Clinical trial NCT01306929
Conditions: Huntington Disease
Keywords: Huntington Disease.
Sponsor: Prilenia
Start date: 2011-03-24; Completion date: 2018-01-05
Enrollment: 134 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Huntington disease (HD) is a hereditary neurodegenerative disorder causing impairment in movement, behavioral dysfunction and dementia. The movement disorder is mainly characterized by chorea (involuntary movements) and a progressive loss of voluntary movement causing a substantial functional impairment over time. The study will assess the long-term safety of pridopidine and the treatment effects during long-term, open-label treatment.

Detailed description:

Arms: arm 1: 45mg bid
Interventions: intervention 1: pridopidine
Intervention descriptions: intervention 1: 45mg bid

Protocol documents:
Prot_000.pdf: 
Official Title: A multi-center, North American, open-label extension study of 
pridopidine (ACR16) in the symptomatic treatment of Huntington’s Disease (Open-
HART). 
NCT Number: NCT01306929 
Document Date: 29 Jun 2017 


Study Number: ACR16C015
IND Number: IND 77,419
Protocol Version: FINAL 6.0
Date: 29 June 2017
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TITLE PAGE
Teva Branded Pharmaceutical Products R&D, Inc
 
USA
CLINICAL STUDY PROTOCOL WITH AMENDMENT 05
A multi-center, North American, open-label extension study of pridopidine 
(ACR16) in the symptomatic treatment of Huntington’s Disease (Open-HART).
SPONSOR TRIAL CODE: ACR16C015
PRINCIPAL COORDINATING INVESTIGATOR
Ray Dorsey, MD, MBA
University of Rochester Medical Center
Rochester, New York
USA
Draft 1
23 October 2009
Draft 2
26 October 2009
Draft 3
12 November 2009
Draft 4
13 November 2009
Draft 5
11 December 2009
Draft 6
13 July 2010
Draft 7
08 September 2010
Draft 8
23 September 2010
Draft 9
19 October 2010
Draft 10
02 November 2010
Draft 11
19 November 2010
FINAL 1.0
07 December 2010
FINAL 2.0
16 July 2012
Draft 2.1
06 December 2012
Draft 2.2
11 December 2012
FINAL 3.0
18 December 2012
FINAL 4.0
02 February 2015
FINAL 5.0
25 August 2016
FINAL 6.0
29 June 2017
THIS PROTOCOL IS A CONFIDENTIAL DOCUMENT
This Protocol is the property of Teva. The information within it is confidential and is
provided to you, for review by you, your staff and applicable Ethics Committee. The
Protocol must be kept in a confidential manner and must be returned to Teva upon
request. No part of this document may be reproduced in any form without permission
from Teva. By accepting this document, you agree that the information contained
herein will not be disclosed to a third party without written authorization from Teva.


Study Number: ACR16C015
IND Number: IND 77,419
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PROTOCOL TITLE: A multi-center, North American, open-label extension study of 
pridopidine (ACR16) in the symptomatic treatment of Huntington’s Disease
(Open-HART).
PRINCIPAL COORDINATING (CHIEF) INVESTIGATOR
Name:
Ray Dorsey, MD, MBA
Title:
Professor of Neurology, Director of Center for Health and Technology
Address:
University of Rochester Medical Center
Center for Health and Technology (CHET)
Clinical Trials Coordination Center (CTCC)
TEVA PERSONNEL
Medical
Safety & Pharmacovigilance 
 
 
 
MANUFACTURER
CONTRACT RESEARCH ORGANIZATION


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OTHER CONTRACTORS AND CONSULTANTS
Study Monitoring
 
 
Clinical Study Supplies - Packaging
 
Clinical Study Supplies – Receiving and Distribution
 


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Central Institutional Review Board
Address:
Central Electrocardiogram
Address:
Central Laboratory
Address:
Video Conferencing
Address:
Mobile Nurses
Address:
Data Management
Address:


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Electronic Data Capture/Interactive Response Technology
Address:


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PROTOCOL APPROVAL SHEET


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1
TABLE OF CONTENTS
TITLE PAGE
1
PRINCIPAL COORDINATING (CHIEF) INVESTIGATOR
2
TEVA PERSONNEL
2
1
TABLE OF CONTENTS
7
1.1
Protocol Synopsis
11
1.2
Schedule of Assessments – Prior to Study Virtualization
17
1.3
Schedule of Assessments – Following Study Virtualization
18
1.4
List of Abbreviations
21
2
BACKGROUND AND RATIONALE
23
2.1
Background
23
2.2
Rationale for Primary Objective and Study Design
24
2.3
Rationale for Dosage Used
25
3
OBJECTIVES
26
3.1
Primary Objectives
26
3.2
Exploratory Objective
26
4
STUDY DESIGN
26
4.1
Centers
26
4.2
Patient and Unique Identification Numbers
26
4.3
Recruitment
26
4.4
Inclusion Criteria
26
4.5
Exclusion Criteria
27
4.6
Conduct of the Study
27
4.6.1
Virtual Transition Visit
28
4.6.2
First Remote Visit
28
4.6.3
Remote Video and Mobile Nurse Visits
29
4.6.4
Safety Evaluation Telephone Contacts
29
4.6.5
Unscheduled Visit(s)
29
4.6.6
End of Treatment Visit
30
4.6.7
End of Study/Early Termination Visit
30
4.6.8
Follow-up
30
4.6.9
Withdrawal From Treatment
30
4.6.10
Study Duration
30
4.7
Definition of Assessments
30
4.7.1
UHDRS
30
4.7.2
Columbia-Suicide Severity Rating Scale
32
4.7.3
Problem Behaviors Assessment – Short Form
32


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4.8
Protection of Clinical Study Patients
32
5
INVESTIGATIONAL MEDICINAL PRODUCT
33
5.1
Assignment of Treatment
33
5.2
Products
33
5.2.1
Study Drug
33
5.2.2
Placebo
33
5.2.3
Control Medication
33
5.3
Dosage and Administration
33
5.3.1
Dose Frequency Reduction
33
5.3.2
Investigational Medicinal Product
34
5.3.3
Placebo/Control Medication
34
5.4
Presentation and Packaging
34
5.5
Blinding
34
5.6
Accountability of Investigational Medicinal Product and Patient Compliance
35
5.7
Concomitant Medication
35
5.7.1
CYP2D6 Substrates With a Narrow Therapeutic Margin
35
5.7.2
CYP2D6 Inhibitors
35
5.7.3
Medication that May Lower the Seizure Threshold
35
5.7.4
Medication That May Cause QTc Prolongation
35
5.7.5
General
36
5.7.6
Other Non-Drug Concomitant Therapy
36
5.7.7
Warnings and Precautions
37
5.7.8
Availability of IMP After the Study
37
6
STUDY METHODS AND ASSESSMENTS
37
6.1
Assessment of Efficacy
38
6.2
ECG Assessments
38
6.3
Laboratory Assessments
39
6.3.1
Collection of Blood Samples
39
6.3.2
Laboratory Results Outside the Normal Range
39
6.3.3
Pregnancy Test
39
6.4
Vital Signs and Physical Examination
40
6.5
Body Weight
40
7
SAFETY PARAMETERS AND ADVERSE EVENTS
40
7.1
Definitions
40
7.1.1
Adverse Event (AE)
40
7.1.2
Pre-Treatment Adverse Event
40
7.1.3
Treatment-Emergent Adverse Event
40
7.1.4
Overdose
40
7.2
Collection and Recording of Adverse Events
41
7.2.1
Collection of Adverse Events
41
7.2.2
Adverse Event
41
7.3
Follow-up of Adverse Events
43
7.4
Adverse Events of Special Interest
44
7.5
Serious Adverse Events
45


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7.5.1
Definitions
45
7.5.2
Collection and Recording of Serious Adverse Events
45
7.5.3
SAE Reporting Responsibilities of the Investigator (or Qualified Designee)
46
7.5.4
Emergency Contact
46
7.6
Expedited Reporting by Teva
47
7.6.1
Responsibilities
47
7.6.2
Expedited Reporting
47
7.7
Premature Discontinuation of Treatment
47
7.7.1
Cessation of Treatment
47
7.7.2
Withdrawal
48
7.8
Replacement Policy for Patients Who Withdraw
49
7.9
Safety Monitoring
49
8
STATISTICAL ANALYSIS
49
8.1
General Statistical Issues
49
8.2
Data Sets
50
8.3
Missing Values
50
8.4
Sample Size and Power Considerations
50
8.5
Disposition of Patients
50
8.6
Demographics and Other Baseline Characteristics
50
8.7
Concomitant Medication During the Study
50
8.8
Efficacy Set
50
8.9
Assessments and Analysis of Safety and Tolerability
50
8.9.1
Exposure
50
8.9.2
Adverse Events
50
8.9.3
Other Safety Parameters
51
9
ETHICAL AND REGULATORY CONSIDERATIONS
51
9.1
Indemnity, Insurance, and Compensation
51
9.2
Informed Consent
52
9.3
Approvals
53
9.3.1
Institutional Review Board/Research Ethics Boards Approval
53
9.3.2
Regulatory Approval
53
9.3.3
Protocol Amendments
54
9.4
Study Documentation and Study Confidentiality
55
9.4.1
eCRF and Data Collection
55
9.4.2
Data Management
55
9.4.3
Confidentiality of Study Documents and Patient Records
56
9.4.4
Confidentiality of Proprietary Information
56
9.4.5
Financial Disclosure
57
10
PUBLICATION OF DATA
57
10.1
Publication
57
11
ADMINISTRATIVE PROCEDURES
58
11.1
Quality Assurance
58
11.2
Monitoring
58


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11.3
Clinical Study Agreement
58
11.4
Investigator (or Qualified Designee) Responsibilities
59
11.5
Clinical Product Complaints
59
11.5.1
Product Complaint Information Needed from the Investigational Center
59
11.5.2
Handling the IMP at the Investigational Center
60
11.5.3
Adverse Events or Serious Adverse Events Associated with a Product Complaint
60
11.5.4
Documenting a Product Complaint
60
SIGNATURE SHEET
61
DSM-IV TR CRITERIA FOR SUBSTANCE ABUSE
62
APPENDIX 1 SUMMARY OF CHANGE AND RATIONALE FOR PROTOCOL AMENDMENT 01 (16 
JULY 2012)
63
APPENDIX 2 SUMMARY OF CHANGE AND RATIONALE FOR PROTOCOL AMENDMENT 02 (18 
DECEMBER 2012)
66
APPENDIX 3 SUMMARY OF CHANGES AND RATIONALE FOR PROTOCOL AMENDMENT 03 (02 
FEBRUARY 2015)
67
APPENDIX 4 SUMMARY OF CHANGES AND RATIONALE FOR PROTOCOL AMENDMENT 04 
(25 AUGUST 2016)
89
APPENDIX 5 SUMMARY OF CHANGES AND RATIONALE FOR PROTOCOL AMENDMENT 05 
(29 JUNE 2017)
109
REFERENCES
178


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1.1
Protocol Synopsis
TITLE
A multi-center, North American, open-label extension 
study of pridopidine (ACR16) in the symptomatic 
treatment of Huntington’s disease (Open-HART).
PHASE
II
OBJECTIVES
The objective is to assess the long-term safety of pridopidine 
and to analyze treatment effects during long-term, open-label 
treatment.
The primary objective is to assess the long-term safety of 
pridopidine treatment and to collect information on UHDRS 
development during long-term, open-label treatment.
The exploratory objective is to evaluate patient and site staff 
satisfaction with virtual study visits and remote assessments 
administered in adult patients with Huntington’s disease (HD).
STUDY DURATION
The study will continue until: 

the investigational medicinal product (IMP)
has been 
authorized for marketing by the respective regulatory 
authority in Canada or the USA; or

the study is discontinued for medical/scientific (risk-benefit) 
or commercial reasons.
STUDY DESIGN
Multi-center, open-label study of pridopidine 45 mg bid for 
patients who completed the HART (ACR16C009) or PRIDE-HD 
(TV7820-CNS-20002) studies and who transitioned from the 
Open-HART pre-virtualization study period.
NUMBER OF 
PATIENTS
47
INCLUSION AND 
EXCLUSION 
CRITERIA 
Inclusion criteria

Patient is able to and has provided written Informed 
Consent prior to all study-related procedures.

[Revision 1] Patient has completed the HART (ACR16C009) 
or the PRIDE-HD (TV7820-CNS-20002) studies and had
remained on IMP during the full on-treatment part of the 
study (including de-escalated patients) or has transitioned 
from the Open-HART pre-virtualization study period. 

