoing follow-up for 
these patients 
 
• Clarify exclusion criterion 13e 
associated with total bilirubin 
• To exclude non- clinically 
significant cases and benign 
conditions of elevated bilirubin 
(such as Gilbert’s syndrome) 
• Correct exclusion criterion no. 14 
to read ‘Substance Use disorder’ 
• Per DSM-5 definitions 
• Change exclusion criterion no.14 
• To add timeframe for suicidal 
ideations 
• Update title of section headings 
• For clarity 
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Protocol Number: PL101-HD301  
 
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Version 7.0, Amendment 8 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
(Inclusion/Exclusion 
Criteria) 
5.2 Inclusion Criteria -
Open-label Extension  
• Add OLE informed consent 
requirement in synopsis and 
Section 5.2 
• Per feedback from ANSM, the 
French competent authority (this 
was incorporated in V4.2 
Amendment 5.0 -French 
Country-specific Amendment) 
1.1 Synopsis (Study 
Duration) 
4.4 Study Duration 
• Add the expected duration of the 
overall study and recruitment 
period 
• Per feedback from French Ethics 
Committee (this was 
incorporated in V4.1 Amendment 
4.0 -French Country-specific 
Amendment) 
1.1 Synopsis (COVID-19 
Mitigation plan) 
4.6 COVID-19 Mitigation 
plan 
10.10 Appendix 10 - 
Guidance to Address 
Global Health Emergencies 
and Potential Impact on the 
Clinical Study 
• Clarify that drug accountability 
will be done at home visits by 
health care professionals 
• To ensure compliance with study 
drug 
1.3.1 Schedule of Activities 
– Main Study 
• Expand any post Week 4 (V3) in- 
clinic visit window to ±28 days. 
The expansion of the in-clinic 
visit window is  only justified in 
case of a global pandemic  
• To ensure participant’s safety 
and study integrity and minimize 
potential missing data during the 
pandemic 
• Clarify the rescreening process 
• Clarify visit schedule for 
participants discontinuing study 
drug but being continued to be 
followed up in the study 
• Clarify in a footnote that all 
baseline assessments except post 
dose ECG should be done pre-
dose 
• For clarity 
• For clarity 
 
 
• To clarify order of study 
procedures at Baseline 
1.3.1 Schedule of Activities 
– Main Study 
10.8 Appendix 8 - ECG 
Monitoring Plan  
• Add ECG assessment at V8 for 
participant not continuing to OLE 
• Safety measure for participants 
who discontinue study drug 
1.3.2 Schedule of Activities 
(OLE) 
• Add plasma sample for 
biomarkers analysis  
• To assess the longitudinal effect 
of treatment on neurofilament 
light and other biomarkers 
5.4 Screen Failures 
• Clarify the rescreening process 
• For clarity 
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Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
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10 November 2022 
 
Version 7.0, Amendment 8 
Section # and Name 
Description of Change 
Brief Rationale 
6.7.2 Prohibited Medication • Add a precautionary statement for 
use with medications eliminated 
via CYP2D6 dependent pathway 
• Per feedback from ANSM, the 
French competent authority (this 
was incorporated in V4.2 
Amendment 5.0 -French 
Country-specific Amendment) 
7.1.3 Psychiatric Stopping 
Rules 
• Clarify text 
• For consistency: to align with 
exclusion criterion no. 14 
7.1.5 Other Excluded 
Conditions during Study 
• Clarify excluded condition 
• For consistency: to align with 
exclusion criterion no. 13 and 
DSM-5 definition 
8.1.5.1 Stroop Word 
Reading (SWR) 
• Clarify procedure 
• For accuracy  
8.2.2 Vital signs 
• Delete requirements to conduct 
triplicate measurements for blood 
pressure and heart rate 
• Not a safety concern. To ease 
burden on participants  
8.3.1 Time Period and 
Frequency for Collecting 
AE and SAE information 
• Remove contradictory text about 
recording AEs occurring before 
first dose in Medical History 
page. 
• For clarity on the AE recording 
methodology 
9.4 Statistical Analyses 
• Indicate that analysis of OLE will 
be detailed in the Statistical 
Analysis Plan (SAP) 
• The SAP is intended to detail all 
planned analyses prior to 
database lock including 
exploratory endpoints and OLE 
(this was incorporated in V4.2 
Amendment 5.0 -French 
Country-specific Amendment) 
10.4.1 Definitions 
(Contraceptive Guidance) 
• Clarify timing of repeat FSH 
assessment for postmenopausal 
women 
• For clarity  
10.6 Appendix 6 Permitted 
Medications 
• Add fluphenazine as permitted 
antipsychotic medications 
• Add permitted medications for 
management of chorea 
• Add antiviral (COVID-19 
vaccines) as permitted medication 
• For clarity 
 
• Per Health Canada request 
 
• For clarity 
 
10.10 Appendix 10- 
Guidance to Address 
Global Health Emergencies 
and Potential Impact on the 
Clinical Study 
• Add Table 8: tabulated study visit 
activities per visit type 
• Add COVID-19 vaccination as 
permitted medication 
• For clarity 
 
• For clarity 
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Prilenia Therapeutics 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
Section # and Name 
Description of Change 
Brief Rationale 
General 
• Update version and date 
• For consistency and accuracy 
• Update table of contents 
• Update for consistency 
throughout protocol 
• Update cross reference/ linking 
throughout 
• Minor corrections/updates 
throughout (punctuation, 
fo1matting, style, etc.) 
Amendments 4 (15 February 2021) and 5 (15 March 2021) are incorporated within 
Amendment 6 (13 May 2021). 
Amendment 3, 25 October 2020 
Overall Rationale for the Amendment: 
The Sponsor has introduced the following modifications to protocol V 4, these changes are 
presented in order of appearance: 
Section # and Name 
3 Objectives and Endpoints 
9 Statistical Consideration 
General 
Description of Change 
• Add text for handling of 
intercurrent events 
• Add statement to reflect that 
separate analyses of the 
primaiy endpoint will be 
perfo1med for EMA and Non­
EMA regions 
• Update version and date 
• Alignment of wording across 
protocol 
• Minor clai·ifications and 
corrections to various sections 
• Update glossaiy 
Amendment 2, 23 September 2020 
Overall Rationale for the Amendment: 
Brief Rationale 
• 
• 
• For consistency and 
accuracy 
The Sponsor has introduced the following modifications to protocol V3, these changes are 
presented in order of appearance: 
CONFIDENTIAL 
118 
10 November 2022 
Version 7.0, Amendment 8 


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Prilenia Therapeutics 
Section # and Name 
1.1 Synopsis 
5.3 Exclusion criteria 
1.1 Synopsis 
4 Study design 
6.9 Open-label Extension (OLE) 
1.1 Synopsis 
1.3 SoA Table 2 
Appendix 10 Guidance to Address 
Global Health Emergencies 
1.3 SoA (Tables 2 and 3) 
Appendix 2 Clinical Laborato1y 
Tests 
Appendix 4 - Contraceptive 
Guidance and Collection of 
Pregnancy Info1mation 
1.3 SoA (Tables 2 and 3) 
Appendix 8 -ECG Monitoring 
Plan 
1.3 SoA OLE (Table 3) 
2.3 .1 Risk assessment 
7 .1 Individual Stopping Rules 
3 Objectives and endpoints 
CONFIDENTIAL 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
Description of Change 
• Delete footnote in exclusion 
criterion 2b 
• Add exclusion criterion 2c 
• Clruify exclusion c1iterion 4 
about serious medical illness 
• Add exclusion laborato1y test 
abno1malities to exclusion 
criterion 12 
• Specify OLE duration to be 
initially for 6 months after the 
last pruticipant completes Week 
65 of the double-blind 
Treatment period; duration may 
be extended pending emerging 
data from the double-blind 
po1tion of the study 
• Update that nearly all clinic 
visits (excepts Vl, V2 and V7) 
can be conve1ted to viitual 
visits 
• Add monthly mine pregnancy 
test 
• Add ECG at Week 26 (Main 
study) & Week 78, 104 (OLE) 
• Evaluate C-SSRS and PBAs 
more frequency during the OLE 
prut of the study 
• Update to include additional 
conditions to trigger study dmg 
discontinuation 
• Add text ru·ound p1imruy 
estimand 
• Add explorato1y endpoints 
119 
Brief Rationale 
• 
• To ensure that 
pruticipants do not 
have severe illnesses 
that may put them at 
risk when pruticipating 
in the study, influence 
the results of the study 
• 
• To enable Sponsor to 
analyze emerging data 
• Risk mitigation for 
COVID-19 
• 
as 
• 
as 
• 
as 
a safety precaution 
• 
as 
a safety precaution 
• 
• To ensure consistency 
with the SAP 
10 November 2022 
Version 7.0, Amendment 8 


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Prilenia Therapeutics 
Section # and Name 
6.4 Measures to miniinize bias: 
randomization and blinding 
7.2 Discontinuation of study drng 
8.2.4 Clinical safety laborato1y 
9 Statistical considerations 
Appendix 1, 10.1.3 Info1med 
Consent Process 
Appendix 1, 10.1.8 Study and Site 
Strut and Closure 
Appendix 8, 10.8 ECG Monito1ing 
Plan 
General 
CONFIDENTIAL 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
Description of Change 
Brief Rationale 
• Clruify blinding and unblinding 
• 
process 
to 
• Delete 'progressive disease' as 
reason for discontinuation 
• Add 'loss of capability to 
consent' as reason for 
discontinuation 
• Clruify safety lab should be 
done per SoA, including home 
visits if unable to conduct in­
clinic visit 
• Update sample size to account 
for atti·ition rate 
• Update ITT population analysis 
defmition 
• Update p11ma1y endpoint 
statistical analysis 
• Clarify the info1med consent 
process 
• Added study te1mination 
criteria 
• Update ECG Monitoring Plan 
• Update version and date 
• Alignment of wording across 
protocol 
• Minor clru·ifications and 
conections to various sections 
• Conect typo, fo1matting, and 
style 
• Update glossruy 
120 
mamtam stu y 
integrity 
• Due to the slow natural 
progression of HD, in 
this tiial of patients 
with early HD, 
progressive disease is 
not expected to lead to 
pe1manent 
discontinuation. 
• 
• 
• 
• 
• 
• 
mamtam stu y 
integrity 
a safety precaution 
• For consistency and 
accuracy 
to 
as 
10 November 2022 
Version 7.0, Amendment 8 


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Prilenia Therapeutics 
Amendment 1, 17 July 2020 
Study drng: P1idopidine 
Protocol Number: PL101-HD301 
Overall Rationale for the Amendment: 
The Sponsor has introduced the following modifications to protocol V2, these changes are 
presented in order of appearance: 
Section # and Name 
1.1 Synopsis 
5.3 Exclusion criteria 
1.1 Synopsis 
1.3 Schedule of Activities 
3 Objectives and endpoints 
8.1 Efficacy Assessments 
1.1 Synopsis 
1.2 Study Schema 
1.3 Schedule of Activities Table 3 
4.1 Overall study design 
4.4 Study duration 
6.9 OLE 
CONFIDENTIAL 
Description of Change 
• Exclude female paiticipants 
who are pregnant, planning to 
become pregnant or breast 
feeding 
• Exclude paiticipants with 
connection to Sponsor or 
Investigator or investigative 
site 
• Update secondaiy and 
explorato1y endpoints 
• Claiified modified CGI-S will 
be used at Baseline and CGI-C 
for on-treatment assessment 
• Remove PGI-S 
• Replace H-QoL with HDQoL 
(pa1ticipant) 
• 
Remove HD-HI 
• Add Q-Motor assessment at 
Screening 
Clai·ify OLE duration 
121 
Brief Rationale 
• To comply with Health 
Canada requirements 
• Per ICH E6(R2) and 
EU requirements 
• 
• Change is more 
clinically meaningful 
measure than seve1ity 
• HDQoL will be used 
as a Patient Reported 
Outcome 
• HDQoL is the standai·d 
quality of life 
• HD-HI is not available 
in all languages and 
cannot be assessed on 
all study paiticipants 
• For training pmposes 
only 
To allow for flexible OLE 
duration. 
10 November 2022 
Version 7.0, Amendment 8 


Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
122 
10 November 2022 
 
Version 7.0, Amendment 8 
1.3 Schedule of Activities 
Table 2 (Main study) 
Table 3 (OLE) 
• Update to reflect changes in 
protocol 
• Expand visit window (Table 2) 
• Clarify pregnancy testing 
(serum / urine) (Table 2) 
For clarity 
2.1 Rationale 
Update study rationale 
Additional clarifications 
and background data 
6.2 Handling missed doses 
Add section 
Additional clarifications 
8.4 Pharmacokinetics 
8.5 Pharmacodynamics/Biomarkers 
8.6 Pharmacogenetics 
Clarify and revise text 
For clarity, accuracy and 
consistency with 
Laboratory Manual 
10.1 Appendix 1 Regulatory, 
Ethical and Study Oversight 
Considerations 
• Clarify data collection when a 
participant withdraws consent 
• Clarify procedures for data 
processing and transfer from 
EU to non-EU regions. 
To comply with EU 
regulations 
10.2  
Remove blood draws for 
coagulation test 
No safety concern has 
been identified 
10.5 Genetics 
Clarify that Sponsor will comply 
with relevant regulations for 
processing genetics data 
To comply with EU 
regulations 
10.10 Guidance to address global 
health emergencies 
Update  
To comply with latest 
FDA guidance from 02 
July 2020 
General 
• Add study name PROOF-HD 
• Update version and date 
• Add document history and 
summary of changes 
• Minor clarifications to various 
sections 
• Correct typo, formatting, and 
style 
• Update glossary 
For consistency and 
accuracy 
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Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
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10 November 2022 
 
Version 7.0, Amendment 8 
11. 
REFERENCES 
Australian Government (April 9, 2020). COVID-19: Guidance on clinical trials for institutions, 
HRECs, researchers and sponsors.  Department of Health and National Health and Medical 
Research Council. from 
https://www1.health.gov.au/internet/main/publishing.nsf/Content/Clinical-Trials. 
 
Coleman, P. D. and Mastroeni, D. (2017). "A call for new approaches to Alzheimer's disease 
research." Neurobiol Aging 57: iii-iv. 
 
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Cudkowicz, M. and Investigators, T. H. S. G. D. (2010). "A futility study of minocycline in 
Huntington's disease." Movement Disorders 25(13): 2219-2224. 
 
Dorsey, E. R., Beck, C. A., Darwin, K., Nichols, P., Brocht, A. F., Biglan, K. M., et al. (2013). 
"Natural history of Huntington disease." JAMA Neurol 70(12): 1520-1530. 
 
Eddings, C. R., Arbez, N., Akimov, S., Geva, M., Hayden, M. R. and Ross, C. A. (2019). 
"Pridopidine protects neurons from mutant-huntingtin toxicity via the sigma-1 receptor." 
Neurobiol Dis 129: 118-129. 
 
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(Coronavirus) pandemic, version 4, released February 04, 2021.  Agency, E. M., from 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf. 
 
FDA (March 2020). FDA Guidance on Conduct of Clinical Trials of Medical Products during 
COVID-19 Public Health Emergency – Guidance for Industry, Investigators and Institutional 
Review Boards. Updated August 30, 2021.  U.S. Department of Health and Human Services 
Food and Drug Administration Center for Drug Evaluation and Research (CDER). from 
https://www.fda.gov/media/136238/download. 
 
Fisher, E. R. and Hayden, M. R. (2014). "Multisource ascertainment of Huntington disease in 
Canada: prevalence and population at risk." Mov Disord 29(1): 105-114. 
 
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62. 
 
Frank, S., Testa, C. M., Stamler, D., Kayson, E., Davis, C., Edmondson, M. C., et al. (2016). 
"Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease: A 
Randomized Clinical Trial." Jama 316(1): 40-50. 
 
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Protocol Number: PL101-HD301  
 
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Version 7.0, Amendment 8 
Geva, M., Kusko, R., Soares, H., Fowler, K. D., Birnberg, T., Barash, S., et al. (2016). 
"Pridopidine activates neuroprotective pathways impaired in Huntington Disease." Hum Mol 
Genet 25(18): 3975-3987. 
 
Grachev, I. D., Meyer, P. M., Becker, G. A., Bronzel, M., Marsteller, D., Pastino, G., et al. 
(2021). "Sigma-1 and dopamine D2/D3 receptor occupancy of pridopidine in healthy volunteers 
and patients with Huntington disease: a [(18)F] fluspidine and [(18)F] fallypride PET study." Eur 
J Nucl Med Mol Imaging 48(4): 1103-1115. 
 
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neuropsychiatric disorders." CNS Drugs 18(5): 269-284. 
 
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Notice to clinical trial sponsors. Updated May 6, 2021. from https://www.canada.ca/en/health-
canada/services/drugs-health-products/drug-products/announcements/management-clinical-
trials-during-covid-19-pandemic.html. 
 
Hersch, S. M., Schifitto, G., Oakes, D., Bredlau, A.-L., Meyers, C. M., Nahin, R., et al. (2017). 
"The CREST-E study of creatine for Huntington disease." Neurology 89(6): 594. 
 
Hocaoglu, M. B., Gaffan, E. A. and Ho, A. K. (2012). "The Huntington's Disease health-related 
Quality of Life questionnaire (HDQoL): a disease-specific measure of health-related quality of 
life." Clin Genet 81(2): 117-122. 
 
HSG (1996). "Unified Huntington's Disease Rating Scale: reliability and consistency. 
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Huntington's Disease Collaborative Research Group (1993). "A novel gene containing a 
trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The 
Huntington's Disease Collaborative Research Group." Cell 72(6): 971-983. 
 
Huntington Study Group (2001). "A randomized, placebo-controlled trial of coenzyme Q10 and 
remacemide in Huntington's disease." Neurology 57(3): 397-404. 
 
Johnston, T. H., Geva, M., Steiner, L., Orbach, A., Papapetropoulos, S., Savola, J.-M., et al. 
(2019). "Pridopidine, a clinic-ready compound, reduces 3,4-dihydroxyphenylalanine-induced 
dyskinesia in Parkinsonian macaques." Movement Disorders 34(5): 708-716. 
 
Kingma, E. M., van Duijn, E., Timman, R., van der Mast, R. C. and Roos, R. A. (2008). 
"Behavioural problems in Huntington's disease using the Problem Behaviours Assessment." Gen 
Hosp Psychiatry 30(2): 155-161. 
 
Landwehrmeyer, G. B., Dubois, B., de Yébenes, J. G., Kremer, B., Gaus, W., Kraus, P. H., et al. 
(2007). "Riluzole in Huntington's disease: a 3-year, randomized controlled study." Annals of 
Neurology 62(3): 262-272. 
 
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Prilenia Therapeutics 
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Protocol Number: PL101-HD301  
 
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Version 7.0, Amendment 8 
Lenoir, S., Lahaye, R. A., Vitet, H., Scaramuzzino, C., Virlogeux, A., Capellano, L., et al. 
(2022). "Pridopidine rescues BDNF/TrkB trafficking dynamics and synapse homeostasis in a 
Huntington disease brain-on-a-chip model." Neurobiol Dis 173: 105857. 
 
Longhitano L., Castracani, C. C., Tibullo D., Avola R., Viola M., Russo G., et al. (2017). 
"Sigma-1 and Sigma-2 receptor ligands induce apoptosis and autophagy but have opposite effect 
on cell proliferation in uveal melanoma." Oncotarget 8: 91099-91111. 
 
Marder, K., Zhao, H., Myers, R. H., Cudkowicz, M., Kayson, E., Kieburtz, K., et al. (2000). 
"Rate of functional decline in Huntington's disease. Huntington Study Group." Neurology 54(2): 
452-458. 
 
McGarry, A., McDermott, M., Kieburtz, K., de Blieck, E. A., Beal, F., Marder, K., et al. (2017). 
"A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease." 
Neurology 88(2): 152. 
 
MHRA (March 19, 2020). Guidance: Managing clinical trials during Coronavirus (COVID-19). 
Last updated November 16, 2021. from https://www.gov.uk/guidance/managing-clinical-trials-
during-coronavirus-covid-19. 
 
Naia, L., Ly, P., Mota, S. I., Lopes, C., Maranga, C., Coelho, P., et al. (2021). "The Sigma-1 
receptor mediates pridopidine rescue of mitochondrial function in Huntington disease models." 
Neurotherapeutics 18(2): 1017-1038. 
 
Pande, A. C., Genève, J., Scherrer, B., Smith, F., Leadbetter, R. A. and de Meynard, C. (1999). 
"A placebo-controlled trial of igmesine in the treatment of major depression." European 
Neuropsychopharmacology 9: 138. 
 
Posner, K., Brown, G. K., Stanley, B., Brent, D. A., Yershova, K. V., Oquendo, M. A., et al. 
(2011). "The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency 
findings from three multisite studies with adolescents and adults." Am J Psychiatry 168(12): 
1266-1277. 
 
Rawlins, M. D., Wexler, N. S., Wexler, A. R., Tabrizi, S. J., Douglas, I., Evans, S. J., et al. 
(2016). "The Prevalence of Huntington's Disease." Neuroepidemiology 46(2): 144-153. 
 
Reilmann, R., McGarry, A., Grachev, I. D., Savola, J. M., Borowsky, B., Eyal, E., et al. (2019). 
"Safety and efficacy of pridopidine in patients with Huntington's disease (PRIDE-HD): a Phase 
2, randomised, placebo-controlled, multicentre, dose-ranging study." Lancet Neurol 18(2): 165-
176. 
 
Reilmann, R. and Schubert, R. (2017). "Motor outcome measures in Huntington disease clinical 
trials." Handb Clin Neurol 144: 209-225. 
 
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Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
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10 November 2022 
 
Version 7.0, Amendment 8 
Ross, C. A., Pantelyat, A., Kogan, J. and Brandt, J. (2014). "Determinants of functional disability 
in Huntington's disease: role of cognitive and motor dysfunction." Mov Disord 29(11): 1351-
1358. 
 
Ryskamp, D., Wu, J., Geva, M., Kusko, R., Grossman, I., Hayden, M., et al. (2017). "The sigma-
1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington 
disease." Neurobiol Dis 97(Pt A): 46-59. 
 
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and (-)-OSU6162 display nanomolar affinities at the sigma-1 receptor." Mol Psychiatry 18(1): 
12-14. 
 
Scarpina, F. and Tagini, S. (2017). "The Stroop Color and Word Test." Front Psychol 8: 557. 
 
Shen, V., Clarence-Smith, K., Hunter, C. and Jankovic, J. (2013). "Safety and Efficacy of 
Tetrabenazine and Use of Concomitant Medications During Long-Term, Open-Label Treatment 
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L. A. (2019). "Impairment and Restoration of Homeostatic Plasticity in Cultured Cortical 
Neurons From a Mouse Model of Huntington Disease." Front Cell Neurosci 13: 209. 
 
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662. 
 
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by pridopidine in the human brain of healthy volunteers and in patients with huntington's disease 
(NCT03019289)." from https://clinicaltrials.gov/ct2/show/NCT03019289. 
 
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chaperone as an inter-organelle signaling modulator." Trends Pharmacol Sci 31(12): 557-566. 
 
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"BDNF, NT-3 and Trk receptor agonist monoclonal antibodies promote neuron survival, neurite 
extension, and synapse restoration in rat cochlea ex vivo models relevant for hidden hearing 
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endpoints for clinical trials in premanifest and early Huntington's disease in the TRACK-HD 
study: analysis of 24 month observational data." Lancet Neurol 11(1): 42-53. 
 
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Prilenia Therapeutics 
Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
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Version 7.0, Amendment 8 
Tesei, A., Cortesi, M., Zamagni, A., Arienti, C., Pignatta, S., Zanoni, M., et al. (2018). "Sigma 
receptors as endoplasmic reticulum stress “gatekeepers” and their modulators as emerging new 
weapons in the fight against cancer." Frontiers in Pharmacology 9(711). 
 
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"Pridopidine: overview of pharmacology and rationale for its use in Huntington's disease." J 
Huntingtons Dis 7(1): 1-16. 
 
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information. GlaxoSmithKline, Research Triangle Park, NC 27709. Available from: 
https://www.gsksource.com/gskprm/htdocs/documents/WELLBUTRIN-TABLETS-PI-
MG.PDF.". 
 
Zielonka, D., Ren, M., De Michele, G., Roos, R. A. C., Squitieri, F., Bentivoglio, A. R., et al. 
(2018). "The contribution of gender differences in motor, behavioral and cognitive features to 
functional capacity, independence and quality of life in patients with Huntington's disease." 
Parkinsonism & Related Disorders 49: 42-47. 
 
