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
Phase: PHASE3
Conditions: Huntington Disease
Sponsor: Prilenia

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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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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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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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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Protocol Number: PL101-HD301 
 
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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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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 
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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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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 
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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 
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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 
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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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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 
 
 
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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 
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 
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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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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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Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
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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  
 
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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  
 
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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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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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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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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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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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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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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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• 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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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  
 
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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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Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
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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 
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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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Version 7.0, Amendment 8 

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Prilenia Therapeutics 
-
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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 
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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 
Version 7.0, Amendment 8 

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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  
 
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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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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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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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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  
 
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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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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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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: 
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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 
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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 
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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 

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Study drug: Pridopidine 
Protocol Number: PL101-HD301  
 
CONFIDENTIAL 
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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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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. 
 
Craufurd, D., Thompson, J. C. and Snowden, J. S. (2001). "Behavioral changes in Huntington 
Disease." Neuropsychiatry Neuropsychol Behav Neurol 14(4): 219-226. 
 
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. 
 
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