Patient is willing and able to take oral medication and able 
to comply with the study specific procedures.

Patient is not participating in another clinical study of an 
investigational intervention.

[New criterion] Patient has a wireless internet connection at 
home (and/or applicable locations) at the first remote visit.

[New criterion] Patient has the ability to transition from in-
person study visits to virtual study visits. The first remote
visit will take place within approximately 30 days after the 
last in-person visit. 
Exclusion criteria

[Revision 1] Ongoing treatment with tetrabenazine or 
deutetrabenazine, seizure threshold lowering medications, 


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or certain antipsychotics and antidepressants (see Protocol 
Section 5.7
and
current Operations Manual for list of 
disallowed medications). 

[Revision 2] Newly instigated or changed treatment with 
neuroleptics/anti-psychotics.

[Revision 3] Use of tricyclic antidepressants or class I & III
antiarrhythmics at any time during the study period.

[Revision 4] Any clinically significant, abnormal laboratory 
result,
including clinically significant hepatic or renal 
impairment, or any ongoing adverse event (AE) that, in the 
opinion of the investigator (or qualified designee), affects 
the patient’s suitability for the study or puts the patient at 
risk if he/she continues in the study.

[Revision 5] A prolonged QTc interval at the first remote
visit (defined as a QTcF interval of >450 ms for both males 
and females using Fredericia's formula) or other clinically 
significant heart conditions as judged by the investigator 
(or qualified designee). 

[Revision 6] Severe intercurrent illness that, in the opinion 
of the investigator (or qualified designee), may put the 
patient at risk when continuing participation in the study.

[Revision 7] Alcohol and/or drug abuse as defined by 
Diagnostic and Statistical Manual - Fourth Edition - Text 
Revision criteria for substance abuse – this includes the 
illicit use of cannabis.

Patients with AEs of suicidal ideation or attempt at any time 
in the past or as measured by a suicide ideation score of ≥3 
on the Columbia-Suicide Severity Rating Scale (C-SSRS) 
(who answer "Yes" to questions 3, 4, and 5 in the scale 
suicidal ideation section), or a score of ≥3 on the Problem 
Behaviors Assessment – Short Form (PBA-s), or patients 
who answer “Yes” on any of the 5 C-SSRS Suicidal Behavior 
Items 
(actual 
attempt, 
interrupted 
attempt, 
aborted 
attempt, preparatory acts, or behavior), if an attempt or 
acts were performed at any time in the past, or patients 
who, in the opinion of the investigator (or qualified 
designee), present a risk of suicide.

Patients with a known history of epilepsy or a history of 
febrile seizure(s) or seizure(s) of unknown cause.

Females who are pregnant or lactating. 

Females who are of child-bearing potential and not taking 
adequate contraceptive precautions (either oral, barrier, or 
chemical contraceptives) are excluded from the study. 
Females of child bearing potential taking acceptable 
contraceptive precautions can be included.

Known allergy to any ingredients of the study medication 
(Please refer to the Investigator Brochure (IB) for a full 
ingredient list).

[Revision 8] Creatinine clearance <60 mL/min at Virtual 
Transition Visit (VTV), calculated using the Cockcroft-Gault 
equation: (140-age) x mass (kg) x [0.85 if female]/72 x 
serum creatinine (mg/dL). It is allowed to repeat the test 
once, if clinically appropriate.


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TREATMENT:
Pridopidine 45 mg twice daily (bid) – two active 45 mg 
capsules taken as two separate doses (90 mg pridopidine per 
day).
ADMINISTRATION 
Oral. Capsules will be swallowed whole with water. One capsule 
should be taken early in the morning and one in the afternoon 
7 to 10 hours after the morning dose, irrespective of food. 
Dose frequency de-escalation to one morning capsule only is 
permitted if tolerability issues arise. Subsequent re-escalation 
to twice-daily dosing may take place. 
PROCEDURE
The signing of informed consent and the VTV will be held at 
the time of the patient’s last in-person Open-HART study visit
and within 30 days prior to the first remote visit (RV1). 
Patients may not transition from in-person visits to remote 
visits before signing informed consent.
After signing informed consent and confirmation of the ability 
to perform virtual study visits, patients will transition from in-
person study visits to remote visits in the Open-HART study.
During the VTV the patient will be asked to appoint a research 
proxy (see Section 9.2).
IMP
will be dispensed at the VTV. All subsequent IMP
dispensation will be shipped directly to the patient. 
Investigators (or qualified designees) will be trained on video 
conferencing equipment and remote connection techniques for 
administration of assessments prior to the patient’s first test
connection. Patients will be provided with a tablet for remote 
video conferencing visits after they have completed their last 
in-person visit and provided written informed consent. A test 
connection will be completed at the patient’s home (and/or 
applicable location) by the vendor prior to the first remote visit 
to ensure that the investigational site and patient video 
conferencing equipment are working properly.
The first remote visit (RV1) is to be completed within 
30 days of the VTV. This visit will be the first virtual visit of the 
study and will be completed via a remote video conference. 
Safety and tolerability will be assessed at all visits of treatment 
until the end of patient participation, including the follow-up 
and End-of-Study (EOS) visits. Assessments will be performed
according to Section 1.3.
Additional remote video visits will be performed at Weeks 26, 
52, and every 26 weeks thereafter (as well as for unscheduled 
visits [USVs]) until study discontinuation. During these virtual 
visits, inquiries about AEs, concomitant medication (including 
changes in use of benzodiazepines and antidepressants), 
changes in use of alcohol and drugs associated with substance 
abuse (legal or illicit),
an evaluation for
research study 
consent, C-SSRS collection, abbreviated PBA-s collection, and 


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the Unified Huntington’s Disease Rating Scale (UHDRS) will be 
conducted by the investigator (or qualified designee). The 
UHDRS will only be collected at virtual visits every 52 weeks
and at EOS/ET or USVs.
The abbreviated PBA-s will be 
collected at visits when the UHDRS (Behavior) is not collected.
Remote video visits will be accompanied by an in-person visit 
from a mobile nurse (within 7 days). Mobile nurses will perform 
safety 
laboratory 
tests, 
pregnancy 
tests, 
vital 
sign 
measurements, electrocardiograms, weight, and study drug 
accountability 
at 
the 
patient’s 
residence 
(and/or 
other 
applicable location) at the time points listed in Section 1.3.
Safety 
evaluation 
telephone 
contacts 
(TCs)
will 
be 
conducted by the investigator (or qualified designee) between 
remote visits at Weeks 13, 39, 65, 91, and every 13 weeks 
thereafter as well as at unscheduled visits (USVs). During 
these TCs, inquiries about AEs, concomitant medications
(including 
changes 
in 
use 
of 
benzodiazepines 
and 
antidepressants), changes in use of alcohol and drugs 
associated with substance abuse (legal or illicit), an evaluation 
for research study consent, C-SSRS collection,
and an
abbreviated PBA-s collection will be conducted by the 
investigator (or qualified designee). The investigator (or 
qualified designee) will also discuss study drug compliance with 
the patient during each TC. Assessments will be collected 
according to Section 1.3.
Patients who discontinue IMP due to safety or tolerability 
reasons, or the inability to complete virtual visits, may remain 
enrolled in the study without treatment at the discretion of the 
investigator (or qualified designee). Patients should complete 
the end-of-treatment (EOT) visit and continue with scheduled 
visits and assessments until the EOS or early termination (ET).
Patients who complete all scheduled visits (remote video and 
TC) will have procedures and assessments performed via 
remote video conference and mobile nurse visit at the EOS/ET 
visit. Patients who withdraw from the study before completing 
the treatment period will have the EOS visit (or ET) procedures 
and assessments performed at his/her final visit.
The end of study is defined as the last visit of the last patient.
All patients will be followed for safety via TCs.
Withdrawal from treatment
If the patient wishes to stop treatment, is judged by the 
investigator (or qualified designee)
to not be suitable for 
continued therapy, or the study is discontinued, a remote visit 
("withdrawal visit", ET visit) should be performed and the 
patient withdrawn from the study. A (telephone) follow-up visit 
(30 d TC follow-up) to collect and report AEs, concomitant 


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medications
(as well as inquiry about changes in use of 
benzodiazepines and antidepressants),
changes in use of 
alcohol and drugs associated with substance abuse (legal or 
illicit), C-SSRS, and an abbreviated PBA-s assessment should 
take place 1 month after the actual discontinuation of IMP took 
place.
Additional criteria for discontinuation of IMP
for individual 
patients are detailed in Section 7.7.1.
Patients who discontinue IMP due to safety or tolerability 
reasons may continue in the study off-IMP and perform the 
scheduled visits and assessments.
Unscheduled visits
may occur as needed and can be 
completed via remote video, in-person visit, or TC (TC will be 
the primary form of contact; remote video or in-person visits 
may be scheduled at the discretion of the investigator [or 
qualified designee]). An
USV
may be used to perform 
assessments per the investigator’s (or qualified designee’s) 
judgement. An USV may also be used to re-consent a patient if 
necessary.
If patients have concerns about the virtual nature of site visits, 
they may request an USV at the investigational center. The 
medical monitor will review individual requests and may 
approve 1 site USV per patient, per year. The assessments at 
site USVs will mirror those obtained during safety evaluation 
TCs 
(see 
Section 4.6.4). 
The 
investigator 
(or 
qualified 
designee) may schedule additional site visits on a case-by-case 
basis for patients that require closer monitoring due to safety 
events.
If a patient has tolerability problems or has to de-escalate the 
investigational 
treatment, 
the 
investigator 
(or 
qualified 
designee) can decide to call the patient to an unscheduled 
study visit at the investigational center. Patients should be 
advised that if tolerability problems continue, then they should 
contact their investigator (or qualified designee) who may then 
withdraw them from the IMP (EOT visit) (see Section 7.7.2).
If a patient attends an USV between the scheduled visits, they 
should be instructed to attend their next visit according to the 
study schedule as planned.
The study will be carried out in accordance with the study 
protocol, guidelines on the International Conference of 
Harmonization for Good Clinical Practice, appropriate Food and 
Drug Administration Code of Federal Regulations, and local 
regulatory requirements.
During the conduct of this study, an Internal Safety Committee 
will review accumulating safety data on a quarterly basis (or 


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meet ad-hoc if a safety concern arises, as detailed in the 
Internal Safety Committee charter), to ensure the continuing 
safety of the study patients and study conduct issues.
Patients excluded from the study due to lack of internet 
connection or inability to transition from in-person study visits 
to virtual study visits may be eligible to enroll in the 
Open-PRIDE-HD study (Study TV7820-CNS-20016).
STATISTICS
All reported adverse drug reactions will be tabulated. Safety 
statistics will be descriptive only. 