 
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SAP_001.pdf: 
Official Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel 
Arm, Multicenter Study Evaluating the Efficacy and Safety of Pridopidine in 
Participants with Early Stage of Huntington Disease 
NCT Number: NCT04556656 
Document Date: 28 March 2023 
 


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Plilenia Therapeutics 
Statistical Analysis Plan PL101 HD301: Final 3.0 28March2023 
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Plidopidine I Page 1 of 88 
STATISTICAL ANALYSIS PLAN 
Study Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel Alm, 
Multicenter Study Evaluating the Efficacy and Safety of Pridopidine in 
Paiiicipants with Eai·ly Stage of Huntington Disease 
Short Title: PRidopidine Outcome On Function in Huntington Disease (PROOF-HD) 
Study No.: 
PL101-HD301 (PROOF-HD) 
Phase: 
III 
IND No.: 
77419 
EudraCT No.: 2020-002822-10 
Based on: 
Clinical Study Protocol PL101-HD301, Version 7.0, Amendment 8.0, 10 
November 2022. 
Case Report Forms: Version MSC020, Version Date: 02/06/2023 
Study Drug: Pridopidine 
Sponsor: 
Prilenia N eurotherapeutics Ltd. 
Greenwork Business Park 
Building D. 1st floor 
Kibbutz Y akum, Israel 
• 
• 


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Statistical Analysis Plan PL101 HD301: Final 3.0 28March2023 
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Plidopidine I Page 2 of 88 
SAP Version History Summary 
SAP 
Approval Date 
Version 
1.0 
7 October 2020 
2.0 
IO November 
2022 
Change 
(Section 2. 3) Description of study design 
and endpoint assessments are updated 
throughout the SAP. 
(Section 2. 3.2.3. 3.2.4. 3.2.5) Change from 
Baseline to Week 26 and 39 are added for 
some non-multiplicity adjusted efficacy 
endpoints to better desc1ibe the change 
over time. Sub-scales for some endpoints 
as well as OLE and safety endpoints are 
clarified in endpoint section. Biomarker 
(Nfl.,) endpoints are added to the OLE 
endpoints. Phrumacodynamic assessments 
ru·e not perfo1med therefore removed from 
the SAP. 
(Section 7.1.1. 7.2. 7.3. 7.4. 5.8) Estimand 
definitions clarified and sensitivity 
analyses for multiplicity-adjusted 
seconda1y endpoints added. The details of 
missing data handling added. 
(Section 2. 3.2.2. 7.4) Hierru·chy of 
seconda1y endpoints changed (cUHDRS 
moved up to #1, propo1tion of pruticipants 
with improvement or no worsening in 
UHDRS-TFC moved to #2, TFC at Week 
52 and 78 moved up to #3 and #4, Q-
Motor lowered to #5, TMS lowered to #6) 
and change from Baseline to Week 65 in 
SDMT added to #7. 
Rationale 
Original 
Keep consistency with 
Protocol Version 7.0, 
Amendment 8.0. 
Changes are made for 
clarity. 
Additional details are 
provided. 
• Based in prut on power 
assessment using 
empirical data from prior 
PRIDE-HD study 
• Moved cUHDRS up in 
the hierarchy as it 
represents a global 
measure of HD 
progression including 
motor, function, and 
cognitive components 
• Moved Q-Motor above 
TMS to include an 
objective measure of 
motor function 
• Moved SDMT into 
multiplicity adjusted 
seconda1y endpoint in 
recognition of the 


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Statistical Analysis Plan PL101 HD301: Final 3.0 28March2023 
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Plidopidine I Page 3 of 88 
SAP 
Approval Date 
Version 
03.0 
28 Mar2023 
Change 
(Section 7.7. 3.5.3. 3.5.4} Analysis of 
Open-label extension period was added, 
and it was cla1ified that regulato1y 
submission will be based on double-blind 
treatment pe1iod data only. 
(Section 3.3) Sample size consideration for 
primruy endpoint in ITT population under 
MNAR assumption was supplemented. 
(Section 3.2. 3.6.3) It was cla1ified that 
only in-clinic assessments would be used 
in the p1ima1y and seconda1y analyses. The 
virtual assessments will be analyzed 
separately as an explorato1y analysis. For 
similru· rationale, the previously planned 
sample size re-estimation to mitigate high 
dropout rate and COVID-19 impact will 
not be perfo1med. 
(Section 7.3.2) Additional pre-specified 
subgroup analyses have been added. 
(Section 8.4. 8.6. 8.7) The clinically 
significant c1ite1ia ru·e updated with 
reference to newly issued FDA Medical 
Queries (FMQ) document. 1. 
Wording or text reruTanged to improve 
readability. 
(Section 2 and 3.2.3) Q-Motor analysis at 
Week 39 removed. 
Rationale 
impo1tance of cognition 
in HD 
• TFC at Week 52 
elevated in hierarchy to 
evaluate an earlier onset 
of response 
• TFC at Week 78 
elevated in hierarchy to 
evaluate durability of 
response within the 
double-blind period 
Additional details are 
provided. 
Keep consistency with 
prima1y analysis for EMA 
and non-EMA regions. 
Given current study status, 
where there is <2% 
missing in-clinic data. 
Additional details are 
provided. 
For consistency with 
guideline document. 
For consistency and 
accuracy. 
This was a typographical 
enor as Q-Motor was not 
1 FDA-Recent tools publicly available (FMQs, safety analytics TLFs), Sep 2022. https://www.regulations.gov/docket/FDA-
2022-N-I96I/document 


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Statistical Analysis Plan PL101 HD301: Final 3.0 28March2023 
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Plidopidine I Page 4 of 88 
SAP 
Approval Date 
Version 
Change 
(Section 3.1) Text added to indicate 
following Blinding-Unblinding Plan after 
database lock. 
(Section 3.2.2) For responder analyses if 
there are fewer that a total of 5 responders 
the analyses will not be performed. 
(Section 3 .2.3) CGI of 0 coITesponds to 
CGI not completed so thresholds were 
updated to account for this. 
(Sections 4.1.3, 4.1.4) Per Protocol Week 
65 and Week 78 Population criteria were 
clarified and efficacy component limited to 
those impacting UHDRS-TFC. 
(Section 5.4) p-values will be presented to 
4 instead of 3 decimal places. 
(Section 5.8.1.1) Since there were very few 
participants (<5) with missing data at 
baseline their data will not be imputed. 
(Section 5.8.1.3) Details on imputation of 
Total or Subscale scores on UHDRS-TFC, 
UHDRS-TMS, HDQoL and their subscales 
that were partially completed were 
provided. 
Rationale 
planned nor collected at 
Week 39. 
For statistical validity of 
OLE data, the Blinding-
Unblinding plan outlines 
maintenance of blind post 
database lock. 
If there are fewer than 5 
responders there is 
insufficient data to reliably 
compare responders 
between treatment groups. 
To exclude Oas a response 
threshold. 
Criteria for completion 
through Week 65 or 78 
and >80% compliance 
were kept as is. Additional 
text was added for 
clarifying other 
participants that may be 
excluded from PP 
population. 
To allow for greater 
precision in presentation 
of p-values. 
Since the trial randomized 
499 participants, missing 
efficacy data on <5 
participant would have 
minimal to no impact on 
analyses. 
This permits use of 
partially completed scales 
or subscales for analyses 
instead of ignoring them. 


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Statistical Analysis Plan PL101 HD301: Final 3.0 28March2023 
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Plidopidine I Page 5 of 88 
SAP 
Approval Date 
Version 
Change 
(Section 5.8.2) Additional detail for 
imputation for AE missing start date was 
included 
(Section 6.2) Clarification on selection on 
CAG repeat assessments analyzed by the 
laborato1y rather than that repo1ted by the 
participant. 
(Section 6.6) No separate table created for 
impo1tant Protocol Deviations (PDs) due to 
COVID-19. 
(Section 7.2) Clarification that analyses of 
Week 65 data will only include data from 
visits through Week 65 (and not beyond). 
(Section 7.3.2) Analysis by Region will be 
for No1th America vs Europe instead of US 
vs Europe. 
(Section 7.3.2) An additional subgroup 
analyses for those participants on Chorea 
medication was added. 
The model for subgroup analyses was 
updated. 
In addition, if a subgroup had a total of 
<50 participants the analyses would not be 
perfo1med. 
Rationale 
In order to dete1mine if 
AEs are TEAEs an 
additional imputation mle 
was added. 
CAG from the laborat01y 
assessment was considered 
more reliable and hence 
used rather than the one 
repo1ted by the pa1ticipant. 
Since there were no 
important PDs due to 
COVID-19. 
The primary endpoint for 
the study is Week 65. The 
study was designed to 
complete when the last 
pa1ticipant completed 
Week 65. 
Analysis was intended by 
region so US and Canada 
will be combined. 
The subgroup of those 
pa1ticipants who were on 
medication for Chorea 
Management was deemed 
impo1tant. 
The primary model for 
subgroup analyses was 
deemed more approp1iate 
with select 2-factor 
interactions as opposed to 
all of them. 
Subgroups with <50 
pa1ticipants would not 
pe1mit a reliable 
compa1ison of the effect of 
Pridopidine vs Placebo. 


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Plidopidine I Page 6 of 88 
SAP 
Approval Date 
Version 
Change 
(Section 7.3.3) Added text to conduct 
additional explorat01y analysis to explore 
impact of confounding factors. 
Added sensitivity analysis on neuroleptic 
use. 
(Section 7.4.2) updated that Cl's for 
obse1ved proportions and the difference 
will be provided using Clopper-Pearson 
method. 
(Section 7.4.3) Subgroup analyses will be 
perfo1med on log2-transfo1med NtL. 
(Section 7.5) Additional analyses on Q-
Motor adjusting for cova1iates that may 
impact it were included. 
(Section 7.5) Added text on robust 
regression or other analyses. 
(Section 7.6) Additional analyses may be 
perfo1med based on subgroups of baseline 
PINHD values 
(Section 7.6) Additional analyses may be 
perfo1med on change from baseline in 
Weight 
(Section 8.2) Inequality signs updated for 
analysis of duration of exposure. 
(Section 8.3) Additional details added on 
calculation of Compliance and display of 
relevant data in Listings. Ranges for 
Rationale 
Since use of neuroleptics 
may impact efficacy and 
was a stratification factor 
in the study a sensitivity 
analysis on its use was 
added. 
Since it provides the exact 
CI for obse1ved 
proportions. 
To better understand 
changes in NtL for the 
different subgroups. 
Since Age, Sex and 
Weight can impact Q-
Motor assessments these 
were added as covaiiates 
that may be explored for 
impact on efficacy. 
In order to minimize the 
impact of outliers that may 
represent unrealistic 
changes in key endpoints, 
text on analyses using 
robust regression or other 
methods was added. 
In order to understand 
impact of PINHD on 
efficacy. 
In order to evaluate 
changes in weight 
Inequality signs were 
made consistent between 
inte1val and cumulative 
thresholds. 
Due to pa1ticipants 
sometimes not returning 
bottles additional details 


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Prill'nia Thl'1'3pl'utics 
Statistical Analysis Plan PL101-HD301: Fmal 3.0 28Mal'ch2023 
I 
Pridopidinl' I Pagl' 7 of 88 
SAP 
Version 
Approval Date 
Change 
compliance were updated to bener reflect 
range of compliance. 
Rationale 
on handling this were 
added. 
(Section 8.4) Updated to reflect that AEs 
Due to the short half-life 
that sta1t more than 14 days after the end of of Plidopidine A Es that 
treatment are not considered TEAEs. 
started more than 14 days 
after the end of treatment 
were not considered 
TEAEs. 
(Section 8.4 and Appendix 12.2) Analyses 
of Abuse Potential was added. 
(Section 8.6) Crite1ia for detection of 
clinically significant laborat01y 
abnonnalities were updated. 
(Section 8. 7) Crite1ia for detection of vital 
signs abnonnalities were updated. 
(Section 8.8.2) C1iteria for the detection of 
HR, PR and QRS abno1malities were 
added. 
(Section 9.1.2) Biomarker (NtL) analyses 
were updated. 
:Minor updates for clarity. 
Analyses of Abuse 
Potential were deemed 
important and added. 
Updated to be consistent 
with Laboratory Nonnal 
Ranges. 
Added to define 
abnormalities in these 
ECG parameters. 
Additional and updated 
analyses were deemed 
approp1iate. 
For improved readability. 
This study is being conducted in compliance with good clinical practice, including the archiving of essential 
documents. 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................. 9 
LIST OF TABLES ......................................................................................................................... 14 
LIST OF FIGURES ....................................................................................................................... 14 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................ 15 
1. 
PREFACE ................................................................................................................... 18 
2. 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 20 
3. 
STUDY DESIGN ....................................................................................................... 26 
3.1. 
General Design and Study Schema ............................................................................. 26 
3.2. 
Primary, Seconda1y and Other Efficacy Endpoints and Safety Endpoints ................. 36 
3.2.1. 
Primary Efficacy Endpoint ......................................................................................... 36 
3.2.2. 
Multiplicity-adjusted Secondary Efficacy Endpoints ................................................. 36 
3.2.3. 
Non-multiplicity Adjusted Secondaiy Efficacy Endpoints ........................................ 37 
3.2.4. 
Other Explorato1y Efficacy Endpoints ....................................................................... 37 
3.2.5. 
Biomarker Endpoints .................................................................................................. 38 
3.2.6. 
Phannacokinetic Endpoints ........................................................................................ 38 
3.2.7. 
Safety Endpoints ......................................................................................................... 38 
3.2.8. 
Tolerability Endpoints ................................................................................................ 38 
3.3. 
Sample Size and Power Considerations ..................................................................... 39 
3.4. 
Randomization and Blinding ...................................................................................... 39 
3.5. 
Sequence of Planned Analyses .................................................................................. .40 
3. 5 .1. 
Interim Analyses ......................................................................................................... 40 
3.5.2. 
Analyses for Safety Monitoring Committee Meetings .............................................. .40 
3.5.3. 
Analyses and Repo1iing of Main Study Results ........................................................ .40 
3.5.4. 
OLE Analyses ............................................................................................................. 40 
3.5.5. 
Other Analyses ............................................................................................................ 41 
3.6. 
COVID-19 Mitigation ................................................................................................ 41 
3.6.1. 
Types of Visits ............................................................................................................ 41 
3.6.2. 
Other Mitigation Strategies Incorporated .................................................................. .43 
3.6.3. 
Mitigation Strategies for Analyses of Primary and Impo1iant Secondary 
Efficacy Endpoints ...................................................................................................... 43 
9 
, 


DocuSign Envelope ID: 8A 16DDE40075-443E 9B53 15F684CED0B5 
3.6.3.1. 
3.6.3.2. 
3.6.4. 
4. 
4.1. 
4.1.1. 
4.1.2. 
4.1.3. 
4.1.4. 
4.1.5. 
4.1.6. 
5. 
5.1. 
5.2. 
5.3. 
5.4. 
5.5. 
5.5.1. 
5.5.1.1. 
5.5.1.2. 
5.5.2. 
5.5.3. 
5.5.4. 
5.5.5. 
5.5.6. 
5.5.7. 
5.5.8. 
5.6. 
5.7. 
Evaluation of the Conelation Between In-clinic UHDRS-TFC Assessment 
and Phone (virtual) UHDRS-TFC Assessment ......................................................... .44 
hnpact on Secondary Endpoints ................................................................................. 44 
hnpact on Protocol Safety Assessments .................................................................... .44 
POPULATIONS I ANALYSIS SETS ........................................................................ .45 
Analysis Populations for the Main Study Period ....................................................... .45 
Intent-to-Treat (ITT) Population ................................................................................ .45 
Modified Intent-to-Treat (mITT) Population ............................................................. .45 
Per Protocol Week 65 (W65PP) Population .............................................................. .45 
Per Protocol Week 78 (W78PP) Population .............................................................. .45 
Safety Population (SP) ................................................................................................ 46 
PK Population (PKP) .................................................................................................. 46 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ............................................................................................................... 47 
General Summa1y Tables, Figures and Individual Paiiicipant Data Listing 
Considerations ............................................................................................................ 47 
General Post Text Summaiy Table and Individual Paiiicipant Data Listing 
Fonnat Considerations ................................................................................................ 48 
Data Management ....................................................................................................... 48 
Data Presentation Conventions ................................................................................... 49 
Derivation and Transformation on Data .................................................................... .49 
Baseline Values .......................................................................................................... 49 
Main Study Baseline ................................................................................................... 49 
OLE Baseline .............................................................................................................. 50 
Baseline Age ............................................................................................................... 50 
Study Day and By-Visit Summaries ........................................................................... 50 
Change and Percent(%) Change from Baseline ......................................................... 50 
End of Study Definition .............................................................................................. 51 
Last Study Dmg Date for the Main Study Analyses .................................................. 51 
Study Periods .............................................................................................................. 51 
Visit Windows ............................................................................................................ 51 
Multiple Compai·isons and Multiplicity ...................................................................... 51 
Analysis by Region and Pooling of Countries with Low Number of 
Pa1iicipants ................................................................................................................. 52 


DocuSign Envelope ID: 8A 16DDE40075-443E 9B53 15F684CED0B5 
5.8. 
5.8.1. 
5.8.1.1. 
5.8.1.2. 
5.8.1.3. 
5.8.2. 
5.8.3. 
5.8.4. 
6. 
6.1. 
6.2. 
6.3. 
6.4. 
6.5. 
6.6. 
7. 
7.1. 
7.1.1. 
7.1.2. 
7.2. 
7.3. 
7.3.1. 
7.3.2. 
7.3.3. 
7.4. 
7.4.1. 
7.4.2. 
7.4.3. 
7.5. 
7.6. 
7.7. 
8. 
Missing Data and Unscheduled Visits ........................................................................ 52 
Missing Efficacy Endpoints ........................................................................................ 52 
Missing Baseline Value .............................................................................................. 52 
Missing Post-baseline Efficacy Data .......................................................................... 52 
Missing Item Scores in Derivation of Total Scale Score ............................................ 53 
Missing Start and Stop Dates for Prior / Concomitant Medication, Medical 
Histo1y for HD Diagnosis and Adverse Events .......................................................... 54 
Missing Demographics, Baseline Characteristics, Exposme or Safety Data ............. 55 
Unscheduled Visits ..................................................................................................... 55 
STUDY POPULATION ............................................................................................. 56 
Pa1iicipant Disposition ................................................................................................ 56 
Demographics and Baseline Characteristics ............................................................... 56 
Pa1iicipant Inclusion and Exclusion Criteria .............................................................. 57 
Medical History .......................................................................................................... 57 
Prior and Concomitant Medications / Therapies ........................................................ 57 
Protocol Deviations .................................................................................................... 57 
EFFICACY ANALYSIS ............................................................................................ 59 
General ........................................................................................................................ 59 
IntercmTent Events (ICEs) and Estimand Strategy ..................................................... 59 
Analysis Populations .................................................................................................. 60 
Primary Efficacy Variable and Analysis .................................................................... 60 
Sensitivity Analyses for Primary Variable ................................................................. 62 
Sensitivity Analyses Under Various Assumptions for Missing Values ..................... 62 
Subgroup Analysis ...................................................................................................... 63 
Other Efficacy Analysis .............................................................................................. 64 
Multiplicity-Adjusted Secondaiy Efficacy Variable and Analysis ............................ 64 
Key Secondaiy Efficacy Vai·iable and Analysis ......................................................... 64 
UHDRS-TFC Response as a Binaiy Endpoint.. ......................................................... 64 
Other Multiplicity Adjusted Secondaiy Efficacy Vai·iable and Analysis ................... 66 
Non-Multiplicity Adjusted Seconda1y Efficacy Variable and Analysis ..................... 67 
Other Explorato1y Efficacy Variable and Analyses ................................................... 67 
OLE Efficacy Analyses .............................................................................................. 68 
SAFETY ANALYSIS ................................................................................................ 70 
11 


DocuSign Envelope ID: 8A 16DDE40075-443E 9B53 15F684CED0B5 
8.1. 
8.2. 
8.3. 
8.4. 
8.5. 
8.6. 
8.7. 
8.8. 
8.8.1. 
8.8.2. 
8.9. 
8.10. 
8.11. 
9. 
9.1. 
9.1.1. 
9.1.2. 
9.1.3. 
10. 
11. 
12. 
12.1. 
12.1.1. 
12.1.2. 
12.1.3. 
12.1.4. 
12.1.5. 
12.1.5.1. 
12.1.5.2. 
12.1.6. 
General ........................................................................................................................ 70 
Dm·ation of Exposm·e .................................................................................................. 70 
Study Treatment Compliance ..................................................................................... 70 
Adverse Events ........................................................................................................... 71 
Deaths ......................................................................................................................... 71 
Clinical Laboratory Tests ........................................................................................... 72 
Vital Signs .................................................................................................................. 73 
Electrocardiography (ECG) ........................................................................................ 74 
ECG Measures Handling and Time Points ................................................................. 74 
ECG Parameters Data Presentations ........................................................................... 7 5 
Columbia-Suicide Severity Rating Scale (C-SSRS) ................................................... 75 
Pregnancy Test. ........................................................................................................... 76 
Physical and Neurological Examination ..................................................................... 76 
PHARMACOKINETIC (PK), BIOMARKER (NFL) AND 
PHARMACOGENOMIC ANALYSIS ...................................................................... 77 
Blood Sampling and Handling .................................................................................... 77 
PK Analysis ................................................................................................................ 77 
Biomarker (NfI.,) Analysis .......................................................................................... 77 
Phaimacogeno1nic Analysis ........................................................................................ 80 
STATISTICAL SOFTWARE .................................................................................... 81 
REFERENCES ........................................................................................................... 82 
APPENDIX ................................................................................................................. 83 
Efficacy Variables Calculation Methods .................................................................... 83 
Unified Huntington's Disease Rating Scale - Total Functional Capacity 
(UHDRS-TFC) ........................................................................................................... 83 
Unified Huntington's Disease Rating Scale - Total Motor Score (UHDRS-
TMS) ........................................................................................................................... 83 
Unified Huntington's Disease Rating Scale - Composite Score (cUHDRS) ............. 83 
Quantitative Motor (Q-Motor) .................................................................................... 84 
Clinical Global Impression ......................................................................................... 85 
Modified Clinical Global Impression of Severity (modified CGI-S) ......................... 85 
Clinical Global Impression - Change (CGI-C) .......................................................... 85 
Exploratory Assessments ............................................................................................ 86 
12 


DocuSign Envelope ID: 8A 16DDE40075-443E 9B53 15F684CED0B5 
12.1.6.1. 
Stroop Word Reading (SWR) ..................................................................................... 86 
12.1.6.2. 
Symbol Digit Modalities Test (SDMT) ................................................................... 86 
12.1.6.3. 
Problem Behaviors Assessment-Short Form (PBA-s) ........................................... 86 
12.1.6.4. 
The Huntington Disease Quality of Life Questionnaire (HDQoL) ....................... 87 
12.2. 
Abuse Potential ........................................................................................................... 87 
13 


DocuSign Envelope ID: 8A 16DDE40075-443E 9B53 15F684CED0B5 
LIST OF TABLES 
Table 1: 
Schedule of Activities - Main Study- Double-blind, Placebo-Controlled 
Period .......................................................................................................................... 29 
Table 2: 
Schedule of Activities - Open-label Extension .......................................................... 34 
Table 3: 
Visit Activities According to the Visit Types ............................................................ .41 
Table 4: 
Criteria for Clinically Significant Laborato1y Values ................................................ 72 
Table 5: 
Criteria to Detennine Clinically Relevant Abnonnalities in Vital Signs ................... 74 
LIST OF FIGURES 
Figure 1: 
Study Schema -Main Study - Double-blind Placebo-controlled Period ................... 28 
Figure 2: 
Study Schema - Open-Label Extension ..................................................................... 28 
14 


DocuSign Envelope ID: 8A 16DDE40075-443E 9B53 15F684CED0B5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse event(s) 
AR(l) 
Autoregressive (1) 
ARH(l) 
Heterogeneous autoregressive (1) 
bid 
Twice daily 
BL 
Baseline 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CAG 
Cytosine adenosine-guanine 
CAP 
CAO-Age-Product 
CGI-C 
Clinical Global Impression of Change 
CGI-S 
Clinical Global Impression of Severity 
CI 
Confidence interval 
COVID-19 
Coronavirns Disease 2019 
CrCl 
Creatinine clearance 
CRF 
Case repo1i f01m 
CSR 
Clinical Study Repo1i 
cUHDRS 
Composite Unified Huntington's Disease Rating Scale 
DNA 
Deoxyribonucleic acid 
DSP 
Diastolic blood pressure 
EDC 
Electronic data capture 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
EoS 
End of Study 
ET 
Early T e1mination 
FDA 
Food and Drng Administration 
HD 
Huntington Disease 
HDQoL 
Huntington Disease Quality of Life Questionnaire 
HR 
Healirate 
ICC 
Intra-class Con-elation Coefficient 
ICE 
Intercunent event 
ICH 
International Conference on Haimonisation 
15 


DocuSign Envelope ID: 8A 16DDE40075-443E 9B53 15F684CED0B5 
IOI 
futer-onset interval 
IRT 
futeractive Response Technology 
IS 
fudependence scale 
ITT 
futent-to-treat 
LLOQ 
Lower limit of quantification 
LSM 
Least square mean 
MAR 
Missing at random 
Med.ORA 
Medical Dictionaiy for Regulato1y Activities 
MI 
Multiple imputations 
ML 
Maximum-Likelihood 
MMRM 
Mixed Model Repeated Measures 
MNAR 
Missing not at random 
mITT 
Modified intent-to-treat 
msec 
Millisecond( s) 
N±L 
Nemofilament light chain 
OLE 
Open-label Extension 
OR 
Odds ratio 
PBA-s 
Problem Behaviors Assessment-Sholi fo1m 
PD 
Protocol deviation 
PINHD 
Prognostic index n01med for HD 
PK 
Phaimacokinetic( s) 
PKP 
PK Population 
PMM 
Pattern-mixture model 
pp 
Per Protocol 
PROOF-HD 
PRidopidine Outcome On Function in Huntington Disease 
PT 
Preferred te1m(s) 
QI 
First Quaiiile 
Q3 
Third Quaiiile 
QD 
Once daily 
Q-Motor 
Quantitative Motor 
QoL 
Quality of life 
16 


DocuSign Envelope ID: 8A 16DDE40075-443E 9B53 15F684CED0B5 
QTcF 
Fridericia-coITected QT inte1val 
SAE 
Serious adverse events 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SE 
Standard EITor 
SDMT 
Symbol Digit Modalities Test 
SMC 
Safety Monitoring Committee 
SoA 
Schedule of Activities 
soc 
System organ class 
SP 
Safety Population 
SWR 
Stroop Word Reading 
TC 
Telephone call 
TEAE 
Treatment-emergent adverse event(s) 
TFC 
Total functional capacity 
TFL 
Table, Figure, Listing 
TMS 
Total Motor Score 
UHDRS 
Unified Huntington's Disease Rating Scale 
ULN 
Upper limit of n01mal 
V 
Visit 
vv 
Virtual Visit(s) 
W65PP 
Per Protocol Week 65 
W78PP 
Per Protocol Week 78 
Wk 
Week 
WOCBP 
Women of childbearing potential 
17 