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1.2
Schedule of Assessments – Prior to Study Virtualization
 


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1.3
Schedule of Assessments – Following Study Virtualization
Study Period
Treatment Period
EOT1
EOS2
/ET
F/U
USV
3,4
Visit Number
RV1
TC1
RV2
TC2
RV3
TC3
RV4
TC4
RV5
RV
RV
TC
RV/ 
TC
Study Procedures and 
Assessments
VTV
Within 30 
days of 
VTV
Week 
13 
(±14 
days)
Week 
26 
(±14
days)
Week 
39
(±14
days)
Week 
52
(±14
days)
Week 
65
(±14
days)
Week 
78
(±14
days)
Week 91
(±14 days)
and every 
13 weeks 
(±14 days)
thereafter
Week 104
(±14 days)
and every 
26 weeks 
(±14 days)
thereafter
Week 
X
(±Y 
days)
Week 
X
(±Y 
days)
Week 
X
(±30
days)
Week 
X
(±Y 
days)
Remote Visit
X
X
X
X
X
X
X
X
Telephone Contact
X
X
X
X
X
X
Informed Consent5
X
X6
Designation of Research 
Proxy
X
Updated Medical History
X7
Eligibility Criteria
X
X
Evaluation for Research 
Study Consent
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Test Connection8
X
Mobile Device Kit
X
X
Training Review
X
Concomitant Medication 
Inquiry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Benzodiazepines and 
Antidepressants Inquiry9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Alcohol/Illicit Drug use 
Inquiry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
Weight
X
X
X
X
X
X
X
X
X
Vital Signs (HR, BP)10 11
X
X
X
X
X
X
X
X
X
12-lead ECG12
X
X
X
X
X
X
X
X
X
Pregnancy Test13
X
X
X
X
X
X
X
Safety Laboratory Tests 
10,14
X
X
X
X
X
X
X
X
X
Creatinine Clearance 
Calculation15
X
X
X
X
X
X
X
X
X
UHDRS16
X
X
X
X
X
X
X
AE Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Trial Code: ACR16C015
IND Number: IND 77,419
Protocol Version: FINAL 6.0
Date: 29 June 2017
Page 19 of 179
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Study Period
Treatment Period
EOT1
EOS2
/ET
F/U
USV
3,4
Visit Number
RV1
TC1
RV2
TC2
RV3
TC3
RV4
TC4
RV5
RV
RV
TC
RV/ 
TC
Study Procedures and 
Assessments
VTV
Within 30 
days of 
VTV
Week 
13 
(±14 
days)
Week 
26 
(±14
days)
Week 
39
(±14
days)
Week 
52
(±14
days)
Week 
65
(±14
days)
Week 
78
(±14
days)
Week 91
(±14 days)
and every 
13 weeks 
(±14 days)
thereafter
Week 104
(±14 days)
and every 
26 weeks 
(±14 days)
thereafter
Week 
X
(±Y 
days)
Week 
X
(±Y 
days)
Week 
X
(±30
days)
Week 
X
(±Y 
days)
C-SSRS17
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviated PBA-s18
X
X
X
X
X
X
X
Satisfaction Survey19
X
X
X
X
X
X
X
Dispense IMP and 
Instructions20
X
X
X
X
X
X
X
X
X
IMP Accountability21
X
X
X
X
X
X
X21
X21
IMP Compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
1 This visit will be undertaken in place of the Early Termination visit when a patient is no longer able to receive IMP for various reasons but 
wishes to remain in the study. Patients who discontinue IMP due to safety or tolerability reasons, or the inability to complete virtual visits, 
may remain enrolled in the study without treatment at the discretion of the investigator (or qualified designee). Patients should complete the 
EOT visit and continue with scheduled visits and assessments until the EOS or ET. For subsequent visits, these patients will follow the 
Schedule of Assessments for the remaining remote video/mobile nurse and safety evaluation telephone contact visits.
2 EOS is defined as the last visit of the last patient. All devices will be returned to the investigational center or vendor at the end of the study.
3 An USV may be performed at any time during the study as deemed necessary by the investigator (or qualified designee). The date and 
reason for an USV will be recorded. Reasons for USVs may include, but are not limited to, need for blood draw for safety labs, a potential 
severe side effect, worsening of symptoms, etc. The following assessments are required at an USV: AE review and concomitant medication
inquiry. Other assessments to be done at the discretion of the investigator (or qualified designee). The primary form of contact will be a TC, 
but video assessments and in-person visits may be scheduled at the discretion of the investigator (or qualified designee).
4 For patients with concerns about the virtual nature of site visits, 1 site USV per year may take place at the investigational site that follows
the assessments required for the safety evaluation TCs. The medical monitor will review individual requests for site visits and approve visits if 
deemed necessary. The investigator (or qualified designee) may schedule additional site visits on a case-by-case basis for patients that 
require closer monitoring due to safety events.
5 Patients will complete the informed consent at their last in-person Open-HART study visit/VTV.
6 An USV may also be scheduled to re-consent patients (if necessary).
7 Medical history collected prior to study virtualization will remain in a separate database while updated medical history will be collected at 
VTV.
8 Test connections are to be completed at home (and/or applicable location) by the vendor prior to the first remote visit to ensure remote 
video conferencing equipment functionality.
9 Information on benzodiazepines and antidepressants will be collected as part of the concomitant medication inquiry.
10 The mobile nurse will complete the collection of safety laboratory tests, measurement of ECGs, and vital signs at home (and/or applicable 
location).
11 Vital signs measurements include HR, BP, and weight.


Trial Code: ACR16C015
IND Number: IND 77,419
Protocol Version: FINAL 6.0
Date: 29 June 2017
Page 20 of 179
Open-HART Protocol with Amendment 05
12 ECGs will be performed every 6 months unless a safety signal is detected. If a safety signal is detected, the mobile nurse will measure 
ECGs every 3 months. An ECG safety signal is defined as a QTcF ≥480 ms and ≤500 ms (≥60 ms increase from VTV).
13 Urine pregnancy tests are to be performed as applicable based on gender and menopausal status. Serum pregnancy tests must be used to 
confirm a positive urine pregnancy test result.
14 Safety laboratory tests include potassium, magnesium, calcium, and creatinine clearance.
15 Creatinine clearance will be calculated using the Cockcroft-Gault equation. Patients that de-escalate to half-doses of IMP will have 
creatinine clearance monitored more frequently than patients at the full dose, as determined by the investigator (or qualified designee).
16 UHDRS includes Motor Assessment, Cognitive Assessment (Stroop Interference, Verbal Fluency, and Symbol Digit Modalities Test), 
Behavioral Assessment, Functional Assessment, Independence Scale, Total Functional Capacity, and Summary sections. UHDRS Motor exam 
will be modified as portions will be considered “unable to rate” (such as rigidity, tandem walking, and retropulsion pull test tasks).
17 The C-SSRS "Since Last Visit" version will be utilized at all visits. If the patient scores >2 on the C-SSRS for suicidal ideation, the safety 
TCs should be performed monthly or bi-monthly per investigator (or qualified designee) judgement.
18 The safety TCs and remote visits will include an abbreviated PBA-s assessment (a subset of PBA-s questions on depressed mood, suicidal 
ideation, anxiety, irritability, loss of motivation, and obsessive-compulsive behaviors) when the UHDRS is not completed.
19 Separate Satisfaction Surveys will be administered to patients and investigators (or qualified designees).
20 Dispensing of IMP after the VTV will occur as direct-to-patient shipments at approximately 13-week intervals.
21 The mobile nurse will perform IMP accountability at each home visit. IMP (unused and used packaging) will be collected by mobile nurses at 
each mobile nurse visit and shipped back to the distributor. All unused IMP will be returned.
Abbreviations: AE=adverse event; BP=Blood Pressure; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiograph; EOS=End 
of study; EOT=End of treatment; ET=Early termination; F/U=Follow-up visit; HR=Heart Rate; PBA-s=Problem Behaviors Assessment–Short 
Form; QTcF= QT interval corrected for heart rate using Fredericia’s formula; RV=Remote visit; TC=Telephone contact; UHDRS=Unified 
Huntington’s Disease Rating Scale; USV=Unscheduled Visit; VTV=Virtual Transition Visit.


Trial Code: ACR16C015
IND Number: IND 77,419
Protocol Version: FINAL 6.0
Date: 29 June 2017
Page 21 of 179
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1.4
List of Abbreviations
AE
Adverse Event
bid
Twice Daily
CFR
Code of Federal Regulations
CI
Confidence Interval
Cmax
Maximum Concentration
CMSU
Clinical Materials Services Unit
CRO
Contract Research Organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CTCC
Clinical Trials Coordination Center
CYP2D6
Cytochrome P450 2D6
D2R
Dopamine D2 Receptor
DSMB
Data Safety Monitoring Board
DSM-IV-TR
Diagnostic and Statistical Manual – Fourth Edition – Text Revision
DTP
Direct-to-patient
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EM
Extensive Metabolizers
EOS
End of Study
EOT
End of Treatment
ET
Early Termination
FDA
Food and Drug Administration
F/U
Follow-up
GCP
Good Clinical Practice
HART
ACR16C009: A Multi-center, Randomized, Double-blind, Parallel-group 
Study Comparing Three Doses of ACR16 Versus Placebo for the 
Symptomatic Treatment of Huntington’s Disease. IND: 77,419.
HD
Huntington’s Disease
HDPE
High-density Polyethylene
HSG
Huntington Study Group
HTT
Huntingtin Gene
IB
Investigator’s Brochure
IC50
Half Maximal Inhibitory Concentration
ICF
Informed Consent Form
ICH
International Council on Harmonisation
ID
Identification
IMP
Investigational Medicinal Product
IND
Investigational New Drug
IRB
Institutional Review Board
IRT
Interactive Response Technology
MermaiHD
ACR16C008: A Multi-center, Multi-national, Randomized, Double-blind, 
Parallel-group Study Comparing ACR16 45 mg Once-daily or Twice-daily 
Versus Placebo for the Symptomatic Treatment of Huntington’s Disease –
Randomized Phase. EudraCT: 2007-004988-22.
mMS
Modified Motor Score
mPPT
Modified Physical Performance Test
MTD
Maximal Tolerated Dose
PBA-s
Problem Behaviors Assessment – Short Form
PDF
Portable Document Format
PET
Positron Emission Tomography


Trial Code: ACR16C015
IND Number: IND 77,419
Protocol Version: FINAL 6.0
Date: 29 June 2017
Page 22 of 179
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PK
Pharmacokinetics
PM
Poor Metabolizers
PRIDE-HD
A Phase 2, Dose-finding, Randomized, Parallel-group, Double-Blind, 
Placebo-controlled Study, Evaluating the Safety and Efficacy of Pridopidine 
45 mg, 67.5 mg, 90 mg, and 112.5 mg Twice-Daily Versus Placebo for 
Symptomatic Treatment in Patients with Huntington’s Disease (TV7820-
CNS-20002) EudraCT: 2013-001888-23; IND 77,419
qD
Once Daily
QTcF
QT Interval Corrected for Heart Rate using Fredericia’s Formula
REB
Research Ethics Board
RV
Remote Visit
RV1
First remote visit
S1R
Sigma-1 Receptor
SAE
Serious Adverse Event
TC
Telephone Contact
TFC
Total Functional Capacity
UHDRS
Unified Huntington’s Disease Rating Scale
UHDRS-TMS
Unified Huntington’s Disease Rating Scale-Total Motor Score
UID
Unique Identification
US/USA
United States of America
USV
Unscheduled Visit 
VTV
Virtual Transition Visit


Trial Code: ACR16C015
IND Number: IND 77,419
Protocol Version: FINAL 6.0
Date: 29 June 2017
Page 23 of 179
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2
BACKGROUND AND RATIONALE
2.1
Background
Huntington’s
disease (HD) is a fatal neurodegenerative disorder with an autosomal 
dominant mode of inheritance (Quinn and Schrag 1998). HD is caused by a 
cytosine-adenine-guanine triplet repeat expansion in the huntingtin gene (HTT), which 
results in an expanded polyglutamine stretch in the HTT protein (Huntington's Disease 
Collaborative Research Group 1993).
HD is characterized by progressive cognitive decline, psychiatric and behavioral symptoms, 
and a movement disorder syndrome often including choreiform movements. The age of 
onset of the signs and symptoms of HD and the rate of disease progression can vary 
greatly. Adult onset HD most often begins between 30 and 40 years of age. The illness 
generally lasts 15 to 20 years and is fatal. Following diagnosis, motor and cognitive 
functions steadily decline, ultimately leading to a state of immobility, dementia, and 
premature death (Ross and Tabrizi 2011). Psychiatric and behavioral symptoms often start 
before the onset of motor symptoms, but may also develop with the progression of disease. 
Not all individuals with HD experience the same psychiatric symptoms, which commonly 
include anxiety, depression, obsessive-compulsive behaviors,
and personality change. 
Patients with HD commit suicide 4 to 8 times more often than the general population (Farrer 
1986, Schoenfeld et al 1984). All patients with HD also have progressive cognitive 
impairment that is often characterized by executive dysfunction, especially early in the 
disease, but other cognitive realms are also affected, including learning and memory, motor 
planning, processing speed, attention, visuospatial processing, timing, emotion processing, 
and working memory. Cognitive impairment is a major contributor to disability among 
patients with HD (Ross et al 2014) and is associated with meaningful decrement in 
functional capacity, driving proficiency, ability to conduct accustomed work, and quality of 
life (Paulsen and Long 2014).
Pridopidine (TV-7820; formerly ACR16 and ASP2314) is an investigational, oral small 
molecule in development for the treatment of HD under investigational new drug (IND) 
application 077419. Pridopidine has been granted orphan drug designation both in the US 
(12 December 2005, Orphan Designation No. 05-2139) and the European Union 
(EU/3/05/288) as a treatment for adults with HD. It was originally described as a dopamine 
stabilizer, with effects regulating dopamine-dependent behaviors. 
 