DocuSign Envelope ID: 8A 16DDE40075-443E 9B53 15F684CED0B5 
1. 
PREFACE 
Huntington Disease (HD) is an autosomal dominant, progressive fatal neurodegenerative 
disorder characterized by motor, cognitive, and behavioral abno1malities. While medications to 
treat chorea and some behavioral symptoms are available, no therapy has yet proven able to 
modify the progressive and inexorable functional decline of the disease. A therapy that maintains 
functional capacity and prevents or delays the development of disability represents a critically 
unmet clinical need. The age of onset of the signs and symptoms of HD and the rate of disease 
progression can vaiy greatly. Adult-onset HD most often begins between 30 and 40 years of age. 
The illness generally lasts 15 to 20 years and is fatal. Following diagnosis, motor and cognitive 
functions steadily decline, ultimately leading to a state of immobility, dementia, and premature 
death. 
The Statistical Analysis Plan (SAP) describes the planned analysis and repo1ting for Prilenia 
Therapeutics study PL101-HD301 (A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 
Pai·allel Alm, Multicenter Study Evaluating the Efficacy and Safety of Pridopidine in 
Paiticipants with Eai·ly Stage of Huntington Disease). The study is also refened to as the 
PRidopidine Outcome On Function in Huntington Disease Paiticipants (PROOF-HD) study. 
The purpose of this Phase 3 study is to evaluate the efficacy and safety of pridopidine 45 mg 
twice daily (bid) as compared to placebo. Efficacy will be assessed for HD pa1ticipants based on 
functional capacity using the Total Functional Capacity (TFC) score in the Unified Huntington's 
Disease Rating Scale (UHDRS) as the prima1y objective. 
Some of the analyses in this SAP ai·e included for the Safety Monitoring Committee (SMC). 
Details of what will be provided to the SMC will be included in the SMC Chaiter or analysis 
plan suppo1ting it. Additional details of phaimacokinetics (PK)and phaimacogenomic analyses 
will be included in SAP addendum, appendix or sepai·ate SAPs. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the International Conference on Haimonisation of Technical Requirements for 
Registration of Phaimaceuticals for Human Use (ICH): E9 Guidance on Statistical Principles in 
Clinical Trials issued Febrnaiy 1998 as well as the ICH E9(Rl) Addendum on Estimands and 
Sensitivity, November 2019. 
The following documents were reviewed in preparation of this SAP: 
• 
Clinical Study Protocol PL101-HD301, Version 7.0, Amendment 8.0, 10 November 
2022 
• 
Clinical Study Repo1t (CSR) and subsequent analyses on the Phase 2 Study TV7820-
CNS-20002, (PRIDE-HD -Pridopidine Dose Evaluation in Huntington's Disease) 
study 
• Case repo1t fo1m (CRF) for PL101-HD301, V07, 3 May 2022 
• ICH E9 Statistical Principles for Clinical Trials 
• ICH E9(Rl) Addendum on Estimands and Sensitivity Analysis in Clinical Trials 
• ICH E3 Structure and Content of Clinical Study Repo1ts 
18 


DocuSign Envelope ID: 8A 16DDE40075-443E 9B53 15F684CED0B5 
• 
Statistical Considerations for Clinical Trials During the Coronavims Disease 2019 
(COVID-19) Public Health Emergency 
• Relevant publications indicated in references related to development of estimands, 
sensitivity analyses and handling of missing data 
The reader of this SAP is encouraged to also read the clinical protocol for details on the conduct 
of this study, and the operational aspects of clinical assessments and timing for pa1ticipant 
completion in this study. When differences exist in descriptions or explanations provided in the 
protocol and this SAP, the SAP prevails, and the differences will be explained in the CSR. 
19 


DocuSign Envelope ID: 8A16DDE4-tl075.443E-9B53-15F684CEDOB5 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
The pwpose of this Phase 3 study is to evaluate the effect of pridopidine 45 mg bid on fi.mctional 
capacity, as well as motor and behavioral features of HD in early-stage participants (HD Stages 
1-2,Baseline TFC score of 7-13). 
Objectives and Endpoints of the Main Study (Primary, Secondary and Safety): 
Objectives 
Prima1y 
• 
To assess the effect of pridopidine on 
functional capacity in pa11icipants with 
Stage 1 -2 HD 
Multiplicity Adjusted Secondaiy Endpoints 
Endpoints 
• Change from Baseline to Week 65 in the 
UHDRS-TFC score 
Key Seconda1y (secondary endpoints are listed by order of hierarchy) 
• 
To assess the effect of pridopidine on a 
composite measure of disease 
progression in participants with HD 
1. Change from Baseline to Week 65 in 
composite UHDRS ( cUHDRS) total score 
Secondary (secondary endpoints are listed by order of hierarchy) 
• 
To evaluate the effect of pridopidine 
on functional capacity, motor fimction, 
and other measures of efficacy over 
time in pa11icipants with HD 
2. Prop011ion of pai1icipants with improvement 
or no worsening ( change from Baseline xO 
points) at Week 65 in UHDRS-TFC 
3. Change from Baseline to Week 52 in 
UHD RS-TFC score 
4. Change from Baseline to Week 78 in 
UHD RS-TFC score 
5. Change from Baseline to Week 65 in 
Quantitative motor (Q-Motor) 
6. Change from Baseline to Week 65 in 
UHDRS-Total Motor Score (TMS) 
7. Change from Baseline to Week 65 in 
Symbol Digit Modalities Test (SDMT) 
8. Change from Baseline to Week 52 in 
UHD RS-TMS score 
20 


DocuSign Envelope ID: 8A 16DDE40075-443E 9B53 15F684CED0B5 
9. Propo1tion of pa1ticipants with improvement 
or no worsening in Clinical Global 
Impression of Change (CGI-C) at Week 65 
Non-multiplicity Adjusted Secondary Endpoints 
• To evaluate the effects of pridopidine 
• Change from Baseline to Week 26 and 39 in 
in pa1ticipants with HD 
the UHDRS-TFC 
• Propo1tion of pa1ticipants with improvement 
or no worsening in UHDRS-TFC ( change 
from Baseline ÑO) at Weeks 26, 39, 52 and 
78 
• Change from Baseline to Weeks 26, 39, 52 
and 78 in cUHDRS 
• Propo1tion of pa1ticipants with change from 
Baseline Ñ-1 in cUHDRS at Weeks 26, 39, 
52, 65 and 78 
• Change from Baseline to Week 26, 39 and 
78 in the UHDRS-TMS score 
• Propo1tion of pa1ticipants with improvement 
or no worsening in UHDRS-TMS ( change 
from Baseline :SO) at Weeks 26, 39, 52, 65 
and 78 
• Change from Baseline to Weeks 26, 39, 52, 
65 and 78 in: 
-
UHDRS-TFC Scale sub-items ( capacity 
to unde1take domestic chores, activities 
of daily living, capacity to manage 
finances, care level and occupation) 
-
UHDRS-TMS sub-scores for: 
0 Gait and balance score ( defined as 
the sum of UHDRS-TMS domains 
gait, tandem walking, and 
retropulsion pull test) 
0 Eye movement 
0 Dystonia 
• Change from Baseline to Weeks 26, 39, 52 
and 78 in SDMT 
21 


DocuSign Envelope ID: 8A16DDE4-tl075.443E-9B53-15F684CEDOB5 
Explorato1y Endpoints 
• To evaluate the explorat01y efficacy 
effects of pridopidine in participants 
with HD 
• To evaluate changes in disease 
biomarker, plasma neurofilament light 
chain (NfI..,), following treatment with 
pridopidine in participants with HD 
• Change from Baseline to Weeks 26, 39, 52, 
65 and 78 in Stroop Word Reading (SWR) 
• Change from Baseline to Weeks 26, 52 and 
78 in Q-Motor 
• Prop01tion of pruticipants with improvement 
or no worsening ( change from Baseline '.SO 
milliseconds (msec) in Q-Motor 
• Change from Baseline to Weeks 26, 52, 65 
and 7 8 in Q-motor 
• Responder analyses on CGI-C using 
different thresholds at Weeks 26, 39, 52, 65 
and 78 
• Change from Baseline to Weeks 26, 52, 65 
and 78 in: 
Problem Behaviors Assessment - Short 
Forni (PBA-s) total score 
o PBA-s sub-score for apathy 
Measurement of quality of life (QoL) 
using the Huntington Disease Quality 
of Life Questionnaire (HDQoL) 
• Change from Baseline to Weeks 26, 52, 65 
and 78 in plasma NfL protein 
• Relationship between Baseline NfI.., ru1d 
changes from Baseline in select efficacy 
endpoints 
• Relationship between changes from 
Baseline to Weeks 26, 52, 65 ru1d 78 in NfL 
and select efficacy endpoints 
• Prop01tion of pruticipants with different 
thresholds for change from Baseline to 
Weeks 26, 52, 65 and 78 in plasma NfI.., 
levels 
22 


DocuSign Envelope ID: BA 16DDE40075-443E 9B53 15F684CED0B5 
• To evaluate the PK of pridopidine and • Plasma concentrations of pridopidine and its 
its main metabolite in pa1ticipants with 
main metabolite at Weeks 26, 52, 65, and 78 
HD 
and at last paiticipants' visit 
• Relationship between plasma concentration 
of pridopidine and clinical outcome 
measures 
Safety and Tolerability Endpoints 
• To evaluate the safety and tolerability of • Incidence ( count and rate) of adverse events 
pridopidine in paiticipants with HD 
(AEs) and serious AEs (SAEs) overall, by 
severity, by relationship to study diug, and 
those that led to withdi·awal from the study 
treatment or study 
• Incidence and shifts of clinically significant 
abno1malities in electrocardiogram (ECG), 
laborato1y tests, vital signs, and 
abno1malities in physical and neurological 
exam 
• Analysis of Columbia-Suicide Severity 
Rating Scale (C-SSRS) throughout the study 
• Tolerability: 
-
The number (%) of paiticipants who 
complete the treatment period 
-
The number (%) of paiticipants who 
fail to complete the treatment period 
due to AEs 
-
The number (%) of paiticipants who 
fail to complete the treatment period 
meeting the QTcF-change, Creatinine 
Cleai·ance (CrCl) or Psychiatric 
Stopping Rules 
Objectives and Endpoints of the Open-Label Extension (OLE) Period: 
Objectives 
Endpoints 
Efficacy 
• To evaluate the long-te1m treatment 
• Propo1tion of pa1ticipants with change from 
effect of pridopidine in paiticipants with 
Baseline (Main Study) to each OLE visit in 
HD who previously completed the Main 
UHDRS-TFC ï-1 
Study 
23 


DocuSign Envelope ID: 8A16DDE4-tl075.443E-9B53-15F684CEDOB5 
Safety and Tolerability Endpoints 
• To evaluate long-tem1 safety and 
tolerability of pridopicline in 
participants with HD who previously 
completed the Main Study 
Biomarker Endpoints 
• Prnp01tion of pruticipants with change from 
Baseline (Main Study) to each OLE visit in 
UHDRS-1FC úO 
• Change from Baseline (Main Study) to OLE 
visits in 
I 
I 
UHDRS-TFC 
cUHDRS 
UHDRS-TMS 
Quantitative motor (Q-Motor): 
SDMT 
SWR 
• Change from Baseline (Main Study) to OLE 
visits in: 
CGI-C 
PBA-s 
HDQoL 
• Incidence ( cmmt and rate) of AEs and SAEs 
overall, by severity, by relationship to study 
drng, and those that led to withdrawal from 
the study treatment or study 
• Incidence and shifts of clinically significant 
abnormalities in ECG, laborato1y tests, and 
vital si gns 
• Analysis of C-SSRS throughout the study 
• Tolerability: 
24 
The number (%) of participants who 
completed the OLE treatment period 
The number (%) of participants who 
failed to complete the OLE treatment 
period due to AEs 


DocuSign Envelope ID: 8A 16DDE40075-443E 9B53 15F684CED0B5 
• To evaluate long-te1m efficacy effects 
of pridopidine on NfL in paiiicipants 
with HD who previously completed the 
Main Study 
• Change from Baseline (Main Study) in NfL 
protein level to each OLE visit 
• Relationship between changes from baseline 
in NfL and selected efficacy endpoints in 
the OLE period 
25 


DocuSign Envelope ID: 8A 16DDE40075-443E 9B53 15F684CED0B5 
3. 
STUDY DESIGN 
3.1. 
General Design and Study Schema 
This is a multicenter, randomized, parallel group, double-blind, placebo-controlled study to 
evaluate the efficacy and safety of pridopidine administered orally at a dose of 45 mg bid versus 
placebo in treatment of functional impaiiment in paiticipants with early HD, defined as Stages 1 
and 2 based on UHDRS-TFC scores (HD 1 is UHDRS-TFC 11-13 and HD2 is UHDRS-TFC 7-
10). It is planned to emoll a total of 480 paiticipants (240 participants within each treatment 
aim). 
The study will consist of a screening period, a double-blind treatment period (hereafter refened 
to as the Main Study) and an OLE as described in study schemas Figure 1- Main Study and 
Figure 2- OLE. 
After having signed an info1med consent, each pa1ticipant will be randomized in a 1 : 1 ratio to 
the active (pridopidine 45 mg bid) or control (placebo) aim, stratified by Baseline HD stage 
(HDl vs. HD2) and Baseline neuroleptic use (Yes/No), for a 65 to 78 weeks double-blinded 
treatment period as the Main Study. 
The Main Study will include an initial 2-week titration period, a 63-week double-blind full-dose 
maintenance treatment period, followed by a variable double-blind treatment period of up to 13 
weeks. 
Staiting on Day 1, during the titration period, all pa1ticipants will self-administer 1 capsule of 
study diug orally, once daily (QD), in the morning for 2 weeks. Thereafter, the study di11g will 
be taken orally bid in the morning and in the afternoon (7-10 hours apait) for 63 weeks ( full-dose 
maintenance double-blind treatment period). Participants who complete the Maintenance period 
(63 weeks) will continue into a var·iable double-blind period of up to 13 weeks or until the last 
paiticipant randomized completes 65 weeks of treatment (2-weeks Titration + 63-weeks full­
dose), whichever comes first. 
The reason for the variable length double-blind period is because the study will be considered to 
have completed when the last pa1ticipant randomized (and who has not discontinued) completes 
65 weeks of double-blind treatment. Pa1ticipants enrolled prior to that in the study will have the 
oppo1iunity to complete 78 weeks in the Main Study. Pa1ticipants enrolled towar·ds the end of the 
study will have completed between 65 and 78 weeks in the Main Study. The primaiy endpoint is 
the change from Baseline to Week 65 in UHDRS-TFC. Change from Baseline to Week 52 and 
78 in UHDRS-TFC are secondaiy endpoints, as indicated in the Section 2. 
As soon as the last participant reaches Week 65, the Main Study End of Study (EoS) visit for all 
remaining paiticipants who ar·e between Week 65 and Week 78 needs to be conducted within 4 
weeks. 
For paiticipants who complete thei.i· Week 65 visit within 4 weeks of the last pa1ticipant 
completing Week 65, the Week 65 visit will be considered the EoS Visit. For paiticipants who 
are beyond 4 weeks from thei.i· Week 65 visit when the last pa1ticipant reaches Week 65, and 
have not had a Week 78 visit, the EoS visit will be conducted within 4 weeks. 
The double-blind will be maintained for all pa1ticipants and Investigators. Following database 
lock at the end of Main Study, the treatment assignment will be unblinded for analysis. Details of 
26 


DocuSign Envelope ID: 8A 16DDE40075-443E 9B53 15F684CED0B5 
personnel unblinded and for those who the blind will be maintained are outlined in the Blinding­
Unblinding Plan. 
For each paiticipant, the last visit in double-blind treatment period will be the Main Study EoS 
visit scheduled between Week 65 and Week 78 if the paiticipant completes all study visits, or 
Early Tennination (ET) visit if the paiticipant withdraws from the study before Week 65. 
At the Main Study End of Study (EoS) visit, eligible paiticipants will have the option to emoll 
into an OLE period, commencing at the Main Study EoS visit and consisting of a 2-week up­
titration period and a maintenance period, and to receive pridopidine until 12 months after the 
last paiticipant completes the double-blind treatment period. The OLE duration may be extended 
pending emerging data from the double-blind po1tion of the study. The Sponsor intends to 
submit a substantial protocol ainendment for the extension of the OLE after ensuring that the 
benefit-risk ratio remains positive following analysis of the data from the Main Study. 
Paiticipants, who ai·e not continuing to the OLE study, will be contacted by phone for a safety 
evaluation of 2 weeks after the Main Study EoS/ET visit. AEs will be monitored for these 2 
weeks until the safety telephone contact 
Throughout the study, paiticipants will be assessed through on-site clinic visits, virtual visits 
(YV) (by phone which may be via regular telephone, smait phone, tablet or computer), as 
specified in the co1Tesponding schedule of activities (SoA) (Table 1 - Main Study, and Table 2 -
OLE) and study schema (Figure 1 - Main Study, and Figure 2 - OLE). 
During the double-blind treatment period of the Main Study, an independent SMC will oversee 
the safety and tolerability based on pa1ticipants' data accmed in the electronic data capture 
(EDC) system, based on an ongoing review of SAEs and periodical review of the accumulating 
safety data. 
27 


DocuSign Envelope ID: 8A16DDE4-tl075.443E-9B53-15F684CEDOB5 
Figure 1: 
Study Schema - Main Study - Double-blind Placebo-controlled Period 
Ser..,,
, ec. r·.,o .. 
w,C•i 
ZwNl• 
_ ... 
• 
1:1 Randomb:atlon 
• 
wz 
°"" ... ..,. ••• , ... -.......... 1111,--.....,_, ... 
11., 
u ..... . 
 
\NJ.q 
• 
VV3 
• 
W4 
w,,s• 
v.r1.1. - .. -.... 
..,,,....,, 
,or1o,.,.u-li, 
z"'""" 
• --· 
 
W"l2 
Abbt'l'Viations: twice daily (bid); Baseline (BL); End of Study (F.oS); Early Ternmation (ET); once daily (QD); Virtual Visit 
(VV); total daily dose (1DD). 
* For each patticipant, the last treatment visit will be the F.oS at either Week 65 or Week 78 if the patticipant completes all study 
visits; or Early Temlination (E1) visit if the participant withdraws from the study befo:e Week 65. 
Figure 2: 
Study Schema - Open-Label Extension 
•·-
-
--
-
-.-- - - - -- - - - - - --- - - - - - - -
--- - - -
--------
01.fVl 
, ......... ,. 
ttudrVS 
We.kn-/ 
M•_.,,..,dtl•S 
... 
OlfV2 
01£Wff"4 
... 
OlfVl 
ruw .. 
u, 
\?-
OI.EWftk3' 
.infe,,flY 
:K.wMls 
1h«e.lfttt 
Abbrl.'-,,iations: Fnd of Study (EoS); Early Tennination (ET); Open-Label Extension (OLE). 
28 
... 
OUV4 
QEWMt§2 
,...i.....,l,_ 
Co«tafr•t 
... 
Stf•tY ro1-.,11 
2,.,..,1r,.,fr,,Ol£ 
&,y 
OlEEoSIU 


DocuSign Envelope ID: 8A 16DDE40075-443E 9B53 15F684CED0B5 
Table 1: 
Schedule of Activities -Main Study - Double-blind, Placebo-Controlled Period 
Study Period 
Screening• 
Double-blind 
Doubleblind, Placebo controlled, Full dose Maintenance Treatment 
Doubleblind 
Follow up 
Procedm·es and 
Titration 
Period 
Variable Pe1iodb 
Safety 
Assessments 
Pe1iod 
Assessment' 
Study Clinic Visit 
Vl 
V2 
V3 
V4 
vs 
V6 
v1• 
VS (Main 
F/U 
BLd 
Study Eos•, f 
/ET') 
Virtual Visit (VV) 
VVl 
VV2 
VV3 
VV4 
BL 
Telephone Call Safety 
j 
j 
j 
j 
j 
j 
Visit 
Study Week 
Day l 
2 
4 
8 
13 
19 
26 
32 
39 
45 
52 
58 
65 
72 
78 
80 (2 weeks 
after Main 
Study EoS/ET 
Visit Windows (days) 
<42 
<7 
±5 
±5 
±14 ±14 ±14h ±14 ±14h ±14 ±14h ±14 
±14h 
±14 
±14h 
±5 
Infonned consent 
X (Main Study) 
X 
X(OLE) if 
(OLE) 
not obtained 
atV7 
Check willingness to 
X i 
enter OLE 
Demography 
X 
Medical and 
X 
psychiatric history 
(including smoking) 
Prior medication and 
X 
treatment history 
Inclusion and 
Xi 
exclusion criteria 
Clinical laboratory 
X 
X 
X 
X 
X 
X 
X 
X 
tests (serum chemistry, 
hematology and 
urinalysis)k 
Pregnancy test (for 
Senun 
Urine 
u 
u 
u 
u 
u 
u 
WOCBP)1 
(U) 
Monthly mi.ne pregnancy tests (at home) 
29 
' 


DocuSign Envelope ID: 8A 16DDE40075-443E 9B53 15F684CED0B5 
Study Period 
Screening• 
Double-blind 
Doubleblind, Placebo controlled, Full dose Maintenance Treatment 
Doubleblind 
Follow up 
Procedm·es and 
Titration 
Period 
Variable Pe1iodb 
Safety 
Assessments 
Pe1iod 
Assessment' 
Study Clinic Visit 
Vl 
V2 
V3 
V4 
vs 
V6 
v1• 
VS (Main 
F/U 
BLd 
Study Eos•, f 
/ETá 
Virtual Visit (VV) 
VVl 
VV2 
VV3 
VV4 
BL 
Telephone Call Safety 
j 
j 
j 
j 
j 
j 
Visit 
Study Week 
Day l 
2 
4 
8 
13 
19 
26 
32 
39 
45 
52 
58 
65 
72 
78 
80 (2 weeks 
after Main 
Study EoS/ET 
Visit Windows (days) 
<42 
<7 
±5 
±5 
±14 ±14 ±14h ±14 ±14h 
±14 
±14h ±14 
±14h 
±14 
±14h 
±5 
Full physical and 
X 
X 
X 
X 
X 
neurological 
examination 
Brief physical 
X 
X 
X 
examination 
12 lead ECG 
X"' 
xn,o 
xo 
xP 
xP 
XJl,q 
Vital signs' 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS (Baseline 
X 
version) 
C-SSRS (since last 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
visit version) 
UHDRS-TFC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
UHDRS-TMS 
X 
X 
X 
X 
X 
X 
X 
UHDRS-IS 
X 
SDMT 
X 
X 
X 
X 
X 
X 
SWR 
X 
X 
X 
X 
X 
X 
Q-Motor 
x• 
X 
X 
X 
X 
X 
PBA-s (Short Fonn) 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-S (modified) 
X 
X 
CGI-C 
X 
X 
X 
X 
X 
HDQoL-P 
X 
X 
X 
X 
X 
30 


DocuSign Envelope ID: 8A 16DDE40075-443E 9B53 15F684CED0B5 
Study Period 
Screening• 
Double-blind 
Doubleblind, Placebo controlled, Full dose Maintenance Treatment 
Doubleblind 
Follow up 
Procedm·es and 
Titration 
Period 
Variable Pe1iodb 
Safety 
Assessments 
Pe1iod 
Assessment' 
Study Clinic Visit 
Vl 
V2 
V3 
V4 
vs 
V6 
v1• 
VS (Main 
F/U 
BLd 
Study Eos•, f 
/ETá 
Virtual Visit (VV) 
VVl 
VV2 
VV3 
VV4 
BL 
Telephone Call Safety 
â 
â 
â 
â 
â 
â 
Visit 
Study Week 
Day l 
2 
4 
8 
13 
19 
26 
32 
39 
45 
52 
58 
65 
72 
78 
80 (2 weeks 
after Main 
Study EoS/ET 
Visit Windows (days) 
<42 
<7 
±5 
±5 
±14 ±14 ±14h ±14 ±14h ±14 ±14h ±14 
±14h 
±14 
±14h 
±5 
Benzodiazepines and 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
antidepressants inquiry' 
Alcohol/illicit dmg use 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
inquuy 
Review of tolerability 
X 
to study dmg prior to 
dose escalation 
Randomization 
X 
Dispense/collect study 
X 
X 
X 
X 
X 
X 
X 
dmg 
(dispense 
only) 
Review study 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
compliance and 
adherence 
Studydmg 
< 
X 
> 
administration 
Adverse event inquuy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
medication u1quuy 
Blood samples for PK 
X 
X 
X 
X 
analysis u 
Plasma sample for 
xw 
xw 
X 
X 
X 
X 
biomarker analysisv 
31 


DocuSign Envelope ID: 8A 16DDE40075-443E 9B53 15F684CED0B5 
Study Period 
Procedm·es and 
Assessments 
Study Clinic Visit 
Virtual Visit (VV) 
Telephone Call Safety 
Visit 
Study Week 
Visit Windows (days) 
Blood sample for 
genetic analysis v,x 
Blood sample for CAG 
repeat analysis vy 
Screening• 
Vl 
VVl 
BL 
<42 
<7 
xw 
X 
Double-blind 
Titration 
Pe1iod 
V2 
BLd 
0 
Day l 
2 
xw 
Double blind, Placebo controlled, Fulldose Maintenance Treatment 
Doubleblind 
Followup 
Period 
Variable Pe1iodb 
Safety 
Assessment' 
V3 
V4 
vs 
V6 
v1• 
VS (Main 
F/U 
Study Eos•, f 
/ETƯ 
VV2 
VV3 
VV4 
0 
0 
0 
0 
0 
4 
8 
13 
19 
26 
32 
39 
45 
52 
58 
65 
72 
78 
80 (2 weeks 
after Main 
Study EoS/ET 
±5 
±5 
±14 ±14 ±14h ±14 ±14h ±14 ±14h ±14 
±14h 
±14 
±14h 
±5 
 
' 
' 
' 
Abbreviations: Baselme (BL); cytosme-adenosme-guanme (CAG); Chrucal Global Impression of Change (CGI-C); Cluucal Global Impression of Seventy (CGI-S); 
Columbia-Suicide Severity Rating Scale (C-SSRS); electrocardiogram (ECG); End of Study (EoS); Early Tenuination (ET); Follow-Up (F/U); Huntington Disease Quality of Life 
Questionnaire-Participant (HDQoL-P); hldependence Scale (IS); Problem Behaviors Assessment - Sho1t Form (PBA-s); pharmacokinetic (PK); Quantitative motor (Q-Motor); 
Symbol Digit Modalities Test (SDMT); Stroop Word Reading (SWR); Total Ftu1ctional Capacity (TFC); Total Motor Score (TMS); Unified Hm1tington Disease Rating Scale 
(UHDRS); Visit (V); Virtual Visit (VV); women of childbearing potential (WOCBP). 
Table Footnotes: 
a. A pa1ticipant not meeting all eligibility requirements may be rescreened only once. Screening assessments may be repeated during the screening period if approved and at the 
discretion of the study Medical Monitor ( or designee ). After the screening period all screening assessments must be repeated except for Cytosine Adenine Guanine (CAG) 
repeat (provided the results are available from a prior screening period). 
b. This period is variable in duration up to 13 weeks. Participants will continue to receive treatment during the double-blind variable period until they reach Week 78 or until the 
last pa1ticipant randomized completes 65 weeks of treatment (2 weeks titration+ 63 weeks foll-dose), whichever comes fast. As soon as the last pa1ticipant reaches Week 65, 
the Main Study EoS visit for all remaining pa1ticipants who are 4 weeks beyond their respective Week 65 visit needs to be conducted within 4 weeks. 
c. Follow-up visit in Main Study is only applicable to participants who are not continuing to Open-label Extension. 
d. All Baseline assessments should be done pre-dose, except post-dose ECG. 
e 
For the last group of participants whose Week 65 visit is within 4 weeks of last participant's Week 65 visit in the Main Study, the End of Study visit will be V7. 
f After completing the Main Study EoS visit, eligible participants will have the option to continue for an Open-label Extension. 
g. When a pa1ticipant discontinues study dmg but continues to be followed in the study, they should first do ET visit and then continue with the follow-up off study treatment as 
scheduled. 
h. Visit window can be expanded any post Week 4 (V3) in-clinic visit window to ±28 days; this applies to V4-8. The expansion of the in-clinic visit window is only in case of a 
global pandemic. 
1. 
To be done once, as early as Main Study Week 58, or at V7 (Main Study Week 65)/Main Study Week 72 (depending on when the participant is anticipated to transition to 
OLE). 
32 