 
 
 
 
 
 
 
Low affinities of 
pridopidine were also found for several other central nervous system receptor targets (in 
addition to the D2R), including serotonin 5-HT1A, 5-HT2A, and 5-HT7, adrenergic alpha-1, 
alpha-2A, and alpha-2C, dopamine D3, muscarinic M2, and histamine H3 (Studies 942038, 
942027, and DPR-2014-055), all in the micromolar range (similar to its affinity towards 
D2R). However, recent studies show that pridopidine has ~100-fold higher affinity for the 
sigma-1 receptor (S1R; IC50 ~ 100nM) (Sahlholm et al 2013; DPR-2014-055).
Receptor occupancy for the S1R and D2R has been evaluated using in vivo positron 
emission tomography (PET) imaging in the rat. The PET imaging confirmed that pridopidine 
occupies the S1R at low doses (≤15 mg/kg) and the D2R at higher doses (more than 


Trial Code: ACR16C015
IND Number: IND 77,419
Protocol Version: FINAL 6.0
Date: 29 June 2017
Page 24 of 179
Open-HART Protocol with Amendment 05
15 mg/kg) (Sahlholm et al 2015). After assessing receptor occupancy using (i) known 
binding affinities of pridopidine to human and rodent S1R and D2R in vitro, (ii) in vivo PET 
imaging in rats, and (iii) the extensive pharmacokinetic (PK) profiling of pridopidine in the 
different species, the clinical dose of 45 mg twice daily (bid) is expected to occupy 60% to 
85% of S1R and <30% of the D2R. It is speculated that at the low 45 mg bid dose, 
pridopidine's effect is mainly mediated by the S1R, while at higher doses a more complex 
activity of pridopidine is initiated by binding to additional low affinity receptors.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
As of January 2017, over 1260 subjects (206 of which were healthy volunteers) have been 
exposed to various oral daily doses of pridopidine in completed and ongoing clinical studies. 
The majority of the safety database is composed of the HD patients from the HART, 
MermaiHD, and PRIDE-HD double-blind, placebo-controlled studies (and their corresponding 
extensions) who received various doses of pridopidine for varying durations for a total of 
958.7 patient years. 
An integrated safety analysis of the HART, MermaiHD, and PRIDE-HD studies was performed 
according to the 7 dose groups (placebo, 10 mg bid, 45 mg once daily (qd), 45 mg bid, 
67.5 mg bid, 90 mg bid, and 112.5 mg bid) investigated in these studies. Based on the 
large safety database, the adverse event (AE) profile of pridopidine 45 mg bid is benign and 
comparable with placebo. 
 
 
 
Thus, the 45 mg bid dose has a favorable safety and tolerability profile compatible with 
continuing development.
2.2
Rationale for Primary Objective and Study Design
The long-term safety profile of pridopidine is not known. For patients previously having 
taken part in a clinical study, an open-label observational study is the most appropriate 
study design.


Trial Code: ACR16C015
IND Number: IND 77,419
Protocol Version: FINAL 6.0
Date: 29 June 2017
Page 25 of 179
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2.3
Rationale for Dosage Used
Patients entering this study were treated with either 0 (placebo), 10, 22.5 or 45 mg 
pridopidine bid in the HART study, or 0 (placebo), 45, 67.5, 90, or 112.5 mg pridopidine bid 
in the PRIDE-HD study. 
The proposed dose selected for this study is pridopidine 45 mg bid. The proposed dose has 
been evaluated in 3 large HD clinical studies (HART, MermaiHD, and PRIDE-HD) as well as 
2 open-label extension studies (Open-HART and Open-PRIDE-HD) and has been generally
well tolerated. In PRIDE-HD, 45 mg bid was the lowest of 4 doses evaluated. 
 
 
 
 
Thus, from a benefit-risk perspective, the Sponsor sees no benefit in 
continuing to explore doses higher than 45 mg bid. 
 
 
 
 Thus, the Sponsor sees no 
therapeutic benefit at exploring doses lower than 45 mg bid.
Both pharmacokinetic data and clear dose-dependent and exposure-dependent QTc findings 
in PRIDE-HD rule out systematic dosing errors. While the HART and MermaiHD studies had 
explored the clinical profile of doses up to 45 mg bid, PRIDE-HD was designed to test the 
high end of exposure on potential clinical benefit (Food and Drug Administration [FDA] Type 
C meeting; 24 July 2013).
The integrated safety analysis and large safety database from the double-blind, placebo-
controlled HART, MermaiHD, and PRIDE-HD studies indicated that the AE
profile of 
pridopidine 45 mg bid is generally well tolerated and comparable with placebo. 
 
 
 
 
 
 
 
The integrated analysis of data from the double-blind, placebo-controlled HART, MermaiHD, 
and PRIDE-HD studies indicated the following: 

 
 
 
 
 
 
 


Trial Code: ACR16C015
IND Number: IND 77,419
Protocol Version: FINAL 6.0
Date: 29 June 2017
Page 26 of 179
Open-HART Protocol with Amendment 05
3
OBJECTIVES
The objective is to assess the long-term safety of pridopidine and to analyze treatment 
effects during long-term, open-label treatment.
3.1
Primary Objectives
The primary objectives are to assess the long-term safety of pridopidine treatment and to 
collect information on Unified Huntington’s Disease Rating Scale (UHDRS) development 
during long-term, open-label treatment.
3.2
Exploratory Objective
The exploratory objective is to evaluate patient and site staff satisfaction with virtual study 
visits and remote assessments administered in adult patients with HD.
4
STUDY DESIGN
This is a multi-center, open-label study of pridopidine 45 mg bid for patients who completed
the HART or PRIDE-HD studies and who transitioned from the Open-HART pre-virtualization 
study period.
4.1
Centers
Multiple Huntington Study Group (HSG) sites will take part in the virtual aspect of this 
ongoing study in the US and Canada.
4.2
Patient and Unique Identification Numbers
Each patient is provided a patient identification number. These numbers are used in 
consecutive order by the site from the site-specific patient identification list provided to the 
site by the Clinical Trials Coordination Center (CTCC); this four-digit number will identify 
patients on all study documents and lab specimens. All PRIDE-HD patients have been 
provided with a new patient identification (ID) number. Patient ID numbers will be 
documented in the database for future reference. Each patient has a CTCC Unique ID 
Number that was issued during the HART (ACR16C009) or PRIDE-HD study (TV7820-CNS-
20002). This number will enable the CTCC to track individual patients across multiple 
studies without storing any personally identifiable information.
4.3
Recruitment
This study is open to all patients who have successfully completed the HART (ACR16C009)
or PRIDE-HD (TV7820-CNS-20002)
studies
and transitioned from the Open-HART 
pre-virtualization study period. No other patients will be recruited into the study.
4.4
Inclusion Criteria

Patient is able to and has provided written Informed Consent prior to all study-related 
procedures.

[Revision 1] Patient has completed the HART (ACR16C009) or the PRIDE-HD (TV7820-
CNS-20002) studies and had remained on IMP during the full on-treatment part of the 
study
(including de-escalated patients)
or has transitioned from the Open-HART 
pre-virtualization study period. 

Patient is willing and able to take oral medication and able to comply with the study 
specific procedures.

Patient is not participating in another clinical study of an investigational intervention.


Trial Code: ACR16C015
IND Number: IND 77,419
Protocol Version: FINAL 6.0
Date: 29 June 2017
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
[New criterion] Patient has a wireless internet connection at home (and/or applicable 
locations) at the first remote visit.

[New criterion] Patient has the ability to transition from in-person study visits to virtual 
study visits. The first remote visit (RV1) will take place within approximately 30 days 
after the last in-person visit. 
4.5
Exclusion Criteria

[Revision 1] Ongoing treatment with tetrabenazine
or deutetrabenazine, seizure 
threshold 
lowering 
medications, 
or 
certain 
antipsychotics 
and 
antidepressants
(see Protocol Section 5.7
and
current Operations Manual for list of disallowed 
medications).

[Revision 2] Newly instigated or changed treatment with neuroleptics/anti-psychotics.

[Revision 3] Use of tricyclic antidepressants or class I & III antiarrhythmics at any time 
during the study period.

[Revision 4] Any clinically significant, abnormal laboratory result, including clinically 
significant hepatic or renal impairment, or any ongoing AE that, in the opinion of the 
investigator (or qualified designee), affects the patient’s suitability for the study or puts 
the patient at risk if he/she continues in the study.

[Revision 5] A prolonged QTc interval at the RV1 (defined as a QTcF interval of >450 ms 
for both males and females using Fredericia's formula) or other clinically significant heart 
conditions as judged by the investigator (or qualified designee).

[Revision 6] Severe intercurrent illness
that,
in the opinion of the investigator 
(or qualified designee), may put the patient at risk when continuing participation in the 
study.

[Revision 7] Alcohol and/or drug abuse as defined by the Diagnostic and Statistical 
Manual - Fourth Edition - Text Revision criteria for substance abuse – this includes the 
illicit use of cannabis.

Patients with AEs of suicidal ideation or attempt at any time in the past or as measured 
by a suicide ideation score of ≥3 on the Columbia-Suicide Severity Rating Scale 
(C-SSRS) (who answer "Yes" to questions 3, 4, and 5 in the scale suicidal ideation 
section), or a score of ≥3 on the Problem Behaviors Assessment – Short Form (PBA-s), 
or patients who answer “Yes” on any of the 5 C-SSRS Suicidal Behavior Items (actual 
attempt, interrupted attempt, aborted attempt, preparatory acts, or behavior), if an
attempt or acts were performed at any time in the past, or patients who, in the opinion 
of the investigator (or qualified designee), present a risk of suicide.

Patients with a known history of epilepsy or a history of febrile seizure(s) or seizure(s) of 
unknown cause.

Females who are pregnant or lactating. 

Females who are of child bearing potential and not taking adequate contraceptive 
precautions (either oral, barrier, or chemical contraceptives) are excluded from the 
study. Females of child-bearing potential taking acceptable contraceptive precautions 
can be included. 

Known allergy to any ingredients of the study medication (Please refer to
the
Investigator Brochure (IB) for a full ingredient list).

[Revision 8] Creatinine clearance <60 mL/min at virtual transition visit (VTV), calculated 
using the Cockcroft-Gault equation: (140-age) x mass (kg) x [0.85 if female]/72 x 
serum creatinine (mg/dL). It is allowed to repeat the test once, if clinically appropriate.
4.6
Conduct of the Study
The ACR16C015 (Open-HART) open-label extension study began in 2011 and has been 
ongoing in the United States and Canada (see Appendix 1) to evaluate the long-term safety
and tolerability of pridopidine administered at a dose of 45 mg bid in adult patients with HD 


Trial Code: ACR16C015
IND Number: IND 77,419
Protocol Version: FINAL 6.0
Date: 29 June 2017
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who completed the treatment period of the HART or PRIDE-HD studies. The primary reason 
for this amendment is to evaluate the feasibility of virtual study conduct and remote 
assessments administered in adult patients with HD receiving pridopidine 45 mg bid. All 
clinical sites will conduct study assessments remotely. The study will consist of a VTV, an 
open-label treatment period, and a follow-up period (30 days after end of treatment). The 
study will continue under the same study number; however, all patients will have to be 
re-consented regardless of their current study status. A CRO will provide oversight and 
many functions will be performed centrally. The study will include both remote visits and 
safety telephone contacts (TC). Remote visits will be considered “virtual” visits and will be 
conducted by investigators (or qualified designees) via real-time video conferencing. Other 
procedures will be performed by qualified nurses who will visit the patients' homes (and/or 
applicable locations).
If patients have concerns about the virtual nature of the site visits, they may request an 
unscheduled visit (USV) at the investigational center. The medical monitor will review 
individual requests and may approve 1 site USV per patient, per year. The assessments at 
site USVs will mirror those obtained during safety evaluation TCs (see Section 4.6.4). The 
investigator (or qualified designee) may schedule additional site visits on a case-by-case 
basis for patients that require closer monitoring due to safety events.
Patients excluded from the study due to lack of internet connection or inability to transition 
from in-person study visits to virtual study visits may be eligible to enroll in the 
Open-PRIDE-HD study (Study TV7820-CNS-20016).
4.6.1
Virtual Transition Visit
The signing of an informed consent form (ICF) and the VTV will be held at the time of the 
patient’s last in-person Open-HART study visit and within 30 days prior to the RV1. Patients 
may not transition from in-person visits to remote visits before signing informed consent.
After signing informed consent and confirmation of the ability to perform virtual study visits, 
patients will transition from in-person study visits to remote visits in the Open-HART study.
During the VTV the patient will be asked to appoint a research proxy (see Section 9.2)
IMP will be dispensed at the VTV. All subsequent IMP dispensation will be shipped directly to 
the patient. 
Investigators (or qualified designees) will be trained on video conferencing equipment and 
remote connection techniques for administration of assessments prior to the patient’s first 
test connection. Patients will be provided with a tablet for remote video conferencing visits 
after they have completed their last in-person visit and provided written informed consent. 
A test connection will be completed at the patient’s home (and/or applicable location) by the 
vendor prior to the RV1
to ensure that the investigational site and patient video 
conferencing equipment are working properly.
4.6.2
First Remote Visit
The RV1 is to be completed within 30 days of the VTV. This visit will be the first virtual visit 
of the study and will be completed via remote video conferencing. Safety and tolerability will 
be assessed at all visits of treatment until the end of patient participation, including the 
follow-up and End-of-Study (EOS) visits. Assessments will be performed according to 
Section 1.3.