DocuSign Envelope ID: 8A 16DDE40075-443E 9B53 15F684CED0B5 
J. 
Inclusion/exclusion criteria should be met before Baseline visit. 
k. 
Safety laboratories should not be collected for participants who are off dmg and remain in the study, unless there are ab1101malities requiring follow-up. 
I. 
Serum pregnancy test will be perfo,med at Screening. At Baseline visit, urine pregnancy test will be pe,fonned before first dose. Both test results must be known before first 
dosing. Ul'ine pregnancy test will be performed at subsequent timepoints. An indetenninate or positive reading for the urine pregnancy test should be followed-up by a semm 
pregnancy test and the participant should be referred to a gynecologist if required. DmIDg the Treatment period, lU'llle pregnancy tests will be performed monthly. Refer to 
Protocol Appendix 4 Section 10.4. 
m. Single ECG to assess eligibility. 
11. Baseline pre-dose assessment will include triplicate ECG administrations. 
o. Single ECG 1-2 hours post-dose. 
p. 
Single ECG pre-dose. 
q. Only for pa1ticipa11ts not continuing to Open-label Extension (single ECG). Participants continuing to OLE, will have triplicate ECG (pre-dose) at VS. 
r. 
Vital signs (body temperattu·e, systolic and diastolic blood pressure, and heait rate) will be measured in a supine position after 5 minutes rest; thereafter, blood pressm·e should 
be measm·ed again after standing for 2 minutes. 
s. 
For training purposes only. 
t. 
This info,mation will be collected as pa,t of the concomitant medication inquiiy. 
u. Blood samples for plasma concentration of stt1dy dmg will be collected 1-2 hom·s after dosing and after the ECG. PK samples should not be collected from paiticipants who 
are off dmg and remain iii the stt1dy 
v 
Always collect blood after ECG is adininistered (not before). 
w. Sample analysis will be drawn at Screeningfil:_Baseline. 
x. Sampling analyses for deoxyribonucleic acid (DNA) extraction will be perfonned only once during the stt1dy, at Screening or at Baselii1e, for futtu·e genetic analysis related to 
pridopidine response or HD. 
y. Sampling analyses for CAG, only if needed. 
33 


DocuSign Envelope ID: 8A 16DDE40075-443E 9B53 15F684CED0B5 
Table 2: 
Schedule of Activities - Open-label Extension 
Study Period 
OpenLabel Titration Pel'iod 
OpenLabel Fnlldose Treatment Pel'iod 
Followup 
Procedm·es and assessments 
Safety Assessment 
Study Clinic Visit 
OLE Vl • (same as 
OLEV2 
OLEV3 
OLE V4+ 
OLE EoS/ETb 
OLE F/U 
Main Study VS) 
Telephone Call Safety Visit 
0 
0 
0 
0 
OLE Study Week 
OLE Day 1 (same 
OLE 
OLE 
OLE Wk13 
OLE Wk 26 OLE Wk39& 
OLE Wk52& 
X 
+2 weeks after 
as Main Study Wk 
Wk2 
Wk4 
every 26 wks 
every 26 wks 
OLEEoS/ET 
78/EoS) 
the1·eafte1· 
thereafter 
Visit Windows (days) 
±1 
±5 
±5 
±14 
±14 
±14 
±14 
±5 
OLE Informed consent 
X (if not obtained at 
Main Study V7) 
Re-confinn eligibility to OLE 
X 
Clinical laboratory tests ( senun 
X 
X 
X 
X 
X 
chemistry, hematology) d 
Urinalysis• 
X 
Pregnancy test (for WOCBP) 
u 
u 
u 
u 
u 
Monthly mine pregnancy test (at home) 
Brief physical examination 
X (full PE) 
X 
X 
X 
X 
12 lead ECG 
:,cf,g 
xg 
Xh 
Xh 
Vital signs 
X 
X 
X 
X 
X 
C-SSRS (since last visit 
X 
X 
X 
X 
X 
X 
X 
X 
version) 
UHDRS-TFC 
X 
X 
X 
X 
UHDRS-TMS 
X 
X 
X 
X 
SDMT 
X 
X 
X 
X 
SWR 
X 
X 
X 
X 
Q-Motor 
X 
X 
X 
X 
X 
PBA-s (Short Fonn) 
X 
X 
X 
X 
X 
X 
X 
CGI-C 
X 
X 
X 
X 
HDQoL 
X 
X 
X 
X 
34 
. 


DocuSign Envelope ID: 8A 16DDE40075-443E 9B53 15F684CED0B5 
Study Period 
OpenLabel Titration Pel'iod 
OpenLabel Fnlldose Treatment Pel'iod 
Followup 
Procedm·es and assessments 
Safety Assessment 
Study Clinic Visit 
OLE Vl • (same as 
OLEV2 
OLEV3 
OLE V4+ 
OLE EoS /ETb 
OLE F/U 
Main Study VS) 
Telephone Call Safety Visit 
â 
â 
â 
â 
OLE Study Week 
OLE Day 1 (same 
OLE 
OLE 
OLE Wk13 
OLE Wk 26 OLE Wk39& 
OLE Wk52& 
X 
+2 weeks after 
as Main Study Wk 
Wk2 
Wk4 
every 26 wks 
every 26 wks 
OLEEoS/ET 
78/EoS) 
the1·eafte1· 
thereafter 
Visit Windows (days) 
±1 
±5 
±5 
±14 
±14 
±14 
±14 
Benzodiazepines and 
X 
X 
X 
X 
X 
X 
X 
X 
antidepressants inquiry 
Alcohol/illicit dmg use inquiry 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense/collect study dmg 
X 
X 
X 
X 
X(collect only) 
Review study compliance and 
X 
X 
X 
X 
X 
X 
X 
X 
adherence 
Study dmg administration 
< 
X 
> 
Adverse event inquiry 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
inquiry 
Plasma sample for biomarker 
xc 
X 
xc 
analysis 
Abbreviations: Clinical Global hnpression of Change (CGI-C); Columbia-Suicide Severity Rating Scale (C-SSRS); electrocardiogran1 (ECG); End of Study (EoS); Early 
Temmiation (ET); Follow-up (F/U); Huntington Disease Quality of Life Questionnaire (HDQoL); Open-label Extension (OLE); Problem Behaviors Assessment- Short Fom1 
(PBA-s); Symbol Digit Modalities Test (SDMT); Stroop Word Reading (SWR); Total Functional Capacity (TFC); Total Motor Score (TMS); Unified Htmtington Disease Rating 
Scale (UHDRS); Visit (V); women of childbearing potential (WOCBP). 
Table Footuotes: 
a. The OLE Vl is the same as Mau1 Study VS ( or V7 /W65 for the last participant in the Mau1 Study). Assessments do not need to be repeated if conducted as pa1t of the Main 
Study. 
b. A pa1ticipant who discontumes study dmg at any point during the OLE, must also be withdrawn from the study and attend an EoS visit. 
c. hi-clinic visit window can be expanded to ±28 days; this applies to all u1-clu1ic visits u1cludu1g OLE Vl-4+ and OLE F/U. The expansion of the in-clinic visit window is only 
u1 case of a global pandemic. 
d Collect blood after ECG is administered (not before). 
e. Urinalysis will be done as pa1t of Main Study VS, not as part of OLE 
f 
Triplicate ECG pre-dose. 
g. Single ECG 1-2 hours post-dose. 
h. Single ECG pre-dose. 
35 
±5 
X 
X 
X 
X 
X 
J. 


DocuSign Envelope ID: 8A16DDE4-tl075.443E-9B53-15F684CEDOB5 
3.2. 
Primary, Secondary and Other Efficacy Endpoints and Safety 
Endpoints 
The study endpoints are based on the study objectives listed in the protocol Section 3 and are 
listed below. 
The endpoints described here as the component of the estimand, "variable ( or endpoint)" in 
Section A.3 .3 "Estimand Attributes" of ICH E9 R(l )2, reflect how efficacy is measured for each 
participant using different assessments (e.g., UHDRS-1FC), timepoints (e.g., Week 65) and 
methods (e.g., change from Baseline, being a responder). The detailed calculation or derivation 
for these endpoints is included in Appendix Section 12.1. 
In order to prese1ve Type I en-or, the multiplicity-adjusted secondary efficacy endpoints will be 
tested in sequential order as indicated in Section 3 .2.2. 
In SAP v 1.0, it was stated that the combined in-clinic and virtual assessments may be used to 
defme UHDRS-TFC related endpoints in the presence of missing values due to the pandemic 
impact of COVID-19. As of September 2022, <2% of all scheduled in-clinic visits from all 
participants were not perfonned or had UHDRS-TFC assessments missing. Since the proportion 
of missing in-clinic visits or assessments is ve1y small, and the UHDRS-1FC virtual assessments 
have not been previously validated, together with the heterogeneity that may exist due to the time 
interval (6 to 7 weeks) between in-clinic and virtual assessments, the UHDRS-1FC-related 
endpoints will be defined using in-clinic visits only. Explorat01y analysis will be performed by 
using virtual UHDRS-TFC assessments for prima1y endpoint (details in Section 7.3). 
3.2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint for this study is: 
• change from Baseline to Week 6 5 in the UHDRS-1FC ( defined as the sum of all 
UHDRS-1FC 5-items ratings [Domestic Chores, Activities of Daily Living, Finances, 
Care Level, and Occupation]) 
3.2.2. 
Multiplicity-adjusted Secondary Efficacy Endpoints 
The key secondary efficacy endpoint for this study is: 
• change from Baseline to Week 6 5 in cUHDRS total score 
The other multiplicit y-adjusted secondary efficacy endpoints for this study are to evaluate the 
efficacy of pridopidine 45 mg bid vs. placebo as measmed by: 
• the proportion of participants with improvement or no worsening in UHDRS-TFC at 
Week 65 (change from Baseline O points) using responder analysis 
• change from Baseline to Week 52 in UHDRS-TFC score 
• change from Baseline to Week 78 in UHDRS-TFC score 
• change from Baseline to Week 65 in Q-Motor 
36 


DocuSign Envelope ID: 8A16DDE4-tl075.443E-9B53-15F684CEDOB5 
• change from Baseline to Week 65 in UHD RS-TMS ( defined as the sum of all 
UHDRS motor domains ratings) 
• change from Baseline to Week 65 in SDMT score 
• change from Baseline to Week 52 in UHDRS-TMS score 
• proportion of par1icipants with no change or improvement in CGI-C at Week 65 
For responder analyses where there are fewer than 5 responders ( overall between both treatment 
groups), the analyses will not be perfonned as too few responders will not allow for comparison 
ofresponders between treated and placebo par1icipants. 
3.2.3. 
Non-multiplicity Adjusted Secondary Efficacy Endpoints 
The non-multiplicity adjusted secondary efficacy endpoints (listed in Section 2) will evaluate the 
efficacy of pridopidine 45 mg bid vs. placebo, as measmed by change from Baseline to post­
baseline scheduled visits in UHDRS-TFC (total score and subscales), cUHDRS, UHDRS-TMS 
(total score and subscales), dystonia score for those participants with severe dystonia at Baseline 
(defined as UHDRS-TMS-dystonia score 4), SDMT, SWR, Q-Motor measurements-
at Weeks 
26, 39, 52, 65 and 78, if not presented as prima1y or multiplicity-adjusted secondary endpoints. 
The proportion of participants with response in cUHDRS, UHDRS-TMS, Q-Moto-
' and CGI-C at Weeks 26, 39 (not for Q-Motor assessments), 52, 65 and 78, if 
not presented as prima1y and multiplicity-adjusted secondary endpoints, will also be evaluated as 
non-multiplicity adjusted secondary efficacy endpoints. The response in each endpoint is defined 
as follows: 
• 
Improvement or no worsening in Q-Motor 
Baseline SO at conesponding post-baseline visit 
with change from 
• 
Improvement or no worsening in UHD RS-TMS with change from Baseline SO at 
conesponding post-baseline visits 
• Change from Baseline in cUHDRS -1 at conesponding post-baseline visits 
• Response in CGI-C defined using diff,erent thresholds (i.e., 1, 1 to 2, I to 3, 1 to 4) at 
conesponding post-baseline visits 
3.2.4. 
Other Exploratory Efficacy Endpoints 
The other explornt01y efficacy endpoints for this study are to evaluate the efficacy of pridopidine 
45 mg bid vs. placebo as assessed by: 
• 
Problem Behaviors assessment, as assessed by the change from Baseline to Weeks 
26, 52, 65 and 78 in PBA-s total score 
• Change from Baseline to Weeks 26, 52, 65 and 78 in PBA-s apathy sub-scores 
• Change from Baseline to Weeks 26, 52, 65 and 78 in HDQoL 
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3.2.5. 
Biomarker Endpoints 
• Evaluate the efficacy of pridopidine 45 mg bid vs. placebo as assessed by the change 
from Baseline to Weeks 26, 52, 65 and 78 in plasma Nfl., protein 
• Evaluate the relationship between Baseline Nfl., and changes from Baseline in select 
efficacy endpoints 
• Evaluate the relationship between changes from Baseline to Weeks 26, 52, 65 and 78 
in plasma Nfl., and select efficacy endpoints for pridopidine 45 mg bid vs. placebo 
• 
Propo1tion of paiticipants with stabilization or improvement in change from Baseline 
to Week 26, 52, 65 and 78 in plasma Nfl., levels 
3.2.6. 
Pharmacokinetic Endpoints 
• To evaluate plasma concentration of pridopidine and its main metabolite at Weeks 26, 
52, 65, and 78. For Week 78 analysis include paiticipants' who had their EoS visit 
between Week 65 and 78. 
• To study the relationship between plasma concentration of pridopidine and clinical 
outcomes including change from Baseline in UHDRS-TFC, UHDRS-TMS, Q-Motor, 
cUHDRS, SDMT, and SWR. 
3.2.7. 
Safety Endpoints 
Safety endpoints will include the following: 
• fucidence of AEs and SAEs throughout the study 
• Changes from Baseline and absolute thresholds as per ICH E14 in QTcF and other 
ECG parameter assessments throughout the study 
• Change in clinical safety laborato1y tests (semm/blood cheinistiy, hematology, and 
urinalysis) and summaiy of abno1malities throughout the study 
• Changes from Baseline C-SSRS throughout the study 
• Change in vital signs and summa1y of abno1malities throughout the study 
• 
Abno1malities in Physical Exam 
• 
Abno1malities in Neurological Exam 
3.2.8. 
Tolerability Endpoints 
Tolerability endpoints will include the following: 
• The number (%) of paiticipants who complete the treatment period on study dmg 
• The number (%) of paiticipants who failed to complete the treatment period on study 
diug due to an AE 
• The number (%) of paiticipants who fail to complete the ti·eatment period due to 
QTcF, CrCl or Psychiatric Stopping Rules 
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3.3. 
Sample Size and Power Considerations 
Based on experience with early HD paiticipants in the prior Phase 2 PRIDE-HD study, we 
expect the difference in mean change from Baseline to Week 65 between the 45 mg bid treated 
and placebo groups to be 0.7 points on the UHDRS-TFC with a standai·d deviation (SD) of 1.9 
points. 
A total sample size of 372 pa1ticipants will provide 94% power to detect a between-group 
difference of 0. 7 points in the mean change from Baseline to 65 weeks in the UHDRS-TFC 
score, with an SD of 1.9 points, using a two-tailed t-test at a significance level of 0.05. Assuming 
a drop-out rate of 22.5%, a total of 480 paiticipants will be randomized. The sample size was 
calculated using SAS version 9 .4 PROC POWER. 
Based on feedback from Regulato1y Authorities, the power assessment was updated as below. 
Assuming a dropout rate of22.5 % in each treatment group early in the study, under assumption 
of Missing Not at Random (MNAR) with imputed values for all discontinued paiticipants 
estimated based on the trajecto1y of placebo pa1ticipants with available data, we anticipate a 
difference in change from Baseline to imputed values at Week 65 for this group to be 0.1 points. 
The overall difference would then be 0.565 (0.7*0.775+0.1 *0.225) or 0.7 points for the 77.5% 
completers and 0.1 points for the 22.5 % paiticipants who discontinue and have imputed data at 
Week 65. A difference of 0.565 points with SD of 1.9 with a sample size of 480 paiticipants 
would provide 90% power (SAS V 9.4 PROC POWER). 
3.4. 
Randomization and Blinding 
Randomization will be used to avoid bias in the treatment assignment, to increase the likelihood 
that known and unknown attributes (e.g., demographics and baseline characteristics) ai·e evenly 
balanced across treatment groups, and to enhance the validity of statistical comparisons. 
Paiticipants who meet eligibility criteria will be randomly assigned at Baseline (Visit 2) to 
receive pridopidine or placebo in a 1: I randomization using an futeractive Response Technology 
(IRT), based upon the stratification vai·iables of HD stage (HDl or HD2) and use of neuroleptics 
(Yes/No). 
This is a double-blind study where all paiticipants, site staff, Sponsor, Clinical Research 
Organizations (CROs) and vendors involved in the conduct, data management or analysis of the 
study will remain blinded to treatment assignments. At the End of the Main Study when the last 
paiticipant has completed the Week 65 visit or has withdrawn from the study, following database 
lock, the treatment assignment will be unblinded for analysis. 
The exceptions to above blinding are the unblinded statistician and programmer who will 
generate the analyses for the SMC and will not othe1wise be involved in the trial, the vendor 
personnel responsible for configuration of the IRT system, and the dmg packaging and labeling 
team (unblinded personnel) who will distribute the pridopidine or placebo diug. Each of these 
groups will have standai·d operating procedures (SOPs) or study specific plans in place for 
maintaining the treatment blind. Dmg concentration info1mation that would unblind the study 
will not be repo1ted to investigative sites or blinded personnel until the study has been unblinded. 
The IRT system will be programmed with blind-breaking instructions. fu case of an emergency, 
the fuvestigator has the responsibility, after consultation with the medical monitor, for 
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detennining if unblinding of a pa1ticipant's study drng assignment is wa1rnnted. Pa1ticipant 
safety must always be the first consideration in making such a determination. If a pa1ticipant's 
study diug assignment is unblinded, the Sponsor must be notified within 24 hours after breaking 
the blind. The date and reason that the blind was broken must be recorded in the source 
documentation and CRF, as applicable. The responsible CRO will also be notified immediately 
of such unblinding without revealing details of the paiticipant's treatment. 
Appropriate personnel at the Sponsor or sponsor designee will unblind suspected unexpected 
serious adverse reactions (SUSARs) for the pmpose of regulato1y repo1ting. The Sponsor will 
submit SUSARs to Regulato1y Agencies in a blinded or unblinded fashion according to local 
regulations. The Sponsor will submit SUSARs to Investigators in a blinded fashion. Details of 
how the blind is maintained during PK analysis will also be included in the blinding/unblinding 
plan. 
3.5. 
Sequence of Planned Analyses 
3.5.1. 
Interim Analyses 
No interim analysis is planned for this study. The analyses after the last paiticipant completes 
Week 65 will be considered the final analyses of the Main Study. See Section 3.5.3 below. 
3.5.2. 
Analyses for Safety Monitoring Committee Meetings 
During the conduct of the Main Study, an independent SMC will be monitoring the safety, 
tolerability and/or efficacy (if needed). 
Details of what data will be reviewed and when during the study will be included in the SMC 
Chatter. 
3.5.3. 
Analyses and Reporting of Main Study Results 
All final, planned Main Study analyses specified in this SAP will be perfo1med only after 
database lock for the Main Study after the last pa1ticipant has completed the Main Study. The 
randomization codes will not be unblinded until this SAP has been finalized and the database 
locked. 
The Main Study is considered to be complete when all paiticipants who have signed info1med 
consent, been randomized, and treated have completed at least Week 65 of the study or 
discontinued from the study eai·lier. 
The regulato1y submission will be based on the analyses of Main Study data. OLE analyses as 
planned in Section 3.5.4 will be provided as update materials after submission. 
3.5.4. 
OLE Analyses 
OLE analyses on the data collected during the OLE period will NOT be perfo1med at the 
database lock for the Main Study. The final analyses for the OLE will be perfo1med after the last 
paiticipant has completed the EoS Visit and the database has been locked for the OLE period. 
The analyses will be used to assess the durability of treatment effect, safety and tolerability of 
pridopidine during the OLE period. 
Interim analyses may be perfo1med on OLE data prior to completion of the OLE. 
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Analyses using external controls such as data collected in ENROLL-HD, a longitudinal, 
multinational, observational registry study may be perfo1med to contextualize the long-te1m 
effect of pridopidine on treating HD in OLE period. These analyses, if required, will be detailed 
in a separate SAP. 
3.5.5. 
Other Analyses 
Additional analyses may be added to this SAP which will be included in an Amendment, 
Appendix or Addendum. 
Any explorato1y analyses completed to suppo1i study analyses, which were not identified in this 
SAP or an Amendment, Appendix or Addendum prior to locking the database and unblinding the 
study, will be documented and repo1ied in changes to the planned analyses section in the CSR. 
3.6. 
COVID-19 Mitigation 
The PROOF-HD study is being conducted during the COVID-19 pandemic and inco1porates 
several mitigation sb.'ategies that are included in the protocol and study plans. For details, refer to 
the protocol Section 10.10. A brief summa1y is included below: 
• Four (4) pre-planned viiiual visits (VVs) have been inco1porated into the protocol at 
different timepoints (perfo1med via telephone) 
• Eve1y in-clinic visit, except Screening, Baseline, and Week 65 visits, can be conve1ied to 
a VV if requii·ed (performed via telephone, sma1i phone, tablet or computer and home 
assessments by healthcare professional) 
• Raters will be tJ.·ained and ready to implement pre-identified remote efficacy and safety 
measures via telephone (see Table 3) during the pre-planned VV and during the 
converted VV 
• Home visit by healthcare professionals will peifo1m essential safety assessments (safety 
labs, urinalysis, pregnancy test, vital signs, and dmg accountability) if clinic visits are 
converted to VV s 
3.6.1. 
Types of Visits 
• 
In-Clinic Visits - Screening, Baseline, W4, W26, W39, W52, W65, W78 (EoS/ET) 
• 
Pre-Planned VVs -at Baseline, W13, W32, and W58 
These have been included as a contingency plan for the integrity of the study primaiy 
endpoint and several seconda1y endpoints 
• 
Converted VVs - In-Clinic Visits that can be replaced by VV if necessaiy - W4, W26, 
W39, and W78 
Table 3: 
Visit Activities According to the Visit Types 
Study Pe1iod 
In- Clinic 
Preplanned 
Converted VV 
Procedures and Assessments 
Visit 
Virtual Visits 
(Home/Phone) 
(Phone) 
Informed consent 
✓ 
X 
X 
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Study Pe1iod 
In- Clinic 
Preplanned 
Converted VV 
Procedures and Assessments 
Visit 
Virtual Visits 
(Home/Phone) 
(Phone) 
Demography 
✓ 
X 
X 
Medical and psychiatric histo1y 
✓ 
X 
X 
Prior medication and treatment 
✓ 
X 
X 
histo1y 
Inclusion and exclusion criteria 
X 
X 
Clinical laborato1y tests (semm 
chemistry, hematology, and 
✓ 
X 
✓ (Home Nursing Se1vice) 
urinalysis)* 
Pregnancy test (for WOCBP)* 
✓ 
X 
✓ (Home Nursing Se1vice) 
Full physical and neurological 
✓ 
X 
X 
examination 
Brief physical examination 
✓ 
X 
X 
12 lead ECG 
✓ 
X 
X 
Vital signs* 
✓ 
X 
✓ (Home Nursing Se1vice) 
C-SSRS (baseline version) 
✓ 
X 
X 
C-SSRS (since last visit version) 
✓ 
✓ 
✓ (Phone) 
UHDRS-TFC* 
✓ 
✓ 
✓ (Phone) 
UHDRS-TMS 
✓ 
X 
X 
UHDRS-1S 
✓ 
X 
X 
SDMT 
✓ 
X 
X 
SWR 
✓ 
X 
X 
Q-Motor 
✓ 
X 
X 
PBA-s (Short Fo1m) 
✓ 
✓ 
✓ (Phone) 
CGI-S (modified) 
✓ 
X 
X 
CGI-C 
✓ 
X 
✓ (Phone) 
HDQoL-P 
✓ 
X 
✓ 
Benzodiazepines and 
✓ 
✓ 
✓ (Phone) 
antidepressants inquiiy 
Alcohol/illicit diug use inquiry 
✓ 
✓ 
✓ (Phone) 
Review of tolerability to study dI11g 
✓ 
X 
X 
prior to dose escalation 
Randomization 
✓ 
X 
X 
Dispense/collect study diug* 
✓ 
X 
✓ (Qualified provider) 
Review study compliance and 
✓ 
X 
✓ (Home Nursing Se1vice) 
adherence* 
Adverse event inquiiy 
✓ 
✓ 
✓ (Phone) 
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Study Pe1iod 
In- Clinic 
Preplanned 
Converted VV 
Procedures and Assessments 
Visit 
Virtual Visits 
(Home/Phone) 
(Phone) 
Concomitant medication inquiiy 
✓ 
✓ 
✓ (Phone) 
Blood samples for PK analysis 
✓ 
X 
X 
Plasma sample for biomarker 
✓ 
X 
X 
analysis 
Blood sample for genetic analysis 
✓ 
X 
X 
ECG 
✓ 
X 
X 
X- assessment not done 
✓- Yes, assessment done 
* Participants who are off study dmg and continue to participate in the study and have their clinic visits converted to virtual visits 
(by phone) will not be required to undergo UHDRS-TFC assessment or get home nlll'sing services during the conveited virtual 
visits. 
3.6.2. 
Other Mitigation Strategies Incorporated 
• A customized guidance to address global health emergencies and potential impact on the 
clinical study is included as an appendix to the protocol Section 10.10. The guidance also 
covers the following: 
3.6.3. 
o Consent can be given orally/remotely by the study pa1ticipant 
o Study paiticipant and person obtaining consent can sign two separate consent 
fo1ms 
o Local laborato1y may be used for safety labs if necessaiy 
o Monitoring activities may be adjusted ( central monitoring, off-site monitoring, 
remote source data verification) 
o Prilenia and the Huntington Study Group (HSG) will continually assess whether 
the limitations imposed by the COVID-19 public health emergency on protocol 
implementation pose new safety risk to the study paiticipants and whether it is 
feasible to mitigate these risks by amending the study protocol and/or procedures 
Mitigation Strategies for Analyses of Primary and Important Secondary 
Efficacy Endpoints 
The impact of COVID-19 resulting in treatment discontinuation is described in Section 7 .1 and 
elsewhere in the SAP for estimand and sensitivity analyses under the ICH E9 R(l) framework 
and related publications2•
3•
4 (Akacha et. al., 2020; Meyer et. al., 2020). As of the SAP Version 2.0 
update in November 2022, due to the minimal impact of COVID-19 on the efficacy endpoints as 
detailed in below sections, no additional efficacy analyses will be perfo1med to address COVID-
19 impact. 
2 ICH E9 R(l) "Addendum on Estimands and Sensitivity Analysis In Clinical Trials to the Guideline on Statistical Principles For 
Clinical Trials." May 2021 ICH Revision 1. 
3 FDA Guidance on Statistical Considerations for Clinical Trials During the COVID-19 Public Health Emergency. Guidance for 
Industry, August 2021. https://www.fda.gov/media/139145/download. 
4FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency Guidance for 
Industry, Investigators, and Institutional Review Boards, March 2020. https://wwwfda.gov/regulatory-information/search-fda­
guidance-documents/fda-guidance-conduct-clinical-trials-medical-products-during-covid-19-public-health-emergency 
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3.6.3.1. 
Evaluation of the Correlation Between In-clinic UHDRS-TFC Assessment and 
Phone (virtual) UHDRS-TFC Assessment 
fu SAP vl .0, it was stated that blinded analyses will be performed to assess reliability of the 
virtual UHDRS-TFC by computing the intra-class con-elation coefficient (ICC) assessed at 
Baseline in-clinic and virtually over the telephone at VVI, and that if the ICC is shown to be 
Ñ0.80, the last available virtual UHDRS-TFC assessments may be used for paiiicipants who 
discontinue prior to Week 65 or do not have an assessment at Week 65. 
However, based on the observed high completion rate (98.9%) of in-clinic UHDRS-TFC 
assessments as of October 2022, the COVID-19 impact is expected to be minimal. There also 
may exist some heterogeneity if combining in-clinic and virtual visits as they ai·e conducted in 
general 6 to 7 weeks apa1i. Fmihe1more UHDRS-TFC vi1iual assessments have not been 
previously validated. Therefore, only the in-clinic UHDRS-TFC will be used for primaiy and 
seconda1y analyses. Additional explorato1y efficacy analyses using viiiual UHDRS-TFC will be 
presented. 
It was also stated in SAP vl.0 that if the nlllllber of pa1iicipants who either discontinue from the 
study or have then· Week 65 assessments impacted by COVID-19 was larger than planned, a 
blinded sample size re-estimation analysis may be conducted. Due to low discontinuation rate 
and minimal impact of COVID-19 on Week 65 UHDRS-TFC assessments, the blinded sample 
size re-estimation will not be perfo1med. 
3.6.3.2. 
Impact on Secondary Endpoints 
As of October 2022, the completion rate of scheduled assessments is >97% for cUHDRS and 
TMS. The COVID-19 impact on secondaiy endpoints is also minimal. 
3.6.4. 
Impact on Protocol Safety Assessments 
The impact of COVID-19 on protocol deviations (PDs ), medications taken, AEs and other key 
safety data will be summarized descriptively in con-esponding safety analysis. 
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4. 
POPULATIONS /ANALYSIS SETS 
4.1. 
Analysis Populations for the Main Study Period 
The populations below are defined using the traditional approach as per ICH E9. The exact 
handling of intercurrent events (ICEs) for each of these are detailed finiher in Section 7 .1 using 
the estimand framework per ICH E9 R(l ). 
4.1.1. 
Intent-to-Treat (ITT) Population 
The intent-to-treat (ITn population will include all randomized paiiicipants. In this population, 
treatment will be assigned based on the treatment to which pa1iicipants were randomized, 
regai·dless of which treatment they actually received. The ITT population is the main analysis 
population of prima1y endpoint for European Medicines Agency (EMA) submission. 
4.1.2. 
Modified Intent-to-Treat (mITT) Population 
The modified intent-to-treat (mITT) population is a subset of the ITT population and will include 
all paiiicipants in the ITT population who received at least 1 dose of study diug and have valid 
in-clinic TFC scores both at Baseline and at least I post-baseline timepoint. The mITT 
population will be analyzed according to the treatment to which the paiiicipant was randomized. 
The mITT population is the main analysis population for primaiy endpoint in non-EMA 
submission. For all other efficacy analyses, the mITT population is the main analysis population 
in both EMA and non-EMA submission. 
All participants who received at least 1 dose of pridopidine and have at least 1 valid in-clinic 
UHDRS-TFC score during the OLE period will be included in the OLE mITT population. 
4.1.3. 
Per Protocol Week 65 (W65PP) Population 
The per protocol Week 65 (W65PP) population is a subset of the mITT population and includes 
all paiiicipants who have a valid UHDRS-TFC at Week 65, were on study dmg with compliance 
>80% during the study, and did not have any impo1iant PDs ( document of PDs resulting in 
exclusion from PP population) or other events ( e.g., receipt of incoITect treatment) impacting the 
TFC assessment. The W65PP population will be used for sensitivity analysis of the primaiy and 
select secondaiy endpoints at Week 65, and will be analyzed according to the actual treatment 
received (See Section 4.1.5 for definition of actual treatment). The W65PP population will be 
finalized prior to locking the database and unblinding the study. 
4.1.4. 
Per Protocol Week 78 (W78PP) Population 
The per protocol Week 78 (W78PP) population is a subset of the mITT population and includes 
all paiiicipants who have a valid UHDRS-TFC at Week 78, were on study diug with compliance 
>80% during the study, and did not have any impo1iant PDs ( document of PDs resulting in 
exclusion from PP population) or other events ( e.g. receipt of incoITect treatment) impacting the 
TFC assessment. The W78PP set will be used for sensitivity analysis of secondaiy endpoints at 
Week 78, and will be analyzed according to the actual treatment received (See Section 4.1.5 for 
definition of actual treatment). The W78PP population will be finalized prior to locking the 
database and unblinding the study. 
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4.1.5. 
Safety Population (SP) 
The safety population (SP) will include all randomized participants who received at least 1 dose 
of study chug. fu this population, treatment will be assigned based upon the treatment 
paiiicipants actually received, regai·dless of the treatment to which they were randomized. The 
safety set will be used for safety analyses and biomarker analysis. 
All participants who receive at least 1 dose of pridopidine during the OLE period will be 
included in the OLE safety population. 
The actual treatment received in the double-blind period will be pridopidine if a paiiicipant 
receives pridopidine for > 10% of total number of doses received; othe1wise, the actual treatment 
will be placebo. The actual treatment received in the OLE will be pridopidine to pridopidine if a 
paiiicipant receives pridopidine for > I 0% of total number of doses received in the double-blind 
period; othe1wise, the actual treatment will be placebo to pridopidine. 
4.1.6. 
PK Population (PKP) 
The PK population (PKP) will include all randomized paiiicipants who received at least 1 dose 
of pridopidine and have at least I valid PK assessment. fu this population, treatment will be 
assigned based upon the treatment participants actually received, regai·dless of the treatment to 
which they were randomized. This PKP will be used for all PK analyses. 
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5. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING 
This section addresses the definitions, algorithms, imputations, and conventions that will apply 
to the analysis and handling of the data in general. Rules that are data specific will be addressed 
in the detailed discussions of individual sections below. This SAP and all Tables, Figures and 
Listings (TFLs) created will use U.S. spelling. 
All changes to this SAP prior to locking the database and unblinding the study will be 
documented in an Addendum. 
Any additional analyses perfo1med or changes to the SAP and Addendums after unblinding the 
study will be described in the CSR under the section "Changes to Planned Analyses". 
5.1. 
General Summary Tables, Figures and Individual Participant Data 
Listing Considerations 
Summaiy tables and listings (e.g., post text tables and individual paiticipant data listings ai·e 
prepai·ed according to ICH Guideline E3) will include a "footer" providing explanato1y notes 
that indicate as a minimum (1) Date and time of output generation; (2) SAS program name, 
including the path that generates the output; (3) Any other output specific details that require 
fmther elaboration; (4) Page number in the fo1mat of Page X of Y. 
Summaiy tables will include reference(s) to the paiticipant data listing(s) to suppo1t the summaiy 
data. The data extraction date links the output to the archived database that is frozen to ensure the 
replication of the results. 
For the Main Study, summaiy tables will display the 2 treatment groups, "Placebo" and 
"Pridopidine 45 mg bid". An overall total column will be included, where appropriate. 
Unless specified, row entries in summaiy tables ai·e always displayed for eve1y catego1y even if 
no data exists for any participants (e.g., a row with all zeros will appear). The summaiy tables 
will cleai·ly indicate the number of paiticipants to which the data apply along with an indication 
for the number of paiticipants with Inissing data. 
If no data exist for any pa1ticipants for a given Table or Listing, a text will be displayed to 
indicate why there is no data. 
In summa1y tables for medications, medical conditions and AE verbatim (repo1ted) te1ms are 
coded to prefeITed te1ms (PT) and body/organ systems ai·e coded per standard dictionai·ies 
mentioned in Section 5.3. 
All relevant data collected in the study will be presented in individual Paiticipant Data Listings 
(unless agreed to with the agency to not create ce1tain listings, e.g., Laborato1y listings, which 
tend to be ve1y large). All listings will include pa1ticipant ID and treatment group. Where 
applicable, listings will also include visit number, visit date, and days relative to the initiation of 
treatment. Individual paiticipant data listings, at a minimum, are s01ted by Treatment, Paiticipant 
ID, Assessment and Visit (Week), as applicable. 
Relevant data derived for analyses will also be included with the raw data in the listings . 
Supporting figures may be generated for key tables. 
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5.2. 
General Post Text Summary Table and Individual Participant Data 
Listing Format Considerations 
The default convention is to number tables and listings using a decimal system to reflect main 
levels of unique tables and listings and sub-levels ofreplicate tables and listings with 2 or more 
numbers separated by 1 or more decimals digits (e.g., Table WW.XX.YY.ZZ). 
1. The first level number will be consistent with the conesponding CSR appendix in which 
the tables or listings will appear. For example, the post-text tables usually occupy 
Appendix 14 and the individual pa1ticipant data listings are in Appendix 16.2. All post­
text tables should have a main number level 14 and listings should have a main number 
level 16.2. The disposition table is usually first in the first section of the repo1t and will 
be numbered Table 14.1. 
2. Paiticipant accounting, final disposition and Baseline and demographic profile should 
appeai· as the second level number. Efficacy Tables would be next (14.2 series) followed 
by safety (Table 14.3 series). 
3. The Table/Listings title should be unique, complete, accurate, and concise. The last line 
of the title should provide the analysis group being summai·ized (e.g., ITT population, 
mITT population, or safety population). If possible, the units of measurement for data 
contained in the table can appear in pai·entheses to conserve space in the body of the 
table. For example, the summa1y of vital signs title could read "Summaiy of Sitting and 
Standing Blood Pressure (mmHg) and Heait Rate (HR) (bpm)." Whether in the title, 
footnotes or body of a table or listing, units must always be specified for all appropriate 
data unless obvious. 
4. If possible, vai·iables being summarized, and statistics reported should appear in the left 
most column of a table. The next columns would be for the assessment, then the visits 
followed by treatment groups for the placebo, pridopidine, and ( optional) all paiticipants, 
respectively. 
5. The definition of all relevant derived variables and decodes for coded data must appeai· 
on the Table and Listings. Tables and Listings should be self-contained and all-relevant 
inf01mation to review the Table or Listing will either be in the titles, column or row 
headers, or in footnotes. 
5.3. 
Data Management 
Data from the study will be entered into the EDC system TrialMaster version 5.0 
(https :/ /www.anjusoftware.com/ solutions/ clinical-trials/trialmaster), a validated electronic 
21CFR Pait 11 compliant EDC system. Data review, coding, and logic, range, cross-fo1m, and 
consistency checks will be perfo1med to ensure quality of the data 5. AEs and medications will be 
coded using Medical Dictionaiy for Regulato1y Activities (MedDRA) version 23.0 (or a later 
version if updated during the study) and the World Health Organization Drng Dictiona1y version 
Mai·ch 2020, B3 (or a later version if updated during the study), respectively. 
5 Guidance on the Management of Clinical Trials Dtumg the COVID-19 (coronavims) Pandemic, Version 5, 2 Oct 2022. 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/guidanceclinicaltrials _ covid 19 _ en. pdf 
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5.4. 
Data Presentation Conventions 
Continuous variables (e.g., age) are summarized using descriptive statistics (the number of 
paiiicipants with available data, the mean, SD, first quaiiile (QI), median, third qua1iile (Q3), 
minimum and maximum). Categorical variables (e.g., race) ai·e summarized using counts and 
percentages. Percentages are calculated using the total paiiicipants per treatment group with 
available data (overall or within relevant subgroup when appropriate). Summai·ies for discrete 
variables will include frequencies and percentages. Unless obvious, denominators used for 
computation of percentages will be indicated in footnotes on tables. 
The following conventions will be applied to all data presentations and summaries. 
• For continuous vai·iables, all mean, Ql (25th percentile), median and Q3 (75th percentile) 
values ai·e fo1matted to one more decimal place than the measured value. SD values ai·e 
fo1matted to two more decimal places than the measured value. Minimum and maximum 
values ai·e presented with the same number of decimal places as the measured value. This 
rnle may be modified to fit data in a given table as long as the data displays relevant 
decimal places for inte1pretation of results. 
• For categorical vai·iables, the number and percentage of responses ai·e presented in the 
fo1m XX (XX.X%) where the percentage is in the pai·entheses and will be rounded to one 
decimal place. 
• Date variables are fo1matted as DDMMMYYYY for presentation. Time is fo1matted in 
milita1y time as HH:MM for presentation. 
• Wherever possible, data will be decimal-centered, or left aligned as appropriate to best 
display the data and column headers. Pai·entheses will also be aligned appropriately for 
best display. This will be detailed in the mock shells. 
• 
P-values, if applicable, will be presented to 4 decimal places. If the p-value is less than 
0.001 then it will be presented as <0.001. If the rounded result is a value of 1.000, it will 