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4.6.3
Remote Video and Mobile Nurse Visits
Additional remote video visits will be performed at Weeks 26, 52, and every 26 weeks 
thereafter (as well as for USVs) until study discontinuation. During these virtual visits, 
inquiries about AEs, concomitant medication (including changes in use of benzodiazepines 
and antidepressants), changes in use of alcohol and drugs associated with substance abuse 
(legal or illicit); an evaluation for research study consent; C-SSRS collection; abbreviated 
PBA-s collection (a subset of PBA-s questions on depressed mood, suicidal ideation, anxiety, 
irritability, loss of motivation, and obsessive-compulsive behaviors); and the UHDRS will be 
conducted by the investigator (or qualified designee). The UHDRS will only be collected at 
remote visits every 52 weeks and at EOS/ET or USVs. The abbreviated PBA-s will be 
collected at visits when the UHDRS (Behavior) is not collected.
Remote video visits will be accompanied by an in-person visit from a mobile nurse (within 
7 days). Mobile nurses will perform safety laboratory tests, pregnancy tests, vital sign 
measurements, ECGs, weight, and IMP accountability at the patient’s residence (and/or 
other applicable location) at the time points listed in Section 1.3. 
4.6.4
Safety Evaluation Telephone Contacts
Safety evaluation TCs will be conducted by the investigator (or qualified designee) between 
remote visits at Weeks 13, 39, 65, 91, and every 13 weeks thereafter as well as at 
unscheduled visits (USVs). During these TCs, inquiries about AEs, concomitant medication 
(including changes in the use of benzodiazepines and antidepressants), changes in use of 
alcohol and drugs associated with substance abuse (legal or illicit), an evaluation for 
research study consent, C-SSRS collection, and abbreviated PBA-s collection will be 
conducted by the investigator (or qualified designee).
The investigator (or qualified 
designee) will also discuss IMP compliance with the patient during each TC. Assessments 
will be collected according to Section 1.3.
4.6.5
Unscheduled Visit(s)
USVs may occur as needed and can be completed via remote video, in-person visit, or TC 
(TC will be the primary form of contact; remote video or in-person visits may be scheduled 
at the discretion of the investigator [or qualified designee]). The USV may be used to 
perform assessments per the investigator’s (or qualified designee’s) judgement.
The
following assessments are required at an USV: AE review and concomitant medication 
inquiry. An USV may also be used to re-consent a patient, if necessary.
If patients have concerns about the virtual nature of site visits, he/she may request an USV
at the site. The medical monitor will review individual requests and may approve 1 site USV
per patient per year. The assessments at site USVs will mirror those obtained during safety 
evaluation TCs (see Section 4.6.4). The investigator (or qualified designee) may schedule 
additional site visits on a case-by-case basis for patients that require closer monitoring due 
to safety events.
If a patient has tolerability problems, or has to de-escalate the investigational medicinal 
product (IMP), the investigator (or qualified designee) can decide to call the patient to an 
USV at the investigational center. Patients should be advised that if tolerability problems 
continue, then they should contact their investigator (or qualified designee) who may then 
withdraw them from the IMP (see Section 7.7.2).
If a patient attends an USV between the scheduled visits, they should be instructed to 
attend their next visit according to the study schedule as planned.


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4.6.6
End of Treatment Visit
This visit will be completed in place of the Early Termination (ET) visit when a patient is no 
longer able to receive IMP for various reasons but wishes to remain in the study. Patients 
who discontinue IMP due to safety or tolerability reasons, or the inability to complete virtual 
visits, may remain enrolled in the study without treatment at the discretion of the 
investigator (or qualified designee). Patients should complete the end-of-treatment (EOT)
visit and continue with scheduled visits and assessments until the end of study (EOS) or ET.
For subsequent visits, these patients will follow the Schedule of Assessments for the 
remaining remote video/mobile nurse and safety evaluation TC visits.
4.6.7
End of Study/Early Termination Visit
Patients who complete all scheduled visits (remote video and TC) will have procedures and 
assessments performed via remote video conference and mobile nurse visit at the EOS/ET 
visit. Patients who withdraw from the study before completing the treatment period will 
have the EOS visit (or ET) procedures and assessments performed at his/her final visit.
The end of study is defined as the last visit of the last patient.
4.6.8
Follow-up
All patients will be followed for safety via TCs.
4.6.9
Withdrawal From Treatment
If the patient wishes to stop treatment, is judged by the investigator (or qualified designee)
to not be suitable for continued therapy, or the study is discontinued, a remote visit 
("withdrawal visit", ET visit) should be performed and the patient withdrawn from the study. 
A (telephone) follow-up visit (30 d TC follow up) to collect and report AEs, concomitant 
medications
(as well as inquiry about changes in use of benzodiazepines and 
antidepressants), changes in use of alcohol and drugs associated with substance abuse 
(legal or illicit), C-SSRS, and an abbreviated PBA-s assessment should take place 1 month 
after the actual discontinuation of IMP took place.
Additional criteria for discontinuation of IMP
for individual patients are detailed in
Section 7.7.1.
Patients who discontinue IMP due to safety or tolerability reasons may continue in the study 
off IMP and perform the scheduled visits and assessments.
4.6.10
Study Duration
The study will continue until:

the IMP has been authorized for marketing by the respective regulatory authority in
Canada or the US; or

the study is discontinued for medical/scientific (risk-benefit) or commercial reasons.
4.7
Definition of Assessments
4.7.1
UHDRS
Components of the UHDRS (Huntington Study Group, 1996) will be assessed, as detailed 
below. All UHDRS components will be assessed in-person at the VTV, and some components 


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will be assessed virtually at the remote visits (RV1, RV3, and RV5) and the EOS/ET and EOT
visits, as well as at any USVs, as needed.
4.7.1.1 Motor
The UHDRS motor assessment comprises 31 assessments from the 15 items, with each
assessment
rated
on
a
5-point
scale
from
0
(normal)
to
4
(maximally
abnormal)
(Huntington Study Group, 1996). A modified motor UHDRS will be done, excluding the 
rigidity, tandem walking, and retropulsion pull test tasks.
4.7.1.2 Function
The functional assessment battery of the UHDRS will be administered. The functional 
assessment scale assesses 25 items associated with functional problems (Huntington Study 
Group, 1996).
This scale assesses 5 functional domains associated with disability (occupation, domestic 
chores, activities of daily living, care level). Individual domain scores range from 2 or 3 
(fully functional) to 0 (severely disable), with a total of 13 points possible (Huntington Study 
Group, 1996).
4.7.1.3 Behavior
This scale measures the frequency and severity of symptoms related to affect, thought
content and coping styles. The total behavioral score is the sum of the product (frequency
score multiplied by severity score) of all responses. Individual subscales for the various
components of the behavioral rating are the product (frequency score multiplied by severity
score) for the individual question (Huntington Study Group, 1996).
4.7.1.4 Independence
This is a rating scale where a patient’s degree of independence is given in percentage (from
0 to 100%); 100% indicated no special care needed and 0% indicated total care required
(Huntington Study Group, 1996).
4.7.1.5 Cognition
The UHDRS Cognitive assessment battery consists of the Stroop Interference Test, Verbal
Fluency Examination, and Symbol Digit Modalities Test.
Stroop Interference Test
The
Stroop
Interference
test
(Stroop, 1935)
measures
the
ability
of
the
patient
to
concentrate and ward off distractions. The test consists of 3 items; naming color rectangles
(red, green, or blue), reading color words written in black, and naming the color of the ink
of incongruent color words. Each test comprises 100 stimuli presented on a card. The test is
scored as the number of correct responses made in 45 seconds.
Verbal Fluency Examination
The verbal fluency examination is part of the cognitive assessment battery of the UHDRS.
This test constitutes the Controlled Oral Word Association Test (Benton et al 1976). This
examination consists of a phonological fluency test. The purpose of the test is to examine
the ability of the patient to produce a series of words in response to their phonological
characteristics, specifically their first letter. The patient is asked to produce as many
responses as possible to a specific letter for 60 seconds. The letters will be appropriate for
the language used.


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Symbol Digit Modalities Test
The symbol digit modalities test is part of the cognitive assessment battery of the UHDRS.
This test constitutes a digit symbol test (Smith, 1968). The patient is given a template of
symbols corresponding to the digits 1-9. The patient has then 90 seconds to write as many
correct responses as possible.
4.7.2
Columbia-Suicide Severity Rating Scale 
The C-SSRS is a 2-page questionnaire designed to systematically and prospectively assess 
and track suicidal AEs (behavior and ideation) throughout clinical studies.
4.7.3
Problem Behaviors Assessment – Short Form
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 et al 
2001; Kingma et al 2008).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 
everyday); and 4 = all day, every day. Severity and frequency scores are multiplied to 
produce an overall ‘PBA score’ for each symptom.
Only the abbreviated PBA-s (i.e. items of the PBA-s relevant to suicidality [depressed mood, 
suicidal ideation, anxiety, irritability, loss of motivation, obsessive-compulsive behaviors]) 
will be collected during the TCs and virtual visits when the UHDRS is not completed. If the 
patient has a positive score 1 and 2 on the suicidal ideation item or depressed mood item of 
the PBA-s, the patient will be monitored more closely and treated according to the 
investigator’s (or qualified designee’s) medical judgment. Patients with C-SSRS or PBA-s 
suicidality scores 1 and 2 may be handled by investigator (or qualified designee)/neurologist 
with a consultancy with psychiatrist(s) where necessary per investigator’s (or qualified 
designee’s) medical judgement.
A referral for psychiatric evaluation is required for AE/serious adverse event (SAE) of 
suicidal ideation/suicidal attempt or significant increase in the suicidality scale from baseline 
(e.g. 2 point increase or higher) or C-SSRS (who answer "Yes" to questions 3, 4, and 5 in 
the scale suicidal ideation section) or PBA-s suicidality score 3 and above. All patients with 
PBA-s suicidal ideation item score ≥3 (i.e. 3, 4) will be discontinued from treatment with 
IMP. Patients who are discontinued from IMP may continue their participation in the study 
and perform the scheduled visits and assessments, while off IMP. They will continue to be 
closely monitored by the investigator (or qualified designee) and will be referred for 
psychiatric evaluation per the investigator’s (or qualified designee’s) medical judgment.
4.8
Protection of Clinical Study Patients
Informed consent will be obtained from each patient prior to initiation of any study activity.


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Designation of a research proxy will be provided by the research patient; the research proxy
will be involved in the patient’s study participation if the investigator (or qualified designee)
determines at some point the patient is no longer able to make decisions independently.
5
INVESTIGATIONAL MEDICINAL PRODUCT
5.1
Assignment of Treatment
All patients will receive pridopidine (TV-7820, formerly ACR16) 45 mg bid – two active 
45 mg capsules taken as two separate doses (90 mg pridopidine per day).
5.2
Products
All products supplied in connection with this study must be used only for this and no other
purpose.
All IMP must be stored in a cool dry place below 25oC. IMP must not be frozen or 
refrigerated.
It is the responsibility of the investigator (or qualified designee) via the mobile nurse to
retrieve all unused and all returned used supplies from the patient and to return the
supplies to the distributor.
5.2.1
Study Drug
Company Name:
Pridopidine (TV-7820, formerly ACR16)
Chemical name:
4-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride
Presentation:
White hard gelatin capsules or light pink/white imprinted capsules
providing 45 mg pridopidine
5.2.2
Placebo
Not applicable.
5.2.3
Control Medication
Not applicable.
5.3
Dosage and Administration
The dose in this study is 45 mg bid. The IMP should be swallowed whole with water.
Sufficient IMP will be provided to allow 100% compliance between visits.
The IMP will be dispensed in-person at the VTV and in DTP shipments at 3-month intervals 
thereafter. Patients may be offered to take the first dose at the investigational center.
5.3.1
Dose Frequency Reduction
In the event of tolerability problems, patients will be instructed to immediately contact their
investigator (or qualified designee) to discuss their AEs. The investigator (or qualified 
designee) will assess whether or not the AEs could be related to IMP and severe enough to
warrant a dose frequency reduction. The patients will be instructed to stop taking 1 of the
2 capsules of their daily dose. Arrangements for an USV at the earliest opportunity will be
made (see Section 4.6.5). At this visit patients will be provided with instructions regarding
the de-escalated dose frequency. Alternatively, patients may be temporarily off drug up to 
60 days per year in the event of tolerability problems, as judged by the investigator (or 
qualified designee).