be displayed as >0.999. 
• Summaries of clinically significant abno1mal values will include all post-baseline values 
(including scheduled, unscheduled, and ET visits). 
• Unless othe1wise stated, any statistical tests perfo1med will use 2-sided tests at the 5% 
significance level. 
5.5. 
5.5.1. 
Derivation and Transformation on Data 
Baseline Values 
Two baselines (Main Study and OLE baselines) ai·e defined as below. Both baselines can be used 
to analyze data collected during OLE period. Only Main Study Baseline will be used to analyze 
data collected during Main Study po1iion. 
5.5.1.1. 
Main Study Baseline 
The Main Study Baseline value for efficacy and safety is the last non-missing observed data 
prior to the first dose of study diug. Since per SoA all Baseline Visit (V2) assessments ( except 
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post-dose ECGs at V2) are perfo1med and recorded prior to paiiicipants taking their first dose of 
study diug, the baseline value will include observations on or prior to the date of first dose of 
study diug. For ECGs, the Baseline value is the average of the 3 (triplicates) ECGs peifo1med at 
Baseline before first diug administration. 
5.5.1.2. 
OLE Baseline 
OLE Baseline is defmed as the last non-missing obse1ved data prior to the first dose of 
pridopidine in the OLE period. In general, the OLE Baseline will be the OLE Day I assessment. 
For ECGs, the OLE Baseline value is the average of the 3 (triplicates) ECGs perfo1med at OLE 
Day I visit before first diug administration. 
Change from Baseline analysis of ECGs will be perfo1med using Main Study or OLE Baseline as 
appropriate. 
5.5.2. 
Baseline Age 
Due to data protection requirements only year of birth and age at time of signing consent will be 
captured on the eCRF and no computation of age will be necessaiy. 
5.5.3. 
Study Day and By-Visit Summaries 
If the date of interest ( date of visit, date of start of medication, date of AE, etc.) occurs on or after 
the first dose date then study day will be calculated as ( date of interest - date of first dose) + 1. If 
the date of interest occurs prior to the first dose date, then study day will be calculated as ( date of 
interest - date of first dose). Study Day I is the date of first dose and as per CDISC Study Data 
Tabulation Model Implementation Guide (SDTMIG) 3.2 requirements, there is no Study Day 0. 
For by-visit summaries and/or statistical models for efficacy, ET visit for a specific measure will 
be assigned to the next closest non-missing planned scheduled visit of this measure. 
5.5.4. 
Change and Percent (%) Change from Baseline 
Obse1ved change in values from Baseline (i.e., Day I) is calculated as (post-Baseline result ­
Baseline result). 
Obse1ved % change in values from Baseline is calculated as [I00*(post-Baseline result ­
Baseline result) / (absolute value at Baseline result)]. 
If either the Baseline or the post-baseline result is missing, the obse1ved change from Baseline is 
set to missing as well. If the Baseline result is missing or 0, or if the post-baseline result is 
missing, then obse1ved % Change from Baseline will be set to missing at that visit. 
For UHDRS -TFC and other efficacy assessments, change from Baseline will be calculated for 
scheduled in-clinic visits at Weeks 26, 39, 52, 65, and 78. For other efficacy and safety 
endpoints, change or % change (where applicable) from baseline to post-baseline visits will be 
calculated per SoA. 
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5.5.5. 
End of Study Definition 
End of the Main Study occurs when the last paiticipant has completed the Week 65 visit or has 
withdrawn from the study. At End of the Main Study, a paiticipant should have either completed 
the double-blind period between Week 65 and Week 78 or discontinued eai·ly from the study. 
End of OLE is defmed as having occuned when the last paiticipant completes the OLE period of 
the study or has withdrawn from the study during OLE period. 
5.5.6. 
Last Study Drug Date for the Main Study Analyses 
For paiticipants that continue beyond Week 65, the last study drng date for the Main Study 
analyses will be derived from the last date of study diug administration on the eCRF page, End 
of Treatment, in the Main Study. 
5.5.7. 
Study Periods 
End of Study Day for each paiticipant 
End of the Main Study Day ( double-blind period) for a paiticipant is defined as the Main Study 
EoS/ET Visit, or last follow-up safety visit or phone call in the Main Study. End of OLE Day 
for a given paiticipant is defined as the last follow-up safety visit or phone call for fmal data 
collection in the OLE period. 
A paiticipant is considered as a Week 65 Completer (Main Study Completer) if he/she has 
completed the Week 65 Visit without discontinuing earlier, regardless of whether they were on 
or off study treatment at Week 65. As per the study design, these paiticipants may have 
completed visits beyond Week 65. 
Treatment periods 
Main Study Treatment Period is defmed as the period from the first dose to the End of the 
Main Study Day. OLE Treatment Period is defmed as the period from 1 day after End of the 
Main Study Day to End of OLE Day. 
5.5.8. 
Visit Windows 
The visit windows for the study are as defmed in the protocol. The by-visit analyses will be 
based on nominal scheduled visits without using the unscheduled visits. Since the evaluation of 
study diug is for chronic use and using an endpoint that changes over a long te1m, delayed visits 
or visits occmTing outside of the specified window ai·e likely to have a minimal impact on 
analyses. 
5.6. 
Multiple Comparisons and Multiplicity 
The primaiy efficacy endpoint, key and other secondaiy efficacy endpoints will be tested 
sequentially in the order specified in Section 2 to account for multiplicity and preserve overall 
Type I enor. Each test will be at a type I enor level ɸ0.05, two-sided to prese1ve the overall 
Type I enor (first test of primaiy efficacy is conducted at 0.05). As soon as a given test yields a 
p-value >0.05, all subsequent tests following it will be considered nominal p-values. 
No adjustments will be made for multiple comparisons in testing other explorato1y efficacy 
endpoints. 
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5.7. 
Analysis by Region and Pooling of Countries with Low Number of 
Participants 
Analyses will be adjusted for region (North America and Europe) as a covariate. Since eve1y 
countiy had 9 or more pa1iicipants, no pooling of subjects is planned for any analyses conducted 
by countiy unless othe1wise specified. No analyses by center are planned. However, if these are 
required to be conducted by regulato1y authorities, centers with too few paiiicipants will be 
pooled. 
5.8. 
5.8.1. 
Missing Data and Unscheduled Visits 
Missing Efficacy Endpoints 
Efficacy variables will be handled using the estimand framework detailed in Section 7 .1. 
5.8.1.1. 
Missing Baseline Value 
Missing Baseline values for efficacy endpoints will not be imputed for analysis based on 
observed data since there are only a few paiiicipants ( <5) missing any baseline efficacy 
endpoints. 
Missing Baseline covai·iate variables used as covariates in analysis models such as Mixed Model 
Repeated Measures (MMRM) will be replaced using mean imputation. Since the pa1iicipants are 
randomized at Baseline to help ensure balance between ti·eatment groups, the missing values will 
be imputed by the mean values, as calculated from a regression model with pooled non-missing 
values for the Baseline variable from both ti·eatment groups as dependent variable adjusting for 
the randomization sti·atification factors. For binaiy variables, coded O or 1 for example, the 
imputed mean will be rounded up to I or down to 0, whichever is neai·est. 
5.8.1.2. 
Missing Post-baseline Efficacy Data 
Missing data will be handled using statistical methods based on National Research Council's The 
Prevention and Treatment of Missing Data in Clinical Trials. 
For an analysis with the MMRM model that uses resu-icted maximum likelihood for estimation, 
no imputation will be used, and the model will include all observed data to estimate the ti·eatment 
effect of change from Baseline to Week 65 in UHDRS-TFC, under the assumption of missing at 
random (MAR). 
To evaluate the possible impact of missing values on the prima1y and select secondaiy efficacy 
analyses, the method of multiple imputations (MI) will be used to evaluate the robustness of data 
assumptions, imputing data under MAR and missing not at random (MNAR), using different 
assumptions about the treatment effect for the unobserved data. Additional details are provided 
below. 
Missing data ai·e considered monotone if after a ce1iain time point the data are no longer 
available. This happens when a pa1iicipant discontinues from the study and there are no 
assessments after the last visit when the paiiicipant was assessed. It is expected that the great 
majority of missing data will have a monotone pattern. Different assumptions, such as MAR and 
MNAR, will be made on the monotone missing pattern to show the robustness of estimates. 
There is also some small amount of non-monotone missing data when there are inte1mediate time 
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points of missing data, such as due to missed visits, which will be assumed to follow MAR 
assumptions. Methods as described below will be adopted to estimate for both non-monotone 
and monotone missing data patterns. 
• Imputation for non-monotone missing data pattern will be based on the initial imputation 
using Markov Chain Monte Carlo (MCMC) by generating 100 datasets with only 
monotone missing data. For participants with intennittent missing values, a monotone 
missingness pattern will be generated in each of the 100 datasets. This imputation step is 
based on the MAR assumption. In both methods below (under MAR or MNAR) the MI 
step will generate 100 complete datasets with no missing values. 
MAR and MNAR imputation vaiy at the handling of monotone missing data pattern. 
• Under the assumptions of MAR that missingness depends on the observed values and can 
be predicted based on a paiticipant's observed data, the missing value will be imputed 
using monotone regression model. The imputation model will include Baseline and all 
post-baseline values for the efficacy endpoint to be imputed, treatment, randomization 
strata, and region. Multiple imputations will be perfo1med to assign the response vai·iable 
at consecutive study visits in a sequential manner for the monotone missing data pattern. 
• Under the assumptions of MNAR that missingness depends on unobserved values and 
cannot be predicted solely based on a paiticipant's obse1ved data, the missing value will 
be imputed using a pattern-mixture model (PMM). In the PMM, the distribution of a 
response is modeled as the mixture of a distribution of the obse1ved responses and a 
distribution of the missing responses. As the missing values for paiticipants in the 
pridopidine group may imply these pa1ticipants no longer receive the treatment, it is then 
reasonable to assume that the conditional distribution of the missing values, given 
obse1ved data, is similai· to that in the placebo group, and impute the missing values in 
pridopidine group based on the conditional distribution from the placebo group. 
This will be realized by PMM with control-based pattern imputation, a vai·iant of the 
copy reference method (Little and Wang, 1996; Ratitch and O'Kelly, 2013). In this 
imputation approach, the model for missing obse1vations is constrncted from the 
obse1ved data in the placebo group only, and then used as the imputation model for 
missing values in pridopidine and placebo groups. Following the chain-based 
imputations, multiply imputed datasets will be analyzed using the same MMRM as for 
primaiy analysis (Section 7.2). 
At the last step, the estimates from all imputed datasets will be combined using Rubin's rnle for 
an overall inference. SAS Procedures, MI, MIXED and MIANAL YZE will be used for above 
steps. 
5.8.1.3. 
Missing Item Scores in Derivation of Total Scale Score 
5.8.1.3.1. Missing items on Unified Huntington's Disease Rating Scale - Total Functional 
Capacity(UHDRS-TFC) 
A TFC is considered valid if all 5 domains are scored. If any item is left blank the TFC is 
considered missing. 
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5.8.1.3.2. Missing items on Unified Huntington's Disease Rating Scale - Total Motor Score 
(UHDRS-TMS) 
If at least 16 out of the 31 items on the TMS are scored, the total TMS score will be computed 
the following way. The observed sum of score from the available items is divided by the total 
number of the available items, and then multiplied by 31 to get the overall TMS score. For 
example, if 20 items were completed with a score of 60, then TMS Score will be (60/20) x 31, or 
93. 
If there are more than 5% of all TMS assessments which required imputation per the above rnle, 
then a sensitivity analysis will be perfo1med excluding those TMS scores that required 
imputation of paitial items. 
5.8.1.3.3. Missing items on HDQoL and Other Subscale Scores 
A similar approach as above will be used by which the score on missing items will be imputed 
using the average of the scores on items that were completed. 
5.8.2. 
Missing Start and Stop Dates for Prior I Concomitant Medication, Medical 
History for HD Diagnosis and Adverse Events 
Missing stait or stop dates for prior/concomitant medications 
The following rnles will be used in this study to define concomitant for medications with 
completely missing stait or stop dates: 
• If both sta1t and stop dates of a medication or therapy are completely missing, this 
medication or therapy will be considered both prior and concomitant. 
• If the stait date of a medication or therapy is completely missing and the stop date is on 
or after the date of the first dose date of study treatment, that medication or therapy will 
be considered both prior and concomitant. 
• If the stop date of a medication or therapy is completely missing and the stait date is after 
the first dose of study diug, that medication or therapy will be considered concomitant. 
For medications with pa1tial missing dates, following imputation rnles will be used: 
• For paitial stait dates, missing month will be imputed with Janua1y and missing day will 
be imputed with first day of the month. 
• For paitial stop dates, missing month will be imputed with December and missing day 
will be imputed with the last day of the month. 
If a medication has a missing or paitial missing stait/end date or time and cannot be dete1mined 
whether the medication is taken before first dose or concomitantly, it will be classified as both 
prior and concomitant. 
Missing dates for Medical Histoiy for HD Diagnosis 
fu order to dete1mine onset of symptoms data are collected for who first noticed symptoms 
(Paiticipant, Family, Rater) and what the symptoms were (Motor, Cognitive, Psychiatric or 
Other). Since dates are not always exactly known a mid-point of interval rnle will be used. If 
date is missing it will be assumed to be the 15th of the month, if month is missing it will assume 
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to be June (6th month). To compute the years since onset of HD symptoms the earliest of these 
dates will be used and subtracted from the screening date. 
Missing start date for AEs 
The treatment-emergent adverse events (TEAEs) are detennined by the sta1i date of the AEs. If 
the staii date of an AE is completely missing, then the AE is considered as treatment-emergent. 
If the staii date of an AE is paiiially missing, the AE sta1i date will be imputed as follows: 
• Missing day -Impute the 1st of the month. If the month and year of AE is same as month 
and year of the first dose of study dmg, then impute first dose date, ensuring the AE is a 
TEAE. 
• Missing day and month - Impute 1st Janua1y. If the year is the same as the year of the 
first dose date, then impute the first dose date, ensuring the AE is a TEAE. 
• If AE sta1i date is completely missing it will be set to the treatment staii date. 
5.8.3. 
Missing Demographics, Baseline Characteristics, Exposure or Safety Data 
Only observed demographics, baseline characteristics, exposure, and safety data will be 
presented. No imputations will be perf01med. For efficacy analysis if a baseline covariate is 
missing it will be imputed as described in Section 5.8.1. 
5.8.4. 
Unscheduled Visits 
Summaries of efficacy data will only use data collected at scheduled visits, unless data is not 
available at the required post-baseline visit and the only available data is from an unscheduled 
visit close to the scheduled visit within an acceptable time window. If the unscheduled visit 
efficacy assessment is not within the acceptable window it will be ignored from the efficacy 
analyses, but will be identified in listings. 
For descriptive statistics on continuous safety variables only data collected at scheduled visits 
will be used. For SllIIlillaIY of abno1malities or shift tables all available data from scheduled and 
unscheduled visits will be used. Abno1mality tables and shift tables will display the worst value 
across all visits, the last available non-missing value, and the values by scheduled visits. For shift 
tables, if there is more than one abno1mality in the time period specified, the worst value will be 
used. When summarizing "worst" values if the pa1iicipant had both a low and high value they 
will be included in both rows. 
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6. 
STUDY POPULATION 
6.1. 
Participant Disposition 
For Main Study analyses, all references to pa1ticipant disposition, etc., refer only to the Main 
Study and exclude the OLE. 
The number of paiticipants who signed info1med consent, or signed consent but were not 
randomized along with reason for screening failure will be summai·ized overall and by region 
and for select countries. 
The number of paiticipants included in each analysis population will be presented by treatment 
group. The paiticipants who ai·e excluded from each of the analysis population and the reason for 
exclusion (for example, exclusion from mITT population because they were not treated, or if 
they were treated but have no post-baseline in-clinic UHDRS-TFC assessment), will be 
summarized by treatment group. These paiticipants will be identified in the listing of paiticipants 
with populations in which they are included. 
The end of the Main Study is reached when all pa1ticipants who have signed inf01med consent, 
been randomized and treated have either completed through Week 65 or discontinued from the 
study (defined in Section 5.5.5). At the end of Main Study, the number of paiticipants who 
completed the Main Study po1tion as well as those that withdraw from the treatment or study will 
be summai·ized along with the reason for withdrawal. The denominator for calculating the 
percentages will be the number of paiticipants within the treatment group in the population being 
summarized. 
fu the OLE analyses, the numbers of pa1ticipants who have emolled in the OLE po1tion, who are 
included in each analysis population, who have completed the OLE, and who withdraw from the 
treatment or study along with the reasons will be summarized. 
6.2. 
Demographics and Baseline Characteristics 
Paiticipant demographics and baseline characteristics will be examined to assess the 
compai·ability of the treatment groups. The continuous variables of paiticipant age, weight, 
height, body mass index, efficacy and safety scales scores at Baseline will be summai·ized using 
descriptive statistics. 
The categorical variables of pa1ticipant sex, race, ethnicity, HD stage (HDI or HD2) and use of 
neuroleptics will be summai·ized using count and percentages for each catego1y. 
Other baseline and disease chai·acteristics may also be summarized. 
A catego1y will indicate paiticipants with missing data. 
Cytosine-adenosine-guanine (CAG) repeat length was repoited by pa1ticipants at Screening and 
recorded in the EDC. For paiticipants who did not repo1t CAG repeats, a plasma sample was 
taken and sent to a laborato1y to dete1mine the CAG repeat length. For paiticipants whose CAG 
repeats were repo1ted by both paiticipant and laborato1y, the value of CAG repeats as dete1mined 
by the laborato1y test will be used. 
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6.3. 
Participant Inclusion and Exclusion Criteria 
Reasons for screen failure including inclusion and exclusion criteria not met prior to 
randomization will be listed for each pa1ticipant. 
6.4. 
Medical History 
All medical histo1y will be coded as per Section 5.3. Pa1ticipants with a medical histo1y 
assessment, by system organ class (SOC) and PT will be Sllilllllarized. Pa1ticipants are counted 
only once in each SOC and only once in each PT catego1y. SOC and PT within SOC will be 
ordered by descending incidence of all paiticipants. 
6.5. 
Prior and Concomitant Medications / Therapies 
All medications (both prior and concomitant) will be coded as per Section 5.3. 
Prior medications will include all medications which had a stait date prior to the first day of 
study diug treatment regardless of when it ended. This includes medications taken and stopped 
prior to V2 Baseline Visit (day of first study dmg treatment) or sta1ted prior to V2 and continued 
to be taken on or after V2. Any medication given at least once after V2 will be defined as a 
concomitant medication. 
Concomitant medications are defined as medications continued or newly received by the 
paiticipants during Main Study Treatment Period or OLE Treatment Period (see definition in 
Section 5.5.7). If a paiticipant took a medication during a specific Treatment Period, this 
medication will be attributed to the treatment the subject received during this Treatment Period. 
As a result, one medication could be attributed to both Main Study and OLE Treatment Periods 
for a pa1ticipant. If missing or paitial dates indicate a medication may have been taken after first 
day of study dmg treatment, it will be considered a concomitant medication. 
The incidence of prior and concomitant medication use will be separately sUilllllai·ized using 
descriptive statistics by WHO (ATC) anatomical therapeutic class and PT (Standai·dized Name) 
for each treatment group and overall in the safety population. Pa1ticipants ai·e counted only once 
in each therapeutic class catego1y, and only once in each PT catego1y. 
Non-phaimacological therapies and procedures will be classified by Med.ORA SOC and PT, and 
will be repo1ted by treatment group and overall for the safety population. 
A sepai·ate sllilllllaiy of prior and concomitant medications taken for COVID-19 symptoms, use 
of tetrabenazine and deutetrabenazine or antidepressants, may be presented sepai·ately by 
treatment groups. 
6.6. 
Protocol Deviations 
All-impo1tant deviations related to study inclusion or exclusion criteria, conduct of the trial, 
paiticipant management or paiticipant assessment will be Sllilllllarized by site and grouped into 
different categories, such as: 
• those who entered the study even though they did not satisfy the entiy criteria 
• those who developed withdi·awal criteria during the study but were not withdi·awn 
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• those who received the wrong treatment or inco1Tect dose 
• those who received an excluded concomitant treatment 
Additional details of reviewing and classifying PDs as impo1tant are detailed in the Protocol 
Deviation Management Plan. 
fu the CSR Appendix 16.2.2, individual paiticipants with impo1tant PDs will be listed. 
Final categorization of PDs will be done prior to database lock and unblinding. 
Since this trial is being conducted during the COVID-19 pandemic, separate summaries of PDs 
related to COVID-19 were planned to be tabulated by treatment groups. However since there 
were no impo1tant PDs due to COVID-19 no sepai·ate Table was created. Additional analyses 
may also be conducted to see the impact of these deviations on inte1pretation of key safety or 
efficacy analyses. Since the impact of COVID-19 related events such as AEs, medications taken, 
etc., will not be fully known until the trial has progressed sufficiently, these will be finalized 
prior to locking the database and unblinding the study. 
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7. 
EFFICACY ANALYSIS 
7 .1. 
General 
Study procedures and timing are summarized in the SoA (Table 1 - Main Study and Table 2 -
OLE). 
Efficacy analyses will be conducted using the estimand framework described in the ICH E9 R(l) 
Guidance and related publications2,. The estimands will be described in detail in the endpoint 
analysis sections hereafter. 
7.1.1. 
Intercurrent Events (ICEs) and Estimand Strategy 
The ICEs considered for the PROOF-HD trial include treatment discontinuation due to, for 
example, death, AEs, progressive disease, or meeting Stopping Rules for QT/CrCl/psychiatric 
reasons. 
If a pa1ticipant has COVID-19 symptoms, their visit can be delayed within a reasonable period 
(up to 4 weeks) to perfo1m UHDRS-TFC and other efficacy and safety assessments until after 
their COVID-19 symptoms have resolved. There is also a low likelihood of pa1ticipants stopping 
study diug or discontinuing from study due to COVID-19. If inte1mittent efficacy assessments 
are missing due to COVID-19 impact, it will be handled by analysis, such as MMRM, under 
MAR assumptions3. 
Also, since pridopidine is taken over a long te1m (65 to 78 weeks) in the Main Study, temporaiy 
treatment intenuptions are expected to have minimal impact on key efficacy endpoints. 
ICH E9 R(l )  describes five strategies to addi·ess ICEs (Mallinckrodt et. al., 2020; Ratitch et. al., 
2020a and 2020b) which include: 
(1) Treatment Policy (similar to ITT principle) where the ICE is ignored; 
(2) Composite where the ICE is taken to be a component of the endpoint as in a responder 
analysis where pa1ticipants who die due to disease progression are considered non­
responders; 
(3) Hypothetical where hypothetical scenai·ios are considered in which the ICE did not occur 
such as excluding observations where the UHDRS was measured while the paiticipant 
was exhibiting COVID-19 symptoms; 
(4) Principal Stratum, where the effect of the treatment is considered only in the stratum of 
interest such as excluding pa1ticipants infected by COVID-19 anytime during the trial, 
and excluding pa1ticipants on antipsychotics; 
(5) While on Treatment, where the response to the treatment prior to discontinuing 
treatment is of interest. 
For the PROOF-HD trial we will use the treatment policy, composite, hypothetical strategies, 
and/or a combination of strategies to address the specific impact of ICEs on efficacy. 
Based on the regulato1y feedback, the main estimand for the primaiy endpoint, change from 
Baseline in UHDRS-TFC at Week 65, will be defined separately for the EMA and non-EMA 
reg10ns. 
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• For the EMA region, an estimand using a composite of treatment policy and hypothetical 
strategies is defined for the prima1y analysis. The treatment policy strategy will apply to 
all observed values including those collected after treatment discontinuation, and the 
hypothetical strategy will apply to missing values using PMM with control-based pattern 
imputation under MNAR assumptions (as described in Section 5.8.1.2). 
• For the non-EMA regions, the prima1y analysis will be based on an estimand using 
treatment policy strategy, under which all observed data will be used regardless of 
occmTence of ICEs. 
For the EMA region, the estimand applying treatment policy strategy (i.e., the primaiy estimand 
for the non-EMA regions) will be used as a supportive estimand, while for the non-EMA 
regions, the estimand applying a composite of treatment policy and hypothetical strategies (i.e., 
the prima1y estimand for EMA region) will be used as a supp01tive estimand. 
The main estimands for secondaiy and explorato1y endpoints will be the same for both EMA and 
non-EMA regions. The main estimand for key secondaiy endpoint, change from Baseline in 
cUHDRS at Week 65, will be based on treatment policy strategy and mITT population. The 
bina1y seconda1y endpoints, for example, the propo1tion of paiticipants with improvement or no 
worsening in UHDRS-TFC, will use combined composite and hypothetical strategies for the 
main estimand. In this estimand, pa1ticipants who discontinue the treatment due to disease 
progression-related death, or meet the Stopping Rules will be considered non-responders, while 
the paiticipants who discontinue the treatment for other reasons will be imputed by hypothetical 
values from treatment discontinuation onwai·d as if the paiticipants had continued receiving the 
study treatment (MAR assumptions). A similai· combined composite and hypothetical strategy 
estimand may be used for sensitivity analyses with MNAR MI under hypothetical strategy. 
Other secondaiy and explorato1y efficacy endpoints for both EMA and non-EMA regions, 
evaluated as changes from Baseline, will follow treatment policy strategy based estimand. Binaiy 
endpoints indicated for responder analyses will follow a similai· estimand strategy as described 
above, where appropriate. 
7.1.2. 
Analysis Populations 
The ITT population is the main analysis population of prima1y endpoint for EMA region. The 
mITT population is the main analysis population for primaiy endpoint in non-EMA regions. 
For all other efficacy analyses, the mITT population is the main analysis population in both 
EMA and non-EMA regions. The ITT and PP populations will also be used as sensitivity 
analyses to show robustness of results for select secondaiy endpoints. 
7 .2. 
Primary Efficacy Variable and Analysis 
The primaiy efficacy variable for this study is the change from Baseline to Week 65 in the 
UHDRS-TFC. The calculation of the UHDRS-TFC is detailed in Appendix 12.1.1. 
The null hypothesis represents no difference between the therapeutic efficacy response in the 
active treatment group compared to the placebo group: 
Ho: µA= µp 
HA: ãLA;t µp 
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Where LA is the mean change from Baseline to Week 65 in UHDRS-TFC for pa1ticipants 
randomized to pridopidine (Active) and µp is the mean change from Baseline to Week 65 in 
UHDRS-TFC for paiticipants randomized to the placebo group. Under the alternative 
hypothesis, there exists a difference between the therapeutic efficacy response in the pridopidine 
(active) group compai·ed to the placebo group. 
Based on regulato1y feedback, the hypothesis testing will be based on the main estimand 
separately defined for EMA and non-EMA regions. 
For non-EMA regions, the main estimand is defined as non-EMA-Estimand: 
• Treatment: Pridopidine 45 mg bid or placebo ( on background of standard of care) that 
paiticipants are randomized to 
• Population: Eai·ly HD Paiticipants (HDl & HD2) defined through the study 
inclusion/exclusion criteria. The mITT population will be used in analyzing this estimand 
• Vai·iable: Change from Baseline to Week 65 in UHDRS-TFC 
• 
Population Level Summaiy: LS-Mean difference between pridopidine and placebo from 
MMRM model in change of UHDRS-TFC from Baseline to Week 65 
• ICEs and Strategies for Addressing ICEs: 
Treatment policy strategy will be used to handle the ICEs, where occunence of an ICE is 
inelevant. All observed values will be used regardless of occunence of an ICE. No 
imputation is perfo1med. 
Analysis will be perfo1med on in-clinic obse1ved data using MMRM. The model will include the 
following effects:-treatment, Baseline UHDRS-TFC, region (Europe, No1th America), 
neuroleptic use (yes, no), Baseline HD stage (HDl and HD2), categorical week, and treatment by 
categorical week interaction. 
The unstmctured covai·iance matrix for repeated obse1vations within paiticipants will be use. If 
the model does not converge, then a simpler covariance stmcture with fewer parameters will be 
used, and we will examine these structures in the following order based on the first structure 
below that converges: 
1. T oeplitz with heterogeneity (TOEPH), 
2. Autoregressive with heterogeneous (1) [ARH(l)], 
3. Compound symmetry with heterogeneous variances (CSH), 
4. Toeplitz (TOEP), 
5. Autoregressive (1) [AR(l)], and 
6. Compound Symmetry (CS). 
Denominator degrees of freedom for the F-test for fixed effects will be estimated using the 
Kenward-Roger approximation. The least square mean (LSM) and standai·d enor (SE) of the 
LSM for each treatment group, the 95% CI and p-value for the compai·isons (change from 
Baseline in pridopidine 45 mg bid vs. placebo) will be presented at Week 65. 
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For EMA regions, the main estimand is defined as EMA-Estimand: 
• 
Treatment: Pridopidine 45 mg bid or placebo ( on background of standard of care) that 
paiiicipants are randomized to 
• Population: Eai·ly HD Paiiicipants (HDl & HD2) defined through the study 
inclusion/exclusion criteria. The ITT population will be used in analyzing this estimand 
• Vai·iable: Change from Baseline to Week 65 in UHDRS-TFC 
• 
Population Level Summaiy: LS-Mean difference between pridopidine 45 mg bid and 
placebo from MMRM model in change of UHDRS-TFC from Baseline to Week 65 
• ICEs and Strategies for Addressing ICEs: 
ICEs include treatment discontinuation or death and will be handled by a composite of 
treatment policy and hypothetical strategies. 
o Treatment policy strategy will apply to all obse1ved values including those 
collected after treatment discontinuation as these values reflect the remaining off­
diug treatment effect in reality. 
o Hypothetical strategy will apply to missing values after the last obse1ved values. 
The method of MI will be applied to impute the missing data using PMM with 
control-based pattern imputation under MNAR assumptions ( details in Section 
5.8.1). 
Since UHDRS-TFC is used as a continuous variable in the MI procedure, the imputed values will 
take continuous values instead of the discrete values ranging from O to 13. To avoid the influence 
of extreme values outside the range, the continuous values will be categorized to 0 if the imputed 
values <0.5, and to 13 if the imputed values ï12.5. All the other values in [0.5, 12.5) will be 
rounded to the nearest integer between 1 and 12. 
The MI method uses SAS PROC MI and MIANAL YZE to generate multiple complete datasets 
and combine the model results from them as described in Section 5.8.1. The LSM and associated 
SE for each treatment group, the 95% CI and p-value for the comparisons (pridopidine 45 mg bid 
vs. placebo) will be presented at Week 65. 
In addition, actual obse1ved values and changes from Baseline to each visit in the UHDRS-TFC 
will be summarized using descriptive statistics. 
For all analysis at Week 65 only data through the Week 65 visit will be included. 
7.3. 
Sensitivity Analyses for Primary Variable 
7.3.1. 
Sensitivity Analyses Under Various Assumptions for Missing Values 
The sensitivity analyses specific for non-EMA regions include the following suppo1iive 
estimand: 
• EMA-Estimand using MAR and MNAR MI methods using ITT population to impute the 
missing values 
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The sensitivity analyses specific for EMA region include the following suppo1tive estimands: 
• Non-EMA-Estimand using MMRM with mITT population 
• EMA-Estimand using MAR MI methods to impute the missing values using ITT 
population 
For both non-EMA and EMA regions, an estimand similar to EMA-Estimand with population 
changed to mITT population will be used for sensitivity analyses, and missing values imputed by 
MAR and MNAR MI methods separately. 
7.3.2. 
Subgroup Analysis 
The treatment effect of the pridopidine active group vs. placebo will be evaluated for the primaiy 
endpoint in paiticipant subgroups according to the following variables at Baseline: 
• Age categorized into three groups (<55, 55 to <65, and ï65 years) 
• 
Sex (Male vs Female) 
• Randomization strata: HD stage (HDl vs HD2) 
• Randomization strata: Baseline neuroleptic use (YIN) 
• Region (No1th America, Europe) 
• 
CAG repeats categorized into 2 groups by median Baseline CAG 
• The CAG-Age-Product (CAP) score calculated as: age *(CAG - 33.66), and categorized 
into two groups by median Baseline CAP 
• Four groups based on crossing median Baseline CAP and median Baseline age 
• Baseline NfL categorized into 2 groups by median Baseline NfL 
• Concomitant use of medication for Chorea management 
Subgroup analyses by median will use the median in the ITT population inespective of the 
population analyzed. 
The primaiy model for subgroup analyses will contain main effects and 2-factor interactions 
Treatment x Week and Treatment x Subgroup to dete1mine the p-value. The structure of the 
covariance matrix will follow the same approach as indicated for the primary endpoint. 
Assessment of impact of subgroups on efficacy will be evaluated by the interaction between 
Treatment x Subgroup. 
For each subgroup (assuming not ah-eady in the prima1y model), the MMRM model under MAR 
will be estimated for each subgroup level to dete1mine the tr·eatment effect and CI. When 
analyzing HD I vs HD2, the randomization str·atification factor of HD stage will not be included 
in the MMRM model. The same applies to subgroups of neuroleptic use. 
The LSM and SE of the LSM change from Baseline for each tr·eatment group, and the 95% CI 
for the compai·isons (pridopidine 45 mg bid vs. placebo) will be presented for each subgroup 
along with the p-value for the interaction te1m. 
If a subgroup has <50 paiticipants in any Treatment a subgroup analysis may not be perfo1med 
since there would be less reliable comparison between the tr·eatment groups. 
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7.3.3. 
Other Efficacy Analysis 
To explore potential impact of other confounding factors on efficacy, the prima1y efficacy 
endpoint, select secondaiy and explorato1y endpoints analyses may be conducted if there are 
enough paiiicipants in these coho1is. 
Following sensitivity analyses may be perfo1med, where applicable: 
• Similai· to non-EMA-Estimand with population changed to Week 65 PP Population 
• 
Non-EMA Estimand with an additional covai·iate, CAP score, included in the analysis 
model 
• EMA-Estimand with an additional covai·iate, CAP score, included in the analysis 
model 
• 
A sensitivity analysis excluding those who had received any neuroleptics during the 
study that could impact efficacy may be perfo1med. 
• fu addition, fmiher sensitivity analysis may be conducted excluding those who had 
changes in neuroleptic use after randomization. 
7.4. 
Multiplicity-Adjusted Secondary Efficacy Variable and Analysis 
7.4.1. 
Key Secondary Efficacy Variable and Analysis 
The key secondaiy efficacy vai·iable is change from Baseline to Week 65 in cUHDRS. The null 
hypothesis is that pridopidine is no different than placebo in improvement of cUHDRS score at 
Week 65. The hypothesis testing will be based on the main cUHDRS estimand similarly defined 
as non-EMA-Estimand for prima1y endpoint (Section 7.2). Change from Baseline to Week 65 in 
cUHDRS will be analyzed using MMRM in the mITT population, under treatment policy 
strategy for handling missing data. The LSM and associated SE for change from Baseline in each 
treatment group, the 95% CI and p-value for the pridopidine treatment effect will be presented at 
Week 65. 
The following sensitivity analyses will be perfo1med for change from Baseline to Week 65 in 
cUHDRS: 
• Analysis based on suppo1iive estimand similai· to EMA-Estimand for primaiy endpoint 
(Section 7.2) using MNAR imputation for missing values in the ITT population 
• Analysis based on suppo1iive estimand similai· to EMA-Estimand for primaiy endpoint 
(Section 7.2) using MAR imputation for missing values in the ITT population 
• Analysis based on suppo1iive estimand similai· to non-EMA-Estimand with population 
changed to W65PP population 
7.4.2. 
UHDRS-TFC Response as a Binary Endpoint 
The binaiy UHDRS-TFC response (yes or no) is defined as achieving improvement or no 
worsening in UHDRS-TFC score, i.e., change from Baseline to Week 65 in UHDRS-TFC ΁ 
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points. The responder analysis will be perfonned for the propo1tion of pa1ticipants with change 
from baseline to Week 65 in UHDRS-TFC ÑO. 
The hypothesis testing to compare the percentage of responders between the two treatment 
groups will be based upon the mITT population. Logistic regression will be used to analyze and 
compare the probability of whether a paiticipant is a UHDRS-TFC responder or not. The model 
will adjust for Baseline UHDRS-TFC, region, Baseline randomization stratification factors of 
nemoleptic use (Yes/No) and HD stage (HDI and HD2). 
The hypothesis testing of the UHDRS-TFC responder analysis is based on the main estimand as 
follows: 
• 
Treatment: Pridopidine 45 mg bid or placebo ( on background of standard of care) that 
paiticipants are randomized to 
• Population: Eai·ly HD Paiticipants (HDI & HD2) defined through the study 
inclusion/exclusion criteria. The mITT population will be used in analyzing this estimand 
• Vai·iable: hnprovement or no worsening (change from Baseline ÑO points) at Week 65 in 
UHDRS-TFC (Defined as responders to treatment) 
• 
Population Level Summaiy: Propo1tion of responders, defined as the propo1tion of 
paiticipants achieving improvement or no worsening in UHDRS-TFC ( change from 
Baseline ïO points) at Week 65 
• ICEs and Strategies for Addressing ICEs: 
ICEs include treatment discontinuation and will be handled by combining composite 
strategy and hypothetical strategy as follows: 
o Composite strategy: Observed UHDRS-TFC values will be used to detennine if a 
paiticipant is a responder or not. For treatment discontinuation due to disease­
progression-related death, or meeting Stopping Rules, the pa1ticipant will be 
considered a non-responder. 
o Hypothetical strategy: For treatment discontinuation due to other reasons not 
included in composite strategy and no TFC data collected afte1wai·d, all values 
after ICEs will be imputed under MAR as if the paiticipants had continued 
receiving the study treatment. The MAR imputation model will include UHDRS­
TFC as a continuous response variable as described in Section 7.2. The UHDRS­
TFC response at Week 65 ( change from Baseline in UHDRS-TFC Ñ0) will then 
be derived using the imputed UHDRS-TFC score as well as the non-missing 
UHDRS-TFC scores. 
The odds ratio (OR) of treatment effect (pridopidine 45 mg bid vs placebo) along with a 2-sided 
95% CI and p-value will be presented. An estimate of OR > I will indicate a beneficial treatment 
effect. Descriptive statistics and 95% CI using Clopper-Pearson will be provided for the 
observed propo1tions at each visit, along with the difference between treatment groups in the 
propo1tions and 95% nonnally approximated CI for the difference. 
Following suppo1tive estimands will be used to support the analysis of this seconda1y endpoint: 
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Suppo1tive Estimand 1: similarly defined as the main estimand for UHDRS-TFC responder 
analysis, but with population changed to ITT population, and :MNAR instead of MAR MI will be 
used under the hypothetical strategy. 
Suppo1tive Estimand 2: similarly defined as the main estimand for UHDRS-TFC responder 
analysis, but with population changed to ITT population. 
Suppo1tive Estimand 3: similarly defined as the main estimand for UHDRS-TFC responder 
analysis, but with ICE handling strategy changed to treatment policy strategy (using observed 
data without imputation). 
Suppo1tive Estimand 4: similarly defined as Suppo1tive Estimand 3 for UHDRS-TFC responder 
analysis, but with population changed to W65PP population. 
7.4.3. 
Other Multiplicity Adjusted Secondary Efficacy Variable and Analysis 
For continuous endpoints such as change from Baseline using observed data only, the main 
estimand will be similar to the non-EMA-Estimand for the primaiy endpoint, analyzed using the 
mITT population with treatment policy strategy to handle ICEs. An MMRM model as described 
in Section 7 .2 for the primaiy endpoint will be used with Baseline value of the analyzed variable 
replacing Baseline UHDRS-TFC as a covariate. For the specified visits, the LSMs, SE of the 
estimates, p-values, and 2-sided 95% Cis will be provided for the within treatment group 
changes from Baseline and for the comparison of change from Baseline between pridopidine and 
placebo. 
Supportive estimands for continuous endpoints will be similai· to the EMA-Estimand for the 
primaiy endpoint, with population as the ITT population and missing values imputed using copy 
reference method under :MNAR assumption. Additional missing value imputation approach 
under MAR assumption may be used as a sensitivity analysis. 
For analysis of change from Baseline in UHDRS-TFC at Week 78, main analysis will include 
observed values at scheduled visits up to 78 weeks. A sensitivity analysis for Week 78 endpoints 
will be perfo1med with assessments between Week 65 and 78 mapped to Week 78. 
For positive response defined using values of continuous variables: 
• Unless othe1wise specified, where a decrease reflects disease progression, a responder 
will be defined as those with no change or improvement ( change from Baseline ÑO) 
• Unless othe1wise specified, where an increase in score reflects disease progression, a 
responder will be defined as those with change from Baseline :SO 
Main estimands for binaiy endpoints will be similar to the main estimand for the bina1y 
UHDRS-TFC response, analyzed in the mITT population and with ICEs handled by a combined 
composite and hypothetical strategy. Suppo1tive estimand for the bina1y endpoints will be 
similai· to Suppo1tive Estimand 1 for the bina1y UHDRS-TFC response. All responder analyses 
or analyses of bina1y vai·iables will be perfo1med using logistic regression as indicated for the 
bina1y seconda1y vai·iable above in Section 7.4.1. 
The p-values from the main estimand will be used in the hierarchical testing for multiplicity 
adjusted secondaiy endpoints following the order described in Section 3.2.2. 
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Subgroup analyses as described in Section 7 .3 .2 for the prima1y efficacy endpoint will also be 
perfonned for the multiplicity adjusted second afy endpoints and log2-transfonned NfL. 
7.5. 
Non-Multiplicity Adjusted Secondary Efficacy Variable and Analysis 
Other non-multiplicity adjusted secondary efficacy variables are listed and defined in Sections 2 
and 3.2.3. 
For continuous variables, an MMRM model as described in Section 7.2 for the primat-y endpoint 
in mITI population will be used, with Baseline value of the analyzed variable replacing Baseline 
UHDRS-1FC as a covariate. For the specified visits, the LSMs, SE of the estimates, p-values, 
and 2-sided 95% Cls will be provided for the within treatment group changes from Baseline and 
for the comparison of change from Baseline between pridopidine and placebo. This will be 
repeated in W65PP or W78PP population depending on whether change to Week 65 or 78 is 
analyzed. 
In addition, actual values and changes from Baseline to each visit will be summarized using 
descriptive statistics for each endpoint. The sub-scale scores of each endpoint will also be 
summarized where applicable. 
The proportion of responders will be analyzed in a similar way to how the binary UHDRS-1FC 
response is analyzed for the main estimand and Suppo11ive Estimand 1. Di
ff.erent thresholds than 
specified above may be explored. Descriptive statistics and 95% CI using normal approximation 
will be provided for the proportions at each visit. hi order to minimize impact of outliers that 
may represent unrealistic changes in key endpoints, analyses using robust regression or other 
methods may be perfonned. 
7.6. 
Other Exploratory Efficacy Variable and Analyses 
Other explorato1y efficacy variables include: 
• Change from Baseline to Weeks 26, 52, 65 and 78 in PBA-s domains subscale scores 
and total scores 
• Change from Baseline to Weeks 26, 52, 65 and 78 in HDQoL 
These will be analyzed similar as described in Section 7 .5 for non-multiplicity adjusted 
seconda1y efficacy variables in their main estimand. 
Responder analyses for select efficacy endpoints, such as UHDRS-TFC and cUHDRS, using 
clinically meaningful thresholds may be perfonned. 
In addition, the obse1ved virtual UHDRS-1FC assessments at vutual Baseline, Weeks 13, 32, 
and 58 and change from virtual Baseline (Day -7 Visit) at each post-baseline vi11ual visit will be 
summarized. 
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The impact of PIN1m, defined as prognostic index normed for HD, on treatment effects for select 
efficacy variables may be explored using categorized PIN1rn score, where PIN1rn = (Plirn - 883) / 
1044, and PIHD= 51 x TMS + ( -34) x SDMT + 7 x Age x (CAG - 34), defined as prognostic 
index for HD (10). 
Treatment effect on change from Baseline in weight over visits may also be explored adjusting 
for sex and age. 
7.7. 
OLE Efficacy Analyses 
The final analyses of OLE data will be performed at the End of OLE when all participants 
complete the OLE EoS visit. Interim analyses may be performed as needed. 
The OLE analysis will be presented using the following labels for treatment group, in the order 
displayed: 
• Placebo bid (Main Study) to Pridopidine 45 mg bid (OLE) 
• Pridopicline 45 mg bid (Main Study) to Pridopidine 45 mg bid (OLE) 
• Total of above two groups (where applicable) 
Proportion of participants with change ofUHDRS-1FC from Main Study Baseline ú-1 by 
treatment group and the difference between treatment groups at each OLE visit will be provided 
along with a 2-sided 95% Cls using normal approx imation and p-values from a logistic 
regression similar to that described in Section 7.4.1. This analysis will be repeated using a 
threshold of0 for proportion of participants with change ofUHDRS-TFC from Main Study 
Baseline úO. 
Summary statistics will be presented for UHDRS-TFC, cUHDRS, UHDRS-TMS, Q-Motor 
and Q-Motor 
-by treatment group and visit during the OLE period as described below: 
• Change from Main Study Baseline and the obse1ved values of UHDRS-TFC, cUHDRS, 
UHD RS-TMS, and Q-Motor measurements at each OLE visit 
• Change from OLE Baseline and the obse1ved values of UHDRS-TFC, cUHDRS, 
UIID RS-TMS, and Q-Motor measurements at each OLE visit 
In addition, the dmability of treatment response to pridopidine in the OLE period will be 
assessed by the prop011ion of participants who continue to respond to pridopicline in OLE among 
the responders in double-blind treatment period. Responders defined using following endpoints 
will be assessed for the durability: 
• Change from Main Study Baseline to Week 65 in UIIDRS-TFC 0, and change from 
Main Study Baseline to each OIE visit in UIIDRS-TFC -1 
• Change from Main Study Baseline to Week 65 in UIIDRS-TFC 0, and change from 
Main Study Baseline to each OIE visit in UIIDRS-TFC or 0 
• Change from Main Study Baseline to Week 65 in cUIIDRS -1, and change from Main 
Study Baseline to each OLE visit in cUIIDRS ú-1.5 
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• Change from Main Study Baseline .:so in UHDRS-TMS at Week 65, and change from 
Main Study Baseline ůO in UHDRS-TMS at each OLE visit 
• Change from Main Study Baseline .:=:;O in Q-Motor 
and change from 
Main Study Baseline ůO msec in Q-Motor 
at each OLE visit 
The Kaplan-Meier curve will be used to display by treatment group the distribution of time to 
first UHDRS-TFC worsening, defined as change from Main Study Baseline <-1, and no further 
UHDRS-TFC response (i.e. change from Main Study Baseline -1) at subsequent visits after fiist 
UHDRS-TFC worsening. Time to first UHDRS-TFC worsening will be censored at the last 
available assessment in the OLE period if UHDRS-TFC worsening is not observed. Cox 
prop01tional hazards model will also be used to quantify the treatment difference in time to first 
UHDRS-TFC worsening with treatment group, region, and randomization stratification factors 
(HD stage and neuroleptic drug use) as the fixed effects. Hazard ratio of pridopidine vs placebo 
group will be displayed with 95% CI and p-value. 
Other responder analyses for select efficacy endpoints in OLE period using clinically meaningful 
thresholds may be perfonned 
For pridopidine-to-pridopidine group in OLE mITT population, summary statistics will be 
presented for the observed values and change from Main Study Baseline in UHDRS-TFC, 
UHDRS-TMS, Q-Motor 
, and Q-Motor 
in both double-blind and OLE periods. An MMRM model as 
described in Section 7.2 excluding treatment and treatment-by-visit effects will be used to fit the 
change from Main Study Baseline in these efficacy endpoints throughout Main Study and OLE 
Treatment Period. The LSM and 95% CI at each visit will be presented. 
For placebo-to-pridopidine group in OLE mITT population, an MMRM model for Change from 
Main Study Baseline in UHDRS-TFC at each visit post Main Study Day 1 through Main Study 
and OLE periods will be used to estimate the gained treatment effect after switching to 
pridopidine treatment. The model will include fu{ed eff.ects of treatment at each period (Main 
Study and OLE Treatment Period), randomization stratification factors (HD stage and 
neluoleptic crug use), categorical effects of study visit within each period ( e.g., 26 weeks and 52 
weeks within each period), interaction of treatment and visit within the period, and Main Study 
Baseline of UHDRS-TFC. The covariance stn1cture fct· the MMRM model will be used similarly 
as described in Section 7.2. Mean difference in treatment effect at eve1y 26 weeks receiving 
pridopidine 45 mg bid vs placebo will be presented along with 95% Cls and p-values. 
For the explorato1y endpoints in OLE, including CGI-C, PBA-s, HDQoL, SDMT, and SWR, the 
summa1y tables of observed values and change from Baseline over time will be provided by 
treatment group and OLE visit. 
No imputation will be perfonned for the OLE analyses. Analyses using external controls may be 
perfonned to contextualize the long-tem1 effect of pridopidine on treating HD in OLE period. 
These analyses, if required, will be detailed in a separate SAP. 
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8. 
SAFETY ANALYSIS 
8.1. 
General 
The SP will be used for all safety analyses based on the actual treatment received. AEs and SAEs 
will be collected from the Screening visit through end of the study period. Safety analyses will 
be presented separately for the Main Study and OLE according to the set of data associated with 
the two po1iions of the study. 
Safety assessments will be summarized and listed for all data collected at in-clinic or VV 
(planned or conve1ied). 
8.2. 
Duration of Exposure 
Duration of exposure to study dmg ( days treated) is the number of days on treatment based on 
the first and last days of treatment with the study diug (last day of study di11g - first day of study 
diug + 1). In addition to summarizing overall treatment exposure in weeks, the weeks of 
exposure using the categories <13 weeks, ï13 to <26 weeks, Ñ26 to <39 weeks, ï39 to <52 
weeks, ï52 to <65 weeks, ï65 to <78 weeks and ï78 weeks will be summarized using the 
number and percentage of pa1iicipants exposed to study di11g by treatment groups. In addition to 
the above intervals the number and percentage of paiiicipants exposed for ï 13 weeks, Ñ26 
weeks, ï52 weeks, Ñ65 weeks, ï78 weeks will also be summai·ized. 
Duration of treatment (days) will also be summarized by treatment group using descriptive 
statistics for continuous parameters as described in Section 5.4. 
8.3. 
Study Treatment Compliance 
Treatment compliance will be calculated using the following fo1mula: 
Compliance(%) = [Total number of doses taken/Total number of scheduled doses] x 100 
The total number of scheduled doses will be calculated based on the number of capsules planned 
for the days of exposure of each paiiicipant. The total number of doses taken will be calculated 
as the difference between capsules dispensed and capsules returned recorded for all bottles 
dispensed. For bottles that are lost and missing the counts of capsules returned, 50% compliance 
is assumed for each lost bottle (i.e., 30 capsules are taken). If a patient has completed or 
withdi·awn from the study without returning any bottles at last visit in Main Study, 50% 
compliance is assumed during the period the capsules in these bottles ai·e expected to be taken, 
i.e., from the bottle dispense date until the earliest of the day prior to next bottle dispensing visit, 
treatment completion date, or early withdi·awal date. The compliance (expressed as %) will be 
summarized with descriptive statistics for continuous parameters by treatment group and overall. 
The initial dose, titrations and Investigator-initiated dose changes that occur throughout the study 
as captured on the Dose Management Log and Missed Dose / Inco1Tect Dosing eCRF pages will 
be displayed in Listings. 
The number and percentage of pa1iicipants with compliance <80%, 80 to 100%, > 100% will also 
be summarized by treatment group and overall. 
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8.4. 
Adverse Events 
All AEs will be coded using Med.DRA Version 23.0 (or a later version if updated during the 
study). 
For statistical analysis, a TEAE is defined as an AE that occurs for the first time or worsens ( as 
captured on the eCRF) on or after initiation of treatment in the conesponding analysis period 
(Main Study or OLE Treatment Period) EoS. Due to the short half-life of Pridopidine (10-12 hrs) 
AEs that staiied more than 14 days after end of treatment ai·e not considered TEAEs. 
The te1ms AEs and TEAEs are used interchangeably in this SAP and unless othe1wise specified 
refer to TEAEs. 
An overall summaiy will be presented by treatment groups that includes the number and 
percentage of pa1iicipants who experienced at least one TEAE for the following categories: All 
TEAEs, serious TEAEs, TEAEs leading to study discontinuation, TEAEs leading to death, 
TEAEs based on maximal Severity, TEAEs leading to study dmg withdrawal anytime during the 
study, TEAEs leading to study dmg withdrawal during titration. When appropriate, a total 
column may appeai· as the last column. 
Summai·ies will be presented for all TEAEs by SOC and PT for the following categories of 
TEAEs: 
• TEAEs, severe TEAEs, Treatment-related TEAEs, Serious TEAEs (see below for more 
details), TEAEs potentially related to QT prolongation, (e.g., palpitations, dizziness, 
syncope, cardiac anhythmias, and sudden death), TEAEs related to abuse potential (See 
Appendix 12.2 for the AE te1ms), TEAEs causing discontinuation from the study. 
The above summaries will include the number of events as well as number and percentage of 
paiiicipants experiencing at least one TEAE in each SOC and PT. To count the number of 
paiiicipants with any TEAEs, a paiiicipant who experiences multiple TEAEs within the same 
SOC will be counted only once for that SOC (if the TEAEs are coded to the same PT). A 
paiiicipant who experiences multiple TEAEs coded to the same PT within the same SOC will be 
counted only once for that PT. The number and percentage of paiiicipants experiencing any 
TEAE will also be provided. All percentages will use the number of paiiicipants in the SP within 
that treatment group as the denominator. In the summaries SOCs will be so1ied in descending 
order based on number of paiiicipants in Total column; PT within SOC will be so1ied by 
descending number of pa1iicipants in Total column. 
TEAEs will also be summarized by maximal severity. Summa1y table will include the number 
and percentage of paiiicipants experiencing at least one TEAE in each SOC, PT, and severity. 
The relation of TEAEs to study dmg will be summarized by their relatedness (related or not 
related). 
Listings for deaths, serious TEAEs, and TEAEs leading to discontinuation will be presented. 
8.5. 
Deaths 
If any pa1iicipant dies during the study all relevant info1mation will be discussed in the 
paiiicipant's na1rntive included in CSR. 
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8.6. 
Clinical Laboratory Tests 
All analysis of clinical laborato1y tests will be perfo1med using data from the central laborato1y. 
Summaiy statistics for cheinistiy, hematology, and urinalysis laborato1y tests will be presented at 
Screening, Baseline, Weeks 4, 26, 39, 52, 65, and 78. All test results and associated no1mal 
ranges will be reported in the standard International System of Units (SI unit). 
Continuous values will be summai·ized using descriptive statistics by treatment group. 
Laborato1y parameters which have an upper and/or lower reference range: Number and 
percentage of pa1ticipants with 6 categories (inissing, clinically significant low, not clinically 
significant low, no1mal, not clinically significant high, clinically significant high) values at each 
visit for each parameter will be summarized by ti·eatment group. If a paiticipant has both low and 
high abno1malities, they will be displayed in both low and high categories based on worst low 
and worst high values. 
Change from Baseline for continuous values will be summai·ized using both continuous summaiy 
statistics as well as shift tables based on n01mal ranges at each post-baseline visit. 
Shift from Baseline (i.e., the disti·ibution of the 5 response categories, catego1y missing will be 
excluded for readability) tables will include shift from Baseline to each post-baseline visit and 
the worst post-baseline value across all visits. 
The incidence of clinically significant (CS) abno1mal values (defined in Table 4) will be 
summarized for laborato1y data. 
Paiticipants with CrCl <30 mL/min, calculated using the Cockcroft-Gault equation [(140 - age) x 
mass (kg) x [0.85 if female] / 72 x semm creatinine (mg/dL)], at any timepoint after the Baseline 
visit 2 will be summarized. 
Table 4: 
Criteria for Clinically Significant Laboratory Values 
Laboratorv Parameters 
SI Units 
Definition of Clinicallv Si1mificant Values 
Serum Chemistry 
Low 
Hieb 
Liver Function 
Alanine aminoti·ansferase (AL TI 
>3 x ULN 
Aspaitate aminoti·ansferase 
>3 x ULN 
(AST) 
Alkaline phosphatase (ALP) 
>3 x ULN 
Gamma-glutamyl ti·anspeptidase 
>3 x ULN 
(GGT) 
Albumin 
g/L 
<31 
Lactate dehvdrogenase (LDID 
>3 x ULN 
Total bilimbin 
>3 x ULN 
Renal Function 
Bicarbonate 
mmol/L 
<18 
Blood urea nitrogen (BUN) 
mmol/L 
>14 
Creatinine 
΂Lmol/L 
> 3 x Baseline 
Creatinine clearance 
mL/sec 
<0.5 
( <30 mL/min) 
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General Chemistry 
Calcium 
mmol/L 
<2.0 
>2.74 
Chloride 
mmol/L 
<88 
>112 
Potassium 
mmol/L 
<3.4 
>6.0 
Hematology 
Low 
High 
Hemoglobin (Males) 
mmol/L 
<7.76 
> 11.92 
(<12.5 g/dL) 
( > 19.2 g/dL) 
Hemoglobin (Females) 
mmol/L 
<6.83 
> 10.98 
(<l 1.0 g/dL) 
(>17.7 g/dL) 
White blood cell counts (WBC) 
109/L 
<3 
>20 
Lymphocytes 
109/L 
<0.75 
>10 
Neutroohils 
109/L 
<l 
Eosinophils 
109/L 
>1.5 
Platelet 
109/L 
<75 
>700 
Box plots will be presented for laborato1y parameters listed in Table 4 by visit. Evaluation of 
mug-induced liver injmy will be perfo1med and displayed in eDISH figure which is a log/log 
scatter plot of peak total bilirnbin vs ALT or AST, both in multiples of ULN, with horizontal and 
ve1iical lines indicating Hy's law thresholds (i.e., ALT=3 x ULN, AST=3 x ULN, and total 
bilirnbin=2 x ULN). 
8. 7. 
Vital Signs 
Summaiy statistics for vital signs will be presented at Screening, Baseline, Weeks 4, 26, 39, 52, 
65, and 78. 
The original protocol required triplicate measurements for blood pressure and HR. It was 
dete1mined as a non-safety concern therefore this requirement was removed as pali of a protocol 
amendment 6.0 dated 13 May 2021 to reduce burden on paiiicipants. Since up to triplicate 
measurements may have been collected, for descriptive statistics of actual values and changes 
from Baseline to each visit and assessment, multiple values around the same timepoint will be 
averaged. 
Actual values and changes from Baseline to each visit and assessment will be summai·ized using 