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IMP re-introduction or dose frequency increase back to the previous dose frequency may be 
considered if the clinical monitor, investigator (or qualified designee), and the patient agree 
that this should be attempted. Alternatively, qd dosing may be maintained.
Patients should be advised that if tolerability problems continue then they should contact
their
investigator (or qualified designee)
who
may
then
withdraw
them
from
IMP
(see Section 7.7.2 for withdrawal procedures).
IMP must be reduced to 45 mg qd for the following events:

Any QTcF increase >60 ms from the first remote visit

QTcF ≥480 ms and ≤500 ms

Creatinine clearance <60 mL/min and >40 mL/min
If an IMP must be reduced to 45 mg qd and the patient is not currently at a study visit 
arrangements for an USV at the earliest opportunity will be made (see Section 4.6.5). At 
this visit, patients will be provided with instructions regarding the de-escalated dose 
frequency.
5.3.2
Investigational Medicinal Product
Capsules will be swallowed whole with water. One capsule should be taken early in the 
morning and one in the afternoon 7 to 10 hours after the morning dose, irrespective of 
food.
5.3.3
Placebo/Control Medication
Not applicable.
5.4
Presentation and Packaging
Teva will provide the IMP. The primary packaging of the 30- and 60-count bottles will be 
done at 
and the secondary 
packaging and labeling of the IMP will be contracted to 
An interactive response technology (IRT) system will be used to manage the inventory and 
distribution of IMP to patients, track IMP, and manage the returns and destruction of the 
product at the conclusion of the study. At the VTV, patients will receive a 6-month supply of 
IMP. After the VTV, 3-month supplies of IMP will be distributed directly to the patient via 
DTP shipments.
The IMP will be packed in high-density polyethylene bottles of 30 or 60 capsules per bottle. 
Four 30-count bottles will be packaged in a patient specific box (for 60-count bottles, kits 
will contain 4 bottles). Kits will be provided for each patient according to the dosing 
schedule at the VTV and at 3-month intervals thereafter. Each box for DTP shipping is good 
for approximately 3 months of dosing. Patient will take home 4 kits at the VTV, and 
subsequent kits will be shipped directly to the patient. Patients will be provided with an 
information sheet. This will include instructions for the patient, in case of tolerability 
problems, to contact the investigator (or qualified designee) immediately. Separate dosing 
instructions will be provided for those patients de-escalating their dose frequency.
The label texts will be completed in accordance with the appropriate country regulatory 
requirements.
5.5
Blinding
Not applicable. This is an open-label study with no blinding.


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5.6
Accountability of Investigational Medicinal Product and Patient Compliance
A record will be kept by the IRT system of all IMP shipped to the patient, used, and
returned. This record gives details of what IMP each patient received.
All unused IMP and used packaging will be returned by the mobile nurse to the distributor at
each visit, and stored until notice of destruction from the Sponsor.
Any
re-labeling
will
be
in
accordance
with
the
appropriate
Good
Manufacturing
Practices/Good Clinical Practice (GCP) requirements.
The electronic Case Report Form (eCRF) will be used by the mobile nurse to perform IMP 
accountability during remote visits. Patient compliance will be assessed via inquiry during 
TCs and by capsule count when the mobile nurse visits the patient. The mobile nurse should
count the number of capsules remaining in the treatment packs and discuss with the patient
any discrepancies between numbers of capsules taken and numbers which should have been
taken since the last visit, and record patient compliance in the eCRF.
5.7
Concomitant Medication
5.7.1
CYP2D6 Substrates With a Narrow Therapeutic Margin
 
 
 
in this study, medication containing 
CYP2D6 substrates with a narrow safety margin, e.g. class I anti-arrhythmics and tricyclic 
antidepressants, must not be used. 
To be eligible for inclusion, patients must not have taken any such drug within 6 weeks of
the first remote visit. Patients who are prescribed such medication during the study
treatment period must be withdrawn from the study (see Section 7.7.2).
5.7.2
CYP2D6 Inhibitors
The dose chosen in the study is considered safe also for poor CYP2D6 metabolizers.
. Drugs that are CYP2D6 inhibitors,
including
paroxetine,
are
therefore
allowed.
However,
the
investigator (or qualified 
designee) should be aware of the likelihood for a higher exposure in these patients when
judging the need for dose de-escalation or withdrawal.
5.7.3
Medication that May Lower the Seizure Threshold
 
 
 
 medications that lower the 
seizure threshold must be avoided, and if a patient should start such a medication during 
the course of the study, he or she must be withdrawn (see Section 7.7.2).
5.7.4
Medication That May Cause QTc Prolongation
In addition to the currently disallowed concomitant medications in the protocol, patients on 
pridopidine should not be allowed to take the following medications known to have a 


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substantial increase on QT interval: antidepressants (citalopram
and
escitalopram); 
antipsychotics (haloperidol, pimozide, clozapine, sertindole, and ziprasidone); and lithium. If 
these drugs are required
for management of the patient, pridopidine should be 
discontinued. 
5.7.5
General
All medications other than the IMP and disallowed medications (prescriptions or over-the-
counter medications) started prior to the study or started during the study, must be
documented on the concomitant therapy form in the eCRF.
Patients should continue on any medications which are already being prescribed. As far as
possible the doses of these medications should be maintained unchanged throughout the
study, unless a clinically-indicated change is needed. New medications may be introduced
when judged clinically necessary.
Treatment with any of the disallowed medications listed in the current Operations Manual 
should not be commenced at any point during the study. If this occurs, the patient must 
discontinue IMP.
Certain antipsychotic medications (see Protocol Section 5.7 and current Operations Manual 
for disallowed medications) are allowed.
Where a change in dose of an existing medication or introduction of a new medication, other
than excluded medications as above, is unavoidable i.e. where it is essential for the
appropriate clinical management of the patient, the patient should wherever possible
complete the IMP and all study assessments as per the study protocol.
Any changes to an existing concomitant medication or any new medication started during
the study should be recorded in the eCRF.
For any concomitant therapy given as a treatment for a new condition or a worsening of an
existing condition, the condition must be documented on the AE Form of the eCRF.
As part of the additional implemented monitoring procedures, information regarding 
changes in use of benzodiazepines and antidepressants will be collected in inquiries about 
concomitant medication. Inquiries about changes in use of alcohol and drugs associated 
with substance abuse (legal or illicit) will also be conducted. The information collected as 
part of the safety monitoring, together with the C-SSRS and the abbreviated PBA-s, will be 
verified with the patient's caregiver, spouse, or other support person (where necessary)1.
5.7.6
Other Non-Drug Concomitant Therapy
Other therapy may be administered as considered appropriate by the patient’s physician.
                                          
1 In accordance with the American Psychiatric Associations 2003 Practice Guideline for the Assessment 
and Treatment of Patients with Suicidal Behaviors.


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5.7.7
Warnings and Precautions
 
 
 
 
 
 
 
 
 
patients with a prolonged QTcF interval 
(defined as a QTcF interval of >450 ms for both males and females), or other clinically 
significant heart conditions will be excluded from clinical studies.
 
 
.
No patients with epilepsy or a history of seizure(s) of unknown cause should be treated with 
pridopidine. Patients included in studies should be monitored carefully as to exaggerated 
central nervous system reactions which may be indicative of a higher likelihood of seizure 
activity.
 
Patients with significant renal impairment (creatinine clearance <40 mL/min) 
should not be treated with pridopidine.
 Medication containing CYP2D6 substrates with a narrow 
safety margin, e.g. class I anti-arrhythmics and tricyclic antidepressants, must therefore not 
be used.
Full details of AEs observed in reported clinical studies with the IMP can be found in the
current Investigator’s Brochure.
5.7.8
Availability of IMP After the Study
The study will continue until the IMP has been authorized for marketing by the respective 
regulatory authorities, or until the study is discontinued for medical/scientific (risk-benefit) 
or commercial reasons. No further treatment is planned by the Sponsor after the end of the 
Open-HART study. Patients are advised to return to their primary physician for additional 
treatment.
6
STUDY METHODS AND ASSESSMENTS
Full details of the required conduct of the study and the schedule of assessments are
provided in Section 1.3.
It is recommended that the same qualified and trained investigator (or qualified designee) 
performs
the
neurological
assessments,
if possible.
If the investigator (or qualified 
designee) cannot perform the assessments at a visit, the substituting investigator (or 
qualified designee)
should
be appropriately accredited.
Investigators
(or qualified 
designees) were trained in motor rating using the UHDRS and other rating scales during the 
preceding HART and PRIDE-HD studies.


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If necessary, other qualified and trained investigators (or qualified designees) can perform
other assessments (e.g. cognitive). The information about all personnel that have direct
patient contact and the trainings that each one has received must be clearly identified and
appropriate regulatory information must be on file.
Mobile nurses will be trained on the conduct of all study assessments before study 
virtualization.
After the VTV, in order to ensure timely assessments and compliance with IMP, it is 
recommended that the maximum period between VTV and each subsequent visit are as
follows:
VTV to RV1
30 days from VTV
VTV to TC 1
13 weeks ±14 days from VTV
VTV to Remote Visit 2
26 weeks ±14 days from VTV
VTV Visit to TC 2
39 weeks ±14 days from VTV
VTV Remote Visit 3
52 weeks ±14 days from VTV
VTV to TC 3
65 weeks ±14 days from VTV
VTV to Remote Visit 4
78 weeks ±14 days from VTV
VTV to TC 4
91 weeks ±14 days from VTV; subsequent
visits are every 13 weeks ±14 days thereafter
(in between remote visits)
VTV to Remote Visit 5
104 weeks ±14 days from VTV; subsequent
visits are every 26 weeks ±14 days thereafter
The schedule continues going forward in this manner, with alternating TCs every 3 months 
and remote visits every 6 months until the patient is withdrawn or the study ends.
6.1
Assessment of Efficacy
May be conducted as decided by Sponsor.
6.2
ECG Assessments
A single resting 12-lead ECG will be performed at VTV and all remote visits by mobile 
nurses. ECGs will be collected using ECG devices and measures of the cardiac intervals and 
morphological assessment. Participants have to be resting, in a comfortable supine position 
and environment, at least 15 minutes before each ECG sampling time point through at least 
10 minutes after the collection.
A prolonged QTc interval at the VTV (defined as a QTcF interval of >450 ms for both males 
and females), or other clinically significant heart conditions as judged by the investigator (or 
qualified designee) is a violation of exclusion criteria and the patient will not be eligible for 
participation in the study.
QTcF Formula to be used: QTcF = QT/3√RR
Any clinically significant abnormalities observed by the investigator (or qualified designee)
must be reported as AEs.
In instances where there is an increase in QT/QTcF of >500ms or 60ms over the 
VTV, a second ECG should be repeated after 10 minutes rest to confirm the finding.
Where confirmed, this should be reported and documented on the eCRF as an AE.