descriptive statistics. The incidence of clinically significant abno1mal values will be summarized 
for select vital signs using descriptive statistics. 
Descriptive statistics for each 01ihostatic vital sign parameter (supine minus standing systolic 
blood pressure [SBP], and supine minus standing diastolic blood pressure [DBP]) at Baseline and 
over time will be presented by treatment group. 
The incidence of 01ihostatic clinically significant abno1mal values (defined in Table 5) will be 
summarized using descriptive statistics. Clinically relevant abno1malities will be summarized 
using two methods (a) the observed values and (b) both observed value and the change relative to 
Baseline. 
A listing for clinically significant abno1mal vital signs will be presented. 
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Table 5: 
Criteria to Determine Clinically Relevant Abnormalities in Vital Signs 
Vital Sie:n 
Observed Value 
Temperature 
>38 °C 
<36 °C 
Heaii rate 
> 100 beats per minute 
<60 beats oer minute 
SBP 
> 160 mm Hg 
> 140 mm Hg 
<90 mm Hg 
DBP 
> 100 mm Hg 
>90 mm Hg 
<50 mm Hg 
Body Weight 
SBP Supine minus Standing 
>20 mm Hg 
DBP Suoine minus Standing 
> 10 mm Hg 
8.8. 
Electrocardiography (ECG) 
8.8.1. 
ECG Measures Handling and Time Points 
Chane:e Relative to Baseline 
Increase of> 1 °C 
Increase of> 15 beats per minute 
Decrease of > 10 beats oer minute 
Increase of> 15 mm Hg 
Decrease of> 15 mm Hg 
Increase of> 15 mm Hg 
Decrease of> 15 mm Hg 
Increase of>7% 
Decrease of >7% 
A single resting 12-lead ECG is conducted after at least 5 minutes of supine rest at Screening 
(Visit 0). If there is evidence of a prolonged QTcF interval at Screening (defined as a QTcF 
interval of >450 msec for men and >4 70 msec for women) then the ECG is repeated twice, and 
the mean of the 3 measurements will be used for the SllillillaIY. 
Planned timepoint ECG assessments are specified in the SoAs (Table 1 and Table 2). 
If the local ECG reading results at the site match any of the below Stopping Rules, the 
paiiicipant should stop taking study medication until the central ECG reader's repo1i is received. 
If the central reader does not rep01i a QT cF interval that would lead to discontinuation according 
to the above, then the pa1iicipant should resta1i study medication. 
Paiiicipants should be discontinued from study drug if any of the following QTcF Stopping 
Rules are met at any visit: 
• QTcF >500 msec (based on any ECG administration) 
• QTcF >480 msec with concunent increase in QTcF >60 msec (ɹQTcF, based on the 
mean value from ECG administrations) from Baseline (Day 1) 
If the local ECG reading results at the site meet the Monitoring Rule (QTcF >480 msec or 
ɹQT cF >60 msec ), the participant can continue the study drug per protocol until the central ECG 
reader's repo1i is received. If central reader confinns meeting a Monitoring Rule, the paiiicipant 
will stay on study diug (per protocol) and will return for a follow-up ECG after 3-14 days. If at 
the follow-up ECG, QTcF change is confnmed (meets Monitoring Rule) then the pa1iicipant will 
be discontinued from study diug. 
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8.8.2. 
ECG Parameters Data Presentations 
Change from Baseline values will be calculated for each pa1ticipant and visit as the value at the 
visit (averaged if measmements are taken in triplicate as described above) subtracted by the 
average Baseline value. 
ECG data summaries and listings will include the following: 
• 
The numbers and percentages of paiticipants with the following clinically potential 
significant values will be presented at Baseline and each post-baseline visit: 
o Absolute QTcF values >450 msec; >480 msec; >500 msec 
o Change from Baseline in QTcF >30 msec; >60 msec 
For HR, PR and QRS use below: 
o HR: decrease of HR from baseline > 10 bpm resulting in HR <60 bpm 
Increase of HR from baseline > 15 bpm resulting in HR > 100 bpm 
o PR: increase of PR from baseline >25% resulting in PR >200 ms 
o QRS: increase of QRS from baseline >25% resulting in QRS > 100 ms 
Data listing of these values together with Baseline value and change from Baseline will also be 
provided: 
• 
The number of pa1ticipants and percentages of ECG interpretation (No1mal/ Abno1mal 
Not Clinically Significant, Abn01mal Clinically Significant) as dete1mined by the ECG 
Central Lab at each scheduled visit and time point as well as the shift table from Baseline 
to each post-baseline visit will be presented by treatment groups 
• 
The number and % of paiticipants with ECG alerts as dete1mined by the ECG Central 
Lab will be presented by treatment groups 
• 
Descriptive statistics and boxplots of quantitative 12-Lead ECG pai·ameters (HR [bpm], 
QTcF [msec], QTcB [msec], QT [msec], PR [msec], QRS [msec] and RR [msec]) and 
changes from Baseline will be presented by scheduled visits, time point and treatment 
group 
• 
Central ECG Review of abno1malities will be summarized. 
8.9. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS will be used to rate the pa1ticipant' s degree of suicidal ideation on a scale 
ranging from "no suicidal ideation" to "active suicidal ideation with specific plan and 
intent". The C-SSRS Baseline version will be completed at Screening (Visit 0), while the C­
SSRS Since Last Visit version will be completed as specified in the SoA (Table I and 
Table 2). 
Summaiy statistics for the C-SSRS at each visit will be presented by treatment group using 
observed data. The Baseline value will be based on the closest non-missing recency score 
prior to first dose of study drng. 
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The number of paiiicipants evaluated and the number and percentage of paiiicipants with any 
positive report of Suicidal Behavior, Suicidal Ideation, and Suicidal Behavior or Ideation at 
Baseline and post-baseline visits will be presented by treatment group. A positive rep01i of Suicidal 
Behavior or Ideation is defined as a "yes" response on any ideation item (positive Suicidal 
Ideation), or a "yes" response to any behavior item (positive Suicidal Behavior). The shift from 
Baseline will be summai·ized by (a) worst post-baseline value (b) Last observed non-missing post­
Baseline value and then ( c) at each post baseline visit. . 
C-SSRS assessment results for each pa1iicipant at each visit will be listed by treatment group using 
observed data. Both lifetime and recency scores at Screening Visit will be listed. 
8.10. 
Pregnancy Test 
Sennn/urine pregnancy test results will be listed for women of child-beai·ing potential only. 
8.11. 
Physical and Neurological Examination 
The physical (full and brief) and neurological examination results, graded as nonnal or abno1mal 
( or for some neurological examinations other categories ai·e used such as hypoactive, 
hyperactive, etc.), will be summarized using counts and percentages at visits described in Table 1 
and Table 2. Denominator for the percentages will be the number of paiticipants in the treatment 
group. 
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9. 
PHARMACOKINETIC (PK), BIOMARKER (NFL) AND 
PHARMACOGENOMIC ANALYSIS 
9.1. 
Blood Sampling and Handling 
Blood samples for plasma concentration of study diug and its main metabolite (TV-45065) will 
be collected 1-2 hours after the dosing and after the ECG is administered as specified in Table 1 
(SoA-Main Study). Samples for PK analysis will be analyzed for the concentration of 
pridopidine and its main metabolite TV-45065 using an appropriate validated method. 
Incuned sample reanalysis may be perfo1med. 
Dmg concentration info1mation that would unblind the study will not be reported to 
investigative sites or blinded study personnel until the study has been unblinded. 
Samples for biomarker analysis of biomarker (NfL) will be collected as detailed in Table 1 
(SoA Main Study). 
Sampling analyses for DNA extraction will be perfo1med only once during the study, for 
future genetic analysis related to pridopidine response or HD. 
Blood samples will always be collected after the ECG is administered (not before). 
9.1.1. 
PK Analysis 
PK assessments include plasma concentration of pridopidine and its main metabolite (TV-45065) 
at Weeks 26, 52, 65, and 78 and at last paiiicipants' visit. 
All pridopidine and TV-45065 concentration data will be listed for paiiicipant at each visit and 
timepoint, including date and time of sample collection and elapsed time from last dose. 
Descriptive statistics of plasma concentrations of pridopidine and TV-45065 as continuous 
variables additionally with geometric mean and coefficient of variation (CV) will be presented 
by treatment groups, scheduled visit and timepoint. For these summaries, values which are below 
lower limit of quantification (LLOQ) will be treated as zero; if the mean of the numbers is 
<LLOQ, the value would be rep01ied as "BLQ" (below limit of quantification). 
Additional PK samples collected in case of an SAE will be listed but not included in the 
summanes. 
An exposure-response conelation between pridopidine plasma concentrations vs efficacy and 
safety measures (including QTcF), as well as explorato1y analysis and additional covariate analysis 
may be perfo1med and repo1ied separately as applicable. 
Additional PK analyses may be specified in a SAP addendum, or separate SAPs. 
9.1.2. 
Biomarker (NIT.,) Analysis 
Biomai·ker assessments include: 
• Change from Baseline to Weeks 26, 52, 65 and 78 in plasma NfL protein 
• Relationship between Baseline NfL and changes from Baseline in select efficacy endpoints 
• Relationship between changes from Baseline to Weeks 26, 52, 65 and 78 in NfL and select 
efficacy endpoints for pridopidine 45 mg bid vs. placebo 
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• Proportion of participants with stabilization or improvement in change from Baseline to 
Weeks 26, 52, 65 and 78 in plasma NfL protein 
Objectives of the Nfl.. analysis 
( 1) To investigate the effect of pridopidine 45 mg bid vs. placebo on changes in log-transfonned 
plasma NfL from Baseline to Weeks 26, 52, 65 and 78 (as pg/mL, with log2 transf.onnation), 
accounting for the effects of Baseline NfL and other possible factors as listed below. 
The main analysis is based on change from Baseline in log2(NfL) over time, and similar 
analysis will be repeated for actual values oflogi-transformed plasma NfL levels. Analysis 
will be perfmmed on obse1ved data using MMRM separately for actual values and change 
from Baseline over time. The model will include the following fixed effects: treatment, 
categarical weeks, Baseline log2(NjL), Age and BAfl at Baseline, randomization stratification 
factors (HD stage and neurolepfic use at Baseline), interaction effect of 
treatt11enf1<categorical weeks. The spatial power covariance matrL'< for repeated obse1vations 
within participants will be used. The denominator degrees of freedom for the tests of fL'<ed 
effects will be approximated by Kenward-Roger method. 
Each fixed eff.ect will be tested at a type I eJTor level ::;0.05, two-sided and the 95% two-sided 
confidence intervals (CI) of the parameters will be computed. The LSMs of actual values and 
change from Baseline in log2(NfL) and associated SE for each treatment group, as well as the 
LSM, 95% CI, and p-value for the treatment difference (pridopidine 45 mg bid vs. placebo) 
will be presented at all visits in analysis. The LSM of change from Baseline in log2(NfL) at 
each visit will be back transformed to the percent change in NfL as 2rsM :--: 100 -100. The 
95% CI of the LSM will also be back transfonned. 
In addition, actual values, change from Baseline to each visit of logi(NfL) and actual value, 
and % change from Baseline in raw NfL value will be summarized using descriptive statistics 
and graphics where applicable. 
To investigate the additional covariates that may have an effect on change in NfL over time, 
more covariates will also be added one at a time or altogether to the above model: CAG 
repeats, age , sex, CAP score, BMI, region, Baseline UHDRS-TFC, Baseline cUHDRS, 
Baseline Q-Motor -Baseline UHDRS-TMS, Baseline SDMT, and Baseline SWR. 
When all covariates are added to the model together, a stepwise model selection approach 
(specifically, a variable needs to be significant at the level of 0.25 to enter the model during 
the first fo1wardstep and to be significant at the level of 0.10 to remain in during the second 
backward step) will be adopted in order to see the most influential covariates on the change 
in NfL over time. Each covariate will be tested at a type I error level ɥ0.05, two-sided and 
the 95% two-sided Cls of the effect estimates will be computed. 
(2) To investigate how Baseline N fL, as a covariate, impacts change from Baseline to Weeks 26, 
52, 65 and 78 in efficacy endpoints including UHDRS-TFC, cUHDRS, Q-Motor-
, UHDRS-TMS, SDMT, and SWR accounting for the eff.ect of pridopidine 
45 mg bid vs placebo. 
The main analysis is based on the change from Baseline in UHDRS-TFC, c UHDRS, Q-
Motor 
UHDRS-TMS, SDMT and SWR over time. Each dependent 
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variable will be fit by one model. Similar analyses will be repeated for actual values of the 
endpoints. 
Analysis will be perfonned on obse1ved data using MMRM separately for actual values and 
change from Baseline. The model will include the following effects: treatment, categorical 
weeh, Baseline value of efficacy endpoint to be analy=e.d, Baseline logi_Nfl-.), randomization 
stratification factors (HD stage and neuroleptic use at Baseline), interaction effects of 
treatmenf"categorical weeks, and treatment* Baseline log2(NJL). The spatial power 
covariance matrix for repeated obse1vations within paiticipants will be used. The 
denominator degrees of freedom for the tests of fixed eff.ects will be approximated by 
Kenward-Roger method. 
Baseline logi_NjL) and its interaction with other factors will be tested at a type I error level 
::;0.05, two-sided ai1d the 95% two-sided CI of the pai·ameters will be computed. 
The LSM and the associated SE of the Baseline N fL-adjusted efficacy endpoint at some 
specified Baseline NtL values (such as median, first quartile [low level], and third quartile 
[high level]) for each treatment group, and the LSM, 95% CI and p-value for the treatment 
difference (pridopidine 45 mg bid vs. placebo) will be presented for all visits. 
To investigate the additional covai·iates that may have an effect on the efficacy endpoints, 
more covai·iates will also be added one at a time or altogether to above model: CAG repeats, 
age, sex, CAP score, BMI, region. When all covariates are added to the model together, a 
stepwise model selection approach, as described in Objective (1), will be adopted to see the 
most influential covai·iates on the change in NfL over time. Each covariate will be tested at a 
type I error level ::;0.05, two-sided and the 95% two-sided Cls of the parameters will be 
computed. 
(3) To investigate the relationship between change in NfL over time and change in clinical 
efficacy endpoints including Ut-IDRS-1FC, cUHDRS, Q-Motm 
Ut-IDRS-TMS, SDMT and SWR accounting for the effect of pridopidine 45 mg bid vs 
placebo. 
The dependent vai·iables investigated ai·e clinical outcomes such as Ut-IDRS-1FC, cUHDRS, 
Q-Motor 
UHDRS-TMS, SDMT and SWR over time, with one dependent 
vai·iable fit at a time. 
The main analysis is based on change from baseline in both efficacy endpoints and 
log2(NtL), and similar analyses will be repeated for actual values of efficacy endpoints and 
logz(NtL). Analysis will be perforated on observed data using MMRM separately for actual 
values and change from Baseline over time. The model for change from Baseline in a 
specific efficacy endpoint over time will include the following effects: treatment, categorical 
weeh, Baseline value of efficacy endpoint to be analy=ed, rai1domizatio11 stratification factors 
(HD stage and neuroleptic use at Baseline), change from Baseline in log2(NjL), interaction 
effects of treatmenf"categorical weeks, treatment*change from Baseline in log2(NJL). The 
spatial power covariance matrix for repeated observations within paiticipai1ts will be used. 
The denominator degrees of freedom for the tests of fixed effects will be approximated by 
Kenward-Roger method. 
The eff.ect of change from Baseline in log2(NIJL) by treatment group will be tested at a type I 
error level ,g).05, two-sided and the 95% two-sided CI of the parameter will be computed. 
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Another simpler approach to perfo1m a simple linear model on the change from Baseline of 
these clinical outcomes at the specified timepoint may be perfo1med. For Week 65 analysis, 
the model will include the following effects: treatment, Baseline log2(NjL), log2(NjL) at 
Weeks 26, 52 and 65, and interaction effects of treatment*log2(NJL) at Baseline and Weeks 
26, 52 and 65. Each covariate related to log2(NjL) will be tested at a type I enor level ɸ0.05, 
two-sided and the 95% two-sided CI of the parameters will be computed. 
To investigate the additional possible covariates that can have an effect on change in efficacy 
endpoints over time, more covariates will also be added one at a time or altogether to the above 
model: CAG repeats, age, CAP score, BMI, region. When all covariates are added to the model 
together, a stepwise model selection approach, as described in Objective (1 ), will be adopted 
to see the most influential covariates on the change in NfL over time. Each covariate will be 
tested at a type I enor level ɺ0.05, two-sided and the 95% two-sided CI of the parameters will 
be computed. 
(4) To investigate the propo1tion of paiticipants with no increase from Baseline to Weeks 26, 52, 
65 and 78 in plasma NfL levels. Other thresholds may also be explored. 
The dependent vai·iable is a bina1y vai·iable which is defined as follows: 
Dependent variable = {1 
if Change from Baseline in log2 (NfL)΃0 
0 
otherwise 
This bina1y variable dichotomizes changes from Baseline in log2(NfL) over time to show 
whether or not there is a beneficial decrease in log2(NfL) from Baseline. Analysis will be 
perfo1med on the bina1y data at each visit using logistic regression model. In this model, the 
log odds of the dependent vai·iable are modelled. 
The model will include the following fixed effects: treatment, Baseline log2(NjL), 
randomization stratification factors (HD stage and neuroleptic use at Baseline), interaction 
effect of treatment*Baseline log2(NjL). 
Each fixed effect will be tested at a type I e1rnr level ɺ0.05, two-sided, and the 95% two­
sided confidence intervals (CI) of the parameters will be computed. Odds Ratios of treatment 
effect with their 95% CI at each visit will be presented in analysis. 
Subgroup analysis which divides the paiticipants by median Baseline NfL level will be 
perfo1med for above objectives where applicable. 
9.1.3. 
Pharmacogenomic Analysis 
Details of pha1macogenomic data collection and analysis will be included in a SAP addendum, 
appendix or separate SAPs. 
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10. 
STATISTICAL SOFTWARE 
All derived datasets, data listings, summaries, and statistical programming/analyses will be 
perfo1med using SAS® 9.4 or higher. 
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11. 
REFERENCES 
1. Ratitch B, O'Kelly M, Tosiello R. Missing Data in Clinical Trials: from Clinical 
Assumptions to Statistical Analysis Using Pattern Mixture Models. Pha1maceutical Statistics. 
2013; 12: 337-347. 
2. Little RJA, Wang Y. Pattern-Mixture Models for Multivariate Incomplete Data with 
Covariates. Biometrics. 1996; 52: 98-111. 
3. National Research Council. The Prevention and Treatment of Missing Data in Clinical Trials. 
Panel on Handling Missing Data in Clinical Trials. Committee on National Statistics, 
Division of Behavioral and Social Sciences and Education. The National Academies Press, 
Washington, DC, USA (2010). Link: https://www.ncbi.nlm.nih.gov/books/NBK209893/ 
4. Schobel SA, et. al., Motor, Cognitive, and Functional Declines Contribute to a Single 
Progressive Factor in Early HD. Neurology. 2017; 89: 2495-2501. 
5. Meyer RD, et. al., Statistical Issues and Recommendations for Clinical Trials Conducted 
During the COVID-19 Pandemic. Statistics in Biophannaceutical Research. Published online 
06 Jul 2020. 
6. Akacha M, et. al., Challenges in Assessing the Impact of the COVID-19 Pandemic on the 
Integrity and Interpretability of Clinical Trials. Statistics in Biopha1maceutical Research. 17 
Aug 2020. 
7. Ratitch B, et. al., Choosing Estimands in Clinical Trials: Putting the ICH E9(Rl) Into 
Practice. Therapeutic Innovation & Regulato1y Science. 54: 324-341. Published online 4 
Janua1y 2020a. 
8. Mallinckrodt CH, et. al., Aligning Estimators With Estimands in Clinical Trials: Putting the 
ICH E9(Rl) Guidelines Into Practice, Therapeutic Innovation & Regulato1y Science. 54: 
353-364. Published online 6 Janua1y 2020. 
9. Ratitch B, et. al., Defining Efficacy Estimands in Clinical Trials: Examples Illustrating ICH 
E9(Rl )  Guidelines, Therapeutic Innovation & Regulato1y Science. 54: 370-384. Published 
online 6 Janua1y 2020b. 
10. Long JD, et. al, Validation of a Prognostic Index for Huntington's Disease. Mov Disord. 
2017 Feb; 32(2): 256-263. 
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12. 
12.1. 
12.1.1. 
APPENDIX 
Efficacy Variables Calculation Methods 
Unified Huntington's Disease Rating Scale - Total Functional Capacity 
(UHDRS-TFC) 
The UHDRS-TFC is the standard and well-accepted clinical scale for staging and tracking 
the progression of HD using functional capacity. Scores range from O to 13, with 13 as the 
least affected and 0 as complete incapacity. The scale assesses the participant's capacity to 
unde1take domestic chores (0=Unable to 2=Normal), activities of daily living (0=Total Care 
to 3=Normal), take care of finances (0=Unable to 3=No1mal), maintain care level (0=Full 
time skilled nursing to 2=Home), and maintain their occupation (0=Unable to 3=No1mal). 
UHDRS-TFC questionnaires are collected as specified in the SoA (Table 1 and Table 2) to 
assess change from Baseline. 
A UHDRS-TFC evaluation will only be considered valid if all 5 assessments of Domestic Chores, 
Activities of Daily Living, Finances, Care Level, and Occupation are completed. If any of these is 
not completed, the UHDRS-TFC assessment will be considered invalid and treated as missing 
value. 
Paiticipants with improvement or no worsening in UHDRS-TFC at a paiticulai· post-baseline 
visit during Main Study are defined as those with change from Baseline ÑO at that visit. 
TFC responders at a scheduled visit during OLE are defmed as participants with change from 
Main Study Baseline in UHDRS-TFC Ñ-1. 
12.1.2. 
Unified Huntington's Disease Rating Scale - Total Motor Score (UHDRS-TMS) 
The UHDRS-TMS is the sum of 31 individual motor ratings from the 15 items of the UHDRS, 
with each assessment rated on a 5-point scale from 0 (no1mal) to 4 (maximally abno1mal). 
Higher scores indicate more severe motor impairment. The worst possible score is 124. UHDRS­
TMS questionnaires are collected to assess change from Baseline. 
The subscales of UHDRS-TMS include: 
• 
Gait and balance score, defmed as the sum of UHDRS Items 13, 14 and 15 (gait, tandem 
walking, and retropulsion pull test) 
• 
Eye movement score, defined as the sum of UHDRS Items l a  Horizontal, l b  Ve1iical, 
2a Horizontal, 2b Ve1iical, 3a Horizontal, 3b Ve11ical ( oculai· pursuit, saccade initiation, 
and saccade velocity) 
• 
Dystonia score, defmed as the sum ofltems l la- l l e  
• Chorea score, defmed as the sum of Items 12a - 12g 
Paiticipants with improvement or no worsening in UHDRS-TMS at a pa1iicular post-baseline visit 
during Main Study ai·e defined as those with change from Baseline :SO at that visit. 
12.1.3. 
Unified Huntington's Disease Rating Scale - Composite Score (cUHDRS) 
The cUHDRS (Schebel et. al., 2017) is a composite measure of motor, cognitive, and global 
functional decline computed as follows: 
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A cUHDRS responder is defined as one with change from Baseline in cU 1-IDRS -1. 
12.1.4. 
Quantitative Motor (Q-Motor) 
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12.1.5. 
Clinical Global Impression 
12.1.5.1. 
Modified Clinical Global Impression of Severity (modified CGI-S) 
The CGI-S (modified) scale was initially designed to assess treatment response in participants 
with mental disorders but is now used widely in a range of illnesses. Illness severity is rated by 
qualified site personnel on a 7-point scale ( 1 = normal, not at all ill to 7 = among the most 
extremely ill participants) as shown in the table below. The assessment is based on qualified site 
personnel judgment, supported by a comprehensive, semi structured, participant/caregiver 
interview. 
CGI-S (modified) will be collected at Baseline. 
Description 
Score 
Nonnal, not at all ill 
1 
Borderline ill 
2 
Mildly ill 
3 
Moderately ill 
4 
Mar kedl v ill 
5 
Severely ill 
6 
Extremely ill 
7 
12.1.5.2. 
Clinical Global Impression - Change (CGI-C) 
The CGI-C scale measures the change in the pa11icipanf s clinical status from a specific point in 
time, using a 7-point scale, ranging from 1 (ve1y much improved) to 7 (ve1y much worse), with a 
score of 4 indicating no change. 
Responder analyses will be performed at Week 65 as a seconda1y efficacy endpoint with analysis 
at all other post-baseline visits as additional efficacy analyses. Responder analyses comparing 
participants randomized to pridopidine vs placebo will be performed using CGI-C for those: 
(a) who have no change or improve (Scores of 1,2,3 or 4) 
(b) who Minimally or more improved (Scores of 1,2, or 3) 
( c) who Are Much or Ve1y Much improved (Scores of 1 or 2) 
(d) who are Ve1y Much improved (Score of I) 
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Description 
Score 
Not assessed 
0 
Ve1y Much Improved 
1 
Much Improved 
2 
Minimally improved 
3 
No change 
4 
Minimally worse 
5 
Much worse 
6 
Ve1y much worse 
7 
12.1.6. 
Exploratory Assessments 
12.1.6.1. 
Stroop Word Reading (SWR) 
The SWR is a neuropsychological test commonly used to measure the pa1ticipant's attention and 
mental flexibility. The paiticipant's accuracy and speed at the SWR will be recorded and used to 
track the progression of cognitive deterioration. Scores reflect the number of conect responses in 
45 seconds. Higher scores indicate better perfo1mance. 
SWR is collected to assess the propo1tion of responders and change from Baseline for efficacy 
endpoints. 
12.1.6.2. Symbol Digit Modalities Test (SDMT) 
The SDMT is a paper and-pencil test of psychomotor speed and working memo1y. Paiticipants 
view a 'key' at the top of the page containing symbols paired with numbers. The remainder of 
the page displays rows of symbols, and the pa1ticipant has 90 seconds to write the conesponding 
number that matches each symbol. Scoring involves slimming the conect substitution within the 
90 second interval (max=l 10). 
SDMT is collected to assess responder analysis and change from Baseline for explorato1y 
efficacy endpoints. 
12.1.6.3. Problem Behaviors Assessment-Short Form (PBA-s) 
The PBA-s is a brief semi-structured inte1view covering the most common behavioral and 
psychiati·ic manifestations of HD. The inte1view is not resti-icted to a single conshuct, but rather 
covers several broad symptom domains relevant to HD, comprising 11 items: low mood, suicidal 
ideation, anxiety, iITitability, anger/aggressive behavior, loss of motivation, perseverative 
thinking or behavior, obsessive-compulsive behaviors, paranoid thinking, hallucinations, 
behavior suggestive of disorientation. Each symptom is rated for severity on a 5-point scale 
according to detailed scoring criteria which roughly conespond to the following: 0 = "not at all"; 
1 = ti·ivial; 2 = mild; 3 = moderate ( disrnpting eve1yday activities) and 4 = severe or intolerable. 
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Each symptom is also scored for frequency on a 5-point scale as follows: 0 = symptom absent; 1 
= less than once weekly; 2 = at least once a week; 3 = most days (up to and including some par1 
of eveiyday); and 4 = all day, eve1y day. 
Severity and frequency scores are multiplied (after setting all values outside the range of 0-4 to 
missing) to produce an overall 'PBA score' for each symptom. 
The total PBA score is calculated by the sum of all PBA scores across symptoms/domains. The 
PBA-s sub-scores include depression score (sum oflow mood, suicidal ideation, and anxiety), 
ini.tability/aggregation score (sum of irritability and anger/aggressive behavior), executive 
function (sum of perseverative thinking or behavior and obsessive-compulsive behaviors), 
apathy (loss of motivation), and psychosis (sumo f paranoid thinking, hallucinations, and 
behavior suggestive of disorientation). 
The PBA assessments are collected to assess change from Baseline for explorat01y efficacy 
endpoints. 
12.1.6.4. The Huntington Disease Quality of Life Questionnaire (HDQoL) 
The HDQoL questionnaire includes 40 items (ranged O='Never' to 6=' All the Time '). The 
HDQoL total score is defined as the sum of the 40 items. The HDQoL total score range is from 0 
to 240. 
HDQoL is collected to assess responder analyses and change from Baseline for explorat01y 
efficacy endpoints. 
12.2. 
Abuse Potential 
Drng abuse potential will be identified usino PT of AEs in accordance with the standardized 
search strategy 
-: 
• 
Abuse, dependence, withdrawal or diversion (using the following PT: drng abuser, 
drug dependence, dependence, drug tolerance, drug tolerance increased, drug 
withdrawal syndrome) 
• 
Euphoria/mood-elevation (using the following PT: dizziness, elevated mood, 
euphoric mood, feeling abnomial, feeling drunk, feeling of relaxation, and 
inappropriate affect) 
• 
Depressant/sedative effects (using the following PT :  asthenia, fatigue, lethargy, 
sedation, sluggishness, somnolence, and stupor to identify AEs with central nervous 
system d epressant effects) 
• 
Stimulant eff.ects (using the following PT: agitation, anxiety, energy increased, 
feeling jitte1y, hype1vigilance, nervousness, psychomotor hyperactivity, and 
restlessness to identify AEs indicating stimulation and anxiety symptoms) 
• 
Perceptual distmbances, dissociative and psychotomimetic effects (using the 
following PT: abnomial dreams, acute psychosis, aggression, anger, communication 
disorder, confusional state, delirimn, delusion, d epersonalisation, derealisation, 
disorientation, dissociation, dissociative disorder, dysaithria, flashback, hallucination, 
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hallucination audito1y, hallucination mixed, hallucination olfacto1y, hallucination 
synaesthetic, hallucination tactile, hallucination visual, hostility, hypoesthesia, 
illusion, indifference, muscle rigidity, nightmare, paraesthesia, paranoia, psychotic 
disorder, senso1y disturbance, somatic delusion, somatic hallucination, thinking 
abno1mal, thought blocking, transient psychosis) 
• Mood disorders and disturbances (using the following PT: abno1mal behaviour, 
affective disorder, affect !ability, depressed mood, depression, emotional disorder, 
emotional distress, impatience, mood altered, mood swings, and personality change) 
• Mental and cognitive impairment (using the following PT: amnesia, cognitive 
disorder, disturbance in attention, memo1y impaiiment, mental impaiiment and 
psychomotor skills impafred) 
• 
Possible discontinuation-emergent stimulant effects (using the following PT: affect 
!ability, agitation, anger, anhedonia, anorexia, anxiety, apathy, appetite suppression, 
bradycardia, decreased appetite, decreased interest, depressed mood, disturbance in 
attention, diug dependence, fatigue, feeling abno1mal, food craving, hangover, 
hyperphagia, hypersomnia, increased appetite, insomnia, nTitability, lethargy, listless, 
malaise, mood altered, mood swings, oral intake reduced, paranoia, restlessness, 
somnolence, suicidal behaviour, suicidal ideation, tension) 
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