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Patients with a QTcF interval of >500 ms or if an increase in the average QTcF value is 
>60 ms from the VTV should be discontinued from the IMP and may remain in the study off 
IMP. A follow-up ECG should be done in 4 weeks.
If the central ECG reading results match the above criterion, the patient should stop taking 
IMP and may remain in the study off IMP.
6.3
Laboratory Assessments
6.3.1
Collection of Blood Samples
Additional blood samples may be done at the discretion of the investigator (or qualified 
designee), if (for example) an AE is suspected (see Section 7). 
6.3.2
Laboratory Results Outside the Normal Range
All laboratory values that fall outside the reference range and are of potential clinical 
relevance should be noted and commented upon by the investigator (or qualified designee).
The appearance of abnormal laboratory results or significant shifts from VTV, considered to
be clinically significant by the investigator (or qualified designee) are to be documented as
an AE (see Section 7.1.1). Any abnormal laboratory results obtained should be considered 
by the investigator (or qualified designee) as related to previous use of pridopidine in Open-
HART, in which case they will be considered treatment-emergent AEs.
Calcium, magnesium, and potassium levels will be drawn every 6 months [hypokalemia is 
defined as a potassium level of <3.5 mEq/L)]. If <3.5 mEq/L, patient’s study drug will be 
suspended until normal (≥3.5 mEq/L).
If hypokalemia is observed, dosing will be interrupted and should not be started again until 
normal electrolyte values are confirmed by re-draw and maintained for 7 days. Patients 
needing more than 14 days to reach stable potassium levels, without IMP, should be 
withdrawn from IMP. The patient will be asked to continue in the study and follow the visit 
schedule as outlined in the protocol.
, and to ensure a reasonable minimum 
clearance in all patients through the renal pathway, patients with a creatinine clearance 
<60 mL/min (calculated by the Cockcroft-Gault formula) will be excluded from the study or 
may be able to take a lower dosage of IMP (45 mg qd) if his/her creatinine clearance is 
<60 mL/min and >40 mL/min, per discretion of the investigator (or qualified designee). 
Patients that de-escalate to half-doses of IMP will have creatinine clearance monitored more 
frequently than patients at the full dose, as determined by the investigator (or qualified 
designee). Patients will be discontinued from treatment with IMP if their creatinine clearance 
decreases to <40 mL/min during their participation in the study. The test may be repeated 
once, if clinically appropriate.
6.3.3
Pregnancy Test
Women of childbearing potential should have a pregnancy test performed and results 
confirmed before study drug administration at the VTV, RV1, and annually thereafter as well 
as at EOT, EOS/ET, and USVs, as needed.


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6.4
Vital Signs and Physical Examination
Systolic and diastolic blood pressure and heart rate must be measured by mobile nurses at
VTV and all remote visits as well as at EOT, EOS/ET, and USVs, as needed. Physical
examination will be performed at the VTV only.
6.5
Body Weight
Patients must be weighed lightly clothed by mobile nurses at the VTV and all remote visits
as well as at EOT, EOS/ET, and USVs, as needed.
7
SAFETY PARAMETERS AND ADVERSE EVENTS
7.1
Definitions
7.1.1
Adverse Event (AE)
An AE is defined as any untoward medical occurrence in a patient or clinical study subject 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of 
a medicinal (investigational) product, whether 
or not 
related to the medicinal 
(investigational) product.
This definition includes accidental injuries, study drug intolerance, overdosing, reasons for 
any unplanned change in medication (drug and/or dose), reasons for any medical, nursing 
or pharmacy consultation, or reasons for admission to hospital or surgical procedures. It 
also includes AEs commonly observed and AEs anticipated based on the pharmacological 
effect of the IMP. In addition, any laboratory abnormality assessed as clinically significant by 
the investigator (or qualified designee) must be recorded as an AE. 
7.1.2
Pre-Treatment Adverse Event
A pre-treatment AE is any untoward medical occurrence arising or observed between 
informed consent and start of IMP. 
7.1.3
Treatment-Emergent Adverse Event
A treatment-emergent AE is any AE occurring after start of IMP and within the time of 
residual drug effect, or a pre-treatment AE or pre-existing medical condition that worsens in 
intensity after start of IMP and within the time of residual drug effect. 
The time of residual drug effect is the estimated period of time after the last dose of the 
IMP, where the effect of the product is still considered to be present based on PK, 
pharmacodynamics, or other IMP characteristics. The time of residual drug effect is for most 
drugs 5 half-lives of the IMP. 
7.1.4
Overdose
A drug overdose is the accidental or intentional use of a drug or medicine in an amount that 
is higher than the recommended daily dose. In the context of this study, this is defined as 
any dose above 90 mg pridopidine (TV-7820) daily.


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7.2
Collection and Recording of Adverse Events
7.2.1
Collection of Adverse Events
The investigator (or qualified designee)
must monitor the condition of the patient
throughout the study from the time of obtaining informed consent until the EOS visit or end 
of follow-up period, as applicable.
AEs include:

Patients positive response to questions about their health (at each visit, AEs will be 
elicited using a standard non-leading question such as “How have you been feeling since 
your last visit?”)

Symptoms spontaneously reported by the patient.

Clinically relevant changes and abnormalities observed by the investigator (or qualified 
designee) (e.g. local and systemic tolerability, laboratory measurements, results of 
physical examinations, etc.).
If a patient suffers from the same AE more than once and the patient recovers in between 
the events, the AEs should be reported separately. 
The investigator (or qualified designee) must record all AEs on the AE Log provided in each 
patient’s eCRF with information about:

AE

Date of onset and time of onset 

Intensity

Causal relationship to IMP

Action taken to IMP

Other action taken 

Date of outcome and time of outcome 

Outcome
Each of the items on the AE Log is described in detail in the following sections.
7.2.2
Adverse Event
AEs should be recorded as diagnoses, if available. If not, separate sign(s) and symptom(s) 
are recorded. Only one diagnosis/symptom should be entered per record. 
Pre-existing clinically significant conditions diagnosed or observed as a result of the 
screening procedures must be recorded as AEs. However, pre-existing, known clinically 
significant conditions observed at screening should be recorded as medical history.
The following exceptions should be noted when recording AEs:

Death is not an event but the cause of death is. An exception is the event of sudden 
death of unknown cause. 

Hospitalization is not an event but the reason for hospitalization is. 

Procedures are not events, the reasons for conducting the procedures are. In general, 
only the reason for conducting the procedure will be captured as an AE. However, if 
deemed necessary by the investigator (or qualified designee), a procedure can be 
captured along with the reason for conducting the procedure. E.g. if the procedure “eye 
surgery” was performed due to “diabetic retinopathy”, “diabetic retinopathy” (the 
reason) must be recorded as an AE, and if the investigator (or qualified designee) assess 
it is of importance, ”eye surgery” can be entered as an additional AE. 


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
Overdoses and medication errors with or without clinical consequences should be 
recorded as AEs. In the presence of clinical consequences these should be reported as 
"XXXX due to overdose". In the absence of clinical consequences this should be specified 
(e.g. overdose, no AE observed)

Pre-planned hospitalization for a pre-existing condition that has been planned prior to 
the start of the study should not be recorded as an AE.

Pregnancy
7.2.2.1 Date of Onset/Time of Onset 
The date/time of onset of the AE is the day the first signs or symptoms of the event 
appeared (regardless of seriousness). For abnormal clinically significant laboratory values or 
an outcome of an examination, the date of onset is the day when the sample was taken or 
the examination performed. For pre-existing clinically significant conditions diagnosed or 
observed as a result of the screening procedures, the date of onset is the date of the 
procedure/observation. If an exact date is not available, the best possible estimate should 
be reported (e.g. in mid-January, 3 weeks ago, etc.).
7.2.2.2 Intensity
The following 3-point rating scale must be used for rating of the intensity of each AE:
MILD:
THE EVENT IS EASILY TOLERABLE AND DOES NOT INTERFERE 
WITH NORMAL DAILY ACTIVITIES.
MODERATE:
THE EVENT IS TOLERABLE AND THE PATIENT IS ABLE TO 
PERFORM MOST OF THE DAILY ACTIVITIES.
SEVERE:
THE EVENT CAUSES INABILITY TO WORK OR PERFORM DAILY
ACTIVITIES.
7.2.2.3 Causal Relationship to the IMP
The reporter must always report his/her evaluation of causal relationship between the event 
and the suspect drug. The causal relationship to the IMP must be rated using the following 
2-point scale: 
Term
Definition
Clarification
No 
reasonable 
possibility 
(not related)
This category applies to AEs 
which, 
after 
careful 
consideration, are clearly due to 
extraneous 
causes 
(disease, 
environment, etc.)
or to AEs, 
which, 
after 
careful 
medical 
consideration at the time they 
are evaluated, are judged to be 
unrelated to the IMP.
An AE
may be considered no reasonable 
possibility if it is clearly due to extraneous 
causes or when (at least 2 of the following):

it does not follow a reasonable temporal 
sequence from the administration of the IMP.

it could readily have been produced by the 
patient’s clinical state, environmental or 
toxic factors, or other modes of therapy 
administered to the patient.

it does not follow a known pattern of 
response to the IMP.

it does not reappear or worsen when the IMP
is re-administered.
Reasonable 
possibility 
(related)
This category applies to AEs for 
which, 
after 
careful 
medical 
consideration at the time they 
are evaluated, a connection with 
the test drug administration can 
neither 
be 
ruled 
out 
with 
certainty nor felt with a high 
An AE may be considered reasonable possibility 
related if or when (at least 2 of the following):

it follows a reasonable temporal sequence 
from administration of the IMP.

it cannot be reasonably explained by the 
known characteristics of the patient’s clinical 
state, environmental or toxic factors, or 


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degree of certainty to be related 
to the IMP.
other modes of therapy administered to the 
patient.

it disappears or decreases on cessation or 
reduction in dose.
There are important 
exceptions when an AE does not disappear 
upon discontinuation of the drug, yet drug-
relatedness clearly exists.

it follows a known pattern of response to the 
IMP.
7.2.2.4 Action Taken to IMP
The action taken to the IMP in response to an AE must be classified as one of the following: 

None

Discontinued

Temporarily discontinued

Dose decreased

Dose increased
7.2.2.5 Other Action Taken 
AEs requiring therapy must be treated with recognized standards of medical care to protect 
the health and well-being of the patient. Appropriate resuscitation equipment and medicines 
must be available to ensure the best possible treatment of an emergency situation.
All actions taken to treat the event should also be reported. If medication is administered to 
treat the AE, this medication should be entered in the Concomitant Medication Log
(regardless of seriousness).
7.2.2.6 Date of Outcome/Time of Outcome
The date/time of outcome must always be collected when the event has recovered, 
recovered with sequelae, or the patient died. If an exact date is not available, the best 
possible estimate should be reported (e.g. in mid-January, 3 weeks ago, etc.).
7.2.2.7 Outcome 
The outcome of an AE must be classified as one of the following:
RECOVERED:
THE EVENT HAS FULLY RECOVERED. IF THE EVENT WAS 
WORSENING OF AN UNDERLYING MEDICAL CONDITION, THE 
EVENT IS CONSIDERED RECOVERED WHEN THE CONDITION HAS 
RETURNED TO THE INITIAL LEVEL.
RECOVERED WITH 
SEQUELAE:
THE EVENT HAS RECOVERED, BUT THE PATIENT HAS DEVELOPED 
CHRONIC SEQUELAE AS A CONSEQUENCE OF THE EVENT.
NOT YET 
RECOVERED:
THE EVENT WAS ONGOING AT THE TIME OF THE REPORT.
DEATH: 
THE PATIENT DIED.
7.3
Follow-up of Adverse Events
During the study, the investigator (or qualified designee) must follow-up on each AE until it 
is resolved or until the medical condition of the patient is stable. 


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After the EOS, the investigator (or qualified designee) must follow-up on any AEs classified 
as serious or as related to the IMP until they are resolved, or until the medical condition of 
the patient is stable, or until 30 days (whichever comes first). All such relevant follow-up 
information must be reported to 
 Teva. If the event is a chronic condition the 
investigator (or qualified designee) and the Sponsor may agree if further follow-up is not 
required.
7.4
Adverse Events of Special Interest
Seizure/Convulsion
The investigator (or qualified designee) must immediately report any case of seizure(s) or 
convulsion(s) as a medically important SAE. The investigator (or qualified designee) shall 
report such cases to 
 Teva following the procedure and timelines for reporting of 
SAEs. Any patient that experiences a seizure must be withdrawn from the study.
Pregnancy
The investigator (or qualified designee) must immediately report all pregnancies in case 
any of the study patients or patient's partner becomes pregnant. If a study patient becomes 
pregnant, the IMP should immediately be stopped and the patient will be withdrawn. Note 
that pregnancy itself is not an SAE, however, pregnancy should be reported using the 
Pregnancy Report Form and should be reported within the same timelines as for SAEs. 
All pregnancies which are identified during the clinical study must be followed up until 
delivery and 1 month after delivery or termination. Follow-up should be done using the 
Pregnancy Report Form.
In case a pregnancy results in an abnormal outcome an SAE Form must be filled in and 
reported within the timelines stated for SAEs.
Suicidal Ideation or Suicidal Attempt
AEs of suicidal ideation or attempt should be reported to the Sponsor within 24 hours of 
learning of the event (expedited reporting, regardless of seriousness). The corresponding 
dedicated eCRF should be completed, but the events should not be marked as serious 
unless deemed serious by the investigator (or qualified designee). The words "protocol 
defined AE" should be added after the AE term. Once the AE of suicidal ideation or attempt 
is received, the patient should be discontinued from the study and from IMP, and referred to 
a psychiatrist for evaluation and monitoring (see Section 7.7.2).
Standard emergency medical procedures should be followed for any medical and safety 
concern when immediate intervention is needed (refer to protocol-specific Escalation Plan).
Reportable Events
If a patient stops IMP due to intolerability or an adverse reaction, the site must notify the 
within 72 hours after being informed that treatment was stopped.
Patients who discontinue treatment with IMP due to safety or tolerability reasons may 
continue in the study off IMP and perform the scheduled visits and assessments.


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7.5
Serious Adverse Events
7.5.1
Definitions 
7.5.1.1 Serious Adverse Event (SAE)
A SAE is any untoward medical occurrence that at any dose:

Results in death,

Is life-threatening2,

Requires inpatient hospitalization or prolongation of existing hospitalization3

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect,

Other important medically condition4.
An AE caused by an overdose or medication error is considered serious if a criterion listed in 
the definition above is fulfilled.
7.5.2
Collection and Recording of Serious Adverse Events
7.5.2.1 Serious Adverse Event Form (SAE Form)
The investigator (or qualified designee) must capture information for each SAE on the SAE 
Form. The information captured should be the same as described in above sections for AEs. 
In addition the following information must also be provided: 

Medical history

Other relevant clinical findings 

Narrative

Reason for seriousness

Concomitant medications
All the information provided in the SAE Form must match the information captured in the 
eCRF.
7.5.2.2 Medical History
Relevant updated medical history should be reported with as detailed information as 
possible including medical term, onset date, and stop date (if not ongoing).
7.5.2.3 Other Relevant Clinical Findings
Other information relevant to the SAE such as hospital records5, results from investigations 
e.g. laboratory parameters, invasive procedures, scans and x-rays, and autopsy results 
should be summarized in the narrative, can be attached to the SAE Form, and must, in any 
                                          
2 Life-threatening refers to an event in which the patient was at risk of death at the time of the event; 
it does not refer to an event which hypothetically might have caused death if it were more severe.
3 Inpatient hospitalization or prolongation should be interpreted as admission for 24 hours or more. 
Pre-planned hospital admission prior to the start of the study is not considered hospitalization.
4 Medical judgment should be exercised in deciding whether an AE is serious in other situations. 
Important AEs that are not immediately life-threatening or result in death or hospitalization but may 
jeopardize the patient or may require intervention to prevent one of the outcomes listed in the 
definition above should also be considered serious.
5 Patient details such as name, address, hospital ID number, etc. must always be concealed before 
sending copies to Teva.


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case, be supplied from the investigator (or qualified designee) upon request from the 
Sponsor. The documents should be provided in English or translated into English.
7.5.2.4 Narrative
The investigator (or qualified designee) must write a narrative of the clinical course leading 
up to and following the event and provide this narrative in the SAE Form sent to Teva. The 
narrative should summarise all relevant clinical and related information, including patient 
characteristics, therapy details, prior medical history, clinical course of the event, and 
laboratory values. The narrative should be presented in a logical time sequence and give a 
full overview of the cause of event(s), making the case understandable to persons without 
existing knowledge of the patient and without access to the patient’s hospital records. If 
laboratory results are presented, reference ranges should be included. If the patient was 
hospitalized, dates of hospital admission and discharge should be included.
7.5.3
SAE Reporting Responsibilities of the Investigator (or Qualified Designee)
All SAEs must immediately be notified to the 
 Teva as soon as it becomes known 
to the investigator (or qualified designee) and not later than within 24 hours of their 
knowledge of the occurrence of an SAE according to contact details given below. The 
notification shall at minimum contain investigational site ID, patient ID, AE, investigator 
causality, and seriousness criterion.
The investigator (or qualified designee) must transmit the completed SAE Form with the 
fullest possible details to Teva Pharmaceuticals by fax or e-mail within 2 calendar days
of their knowledge of the SAE.
Serious Adverse Event Reporting Contact Information
It is the responsibility of the investigator (or qualified designee) to comply with their local 
institutional review board (IRB) or research ethics board (REB) regulations regarding the 
reporting of AEs.
Standard emergency medical procedures should be followed for any medical and safety 
concern when immediate intervention is needed (refer to protocol-specific Escalation Plan).
7.5.3.1 SAEs Occurring After End-of-Study
If the investigator (or qualified designee) becomes aware of an SAE after the EOS, which 
he/she assesses to be related to the IMP, the SAE should be reported to Teva. This applies 
no matter how long after the end of the study the SAE occurred.
7.5.4
Emergency Contact
In case of emergency or and/or where further advice is required regarding the handling of 
SAEs, the emergency 24 hour contact phone number should be used.
EMERGENCY CONTACT:
]
Emergency calls will be handled by a fully qualified clinician. A clinician will be available 
24 hours a day, 7 days a week on the telephone number above.


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7.6
Expedited Reporting by Teva 
7.6.1
Responsibilities
Teva is responsible for reporting relevant safety information to all regulatory authorities, 
investigators (or qualified designees), and central IRBs/ethics committees (ECs).
7.6.2
Expedited Reporting
All AEs that are serious, unexpected, and considered related to the IMP judged by 
either the investigator (or qualified designee) or Teva require expedited reporting.
The expectedness is assessed by Teva according to the (Investigator’s Brochure) IB in force 
at the time of the event.
All available information relevant to the evaluation of the SAE will be reported.
SAEs will be considered reportable regardless of whether or not the IMP was used in 
accordance with the provisions in the Protocol and/or the IB.
7.6.2.1 Timelines for Expedited Reporting
Fatal or life-threatening serious, unexpected, related cases occurring in clinical 
studies require very rapid reporting. Regulatory authorities, ECs and investigators (or 
qualified designees) shall be notified (e.g. by telephone, facsimile transmission, or in 
writing) as soon as possible but no later than 7 calendar days after first knowledge by 
Teva. This should be followed by a report that must be as complete as possible within 
8 additional calendar days.
Serious 
cases 
that 
are 
unexpected 
and 
related 
and 
are 
not 
fatal 
or 
life-threatening, must be submitted as soon as possible but no later than 15 calendar 
days after first knowledge by Teva that the case meets the minimum criteria for expedited 
reporting.
7.7
Premature Discontinuation of Treatment
If a patient prematurely discontinues treatment the reason for discontinuation should be 
recorded on the eCRF.
In the event of tolerability problems during the first 4 weeks, patients will be instructed to 
immediately contact their investigator (or qualified designee) to discuss their AE(s). Patients 
who experience any intolerable AEs during the first 4 weeks of the study that, in the opinion 
of the investigator (or qualified designee) could be related to IMP, will attend an EOT visit 
and discontinue IMP. In the event of tolerability problems during the remainder of the 
study, please refer to Section 5.3.1.
7.7.1
Cessation of Treatment
A patient will be classified as having ceased treatment when he or she discontinues IMP, 
prior to the completion of the prescribed course for any of the following reasons:

AE

Death

Lost to follow up

Patient withdrew consent

Major protocol violation

Pregnancy


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
Treatment is no longer appropriate

Termination of study
If hypokalemia is observed, dosing will be interrupted and should not be started again until 
normal electrolyte values are confirmed by re-draw and maintained for 7 days. Patients 
needing more than 14 days to reach stable potassium levels, without IMP, should be 
withdrawn from the IMP. The patient will be asked to continue in the study and follow the 
visit schedule as outlined in the protocol. 
In instances where there is an increase in QT/QTcF of >500ms or 60ms over VTV, a second 
ECG should be repeated after 10 minutes rest to confirm the finding. Where confirmed, this 
should be reported and documented on the eCRF as an AE. 
Patients with a QTcF interval of >500 ms, or with an increase in the average QTcF value 
>60 ms from the VTV, should be discontinued from the study. A follow-up ECG should be 
done in 4 weeks.
Patients should also be discontinued if:

they experience a seizure or convulsions (regardless of the relationship to treatment); 

their body weight decreases to <50 kg (may be discontinued based on investigator (or 
qualified designee) or Sponsor discretion); 

and/or if creatinine clearance decreases to <60 mL/min (calculated using the 
Cockcroft-Gault equation). It is allowed to repeat the test once, if clinically appropriate.

they experience an AE/SAE of suicide ideation or attempt; or 

they have a C-SSRS suicidal ideation score ≥3 (i.e. who answer "Yes" to questions 3, 4, 
and 5 in the scale suicidal ideation section); or

they have a C-SSRS report of suicidal act; or

they have an abbreviated PBA-s suicidal ideation item score ≥3 (i.e. 3, 4). 
Patients who discontinue treatment with IMP due to safety or tolerability reasons may 
continue in the study off IMP and perform the scheduled visits and assessments.
7.7.2
Withdrawal
Patients have the right to discontinue IMP at any time and for any reason. The investigator 
(or qualified designee) also has the right to discontinue IMP if he/she feels that treatment is 
no longer appropriate, if in his/her opinion the patient’s clinical condition is worsening or for 
an AE(s).
A complete evaluation, as detailed in the study protocol for the EOS Visit, should be carried 
out at the time of discontinuation. The patient will then be withdrawn from the study.
If the reason for premature discontinuation is an AE or an abnormal laboratory test result, 
the principal specific event or test must be reported on the appropriate section(s) of the 
eCRF. 
All patients for whom an AE of suicidal behavior/ideation was reported at any time during 
the study should be discontinued from IMP and the need for an evaluation by a psychiatrist 
should be assessed. Discontinued patients should attend an ET visit remotely to return IMP, 
perform IMP accountability, and will be asked to complete all protocol required study 
procedures. AEs of suicidal behavior/ideation should be followed until resolution of the 
suicidal behavior/ideation.


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All patients who are discontinued from the IMP due to active suicidal behavior/ideation 
should be referred to a psychiatrist and followed by the investigator (or qualified designee)
until resolution of the suicidal behavior/ideation.
Patients who discontinue IMP due to safety or tolerability reasons may continue in the study 
off drug and perform the scheduled visits and assessments.
A patient will be considered to have withdrawn from a study in the following circumstances: 
death, lost to follow-up, if the patient has withdrawn informed consent, or the investigator 
(or qualified designee) feels that the treatment is no longer appropriate. If withdrawal is 
due to an SAE the procedure detailed in Section 7.5.3 should be followed. 
Patients with a QTcF interval of >500 ms or if an increase in the average QTcF value is 
>60 ms from the VTV should be discontinued from the study. A follow-up ECG should be 
done in 4 weeks.
7.8
Replacement Policy for Patients Who Withdraw
There will be no replacement of patients that withdraw from the study. Patients withdrawing 
will not be replaced.
7.9
Safety Monitoring
The Sponsor is responsible for continuous safety monitoring, including all AEs, monitoring 
reports, and any other safety-related information. 
During the conduct of this study, an Internal Safety Committee reviews accumulating safety 
data on a quarterly basis (or meet ad-hoc if a safety concern arises, as detailed in the 
Internal Safety Committee charter), to ensure the continuing safety of the study patients 
and study conduct issues.
The Internal Safety Committee receives safety data periodically in an unblinded fashion. 
They have the right to recommend discontinuation of the study for safety reasons. 
All Internal Safety Committee sessions are open. The conduct and specific details regarding 
the Internal Safety Committee sessions are outlined in the Internal Safety Committee 
charter.
8
STATISTICAL ANALYSIS
8.1
General Statistical Issues
Continuous data will be summarized using descriptive statistics where the following will be 
reported:

n (number of observations)

Number of missing observations

Mean

Standard deviation 

Minimum 

Median

Maximum 
Categorical data will generally be presented using count and percentage.
Specifications will be detailed in the statistical analysis plan.


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8.2
Data Sets
The analysis set for safety analysis is defined as all patients who were enrolled in the HART 
or PRIDE-HD studies and who received IMP, or who continued treatment in the Open-HART 
study.
The analysis set for efficacy analysis is defined as all patients who were enrolled in the 
HART or PRIDE-HD studies or continued treatment in the Open-HART study and for whom 
there is at least one post-virtualization visit with efficacy data. 
8.3
Missing Values
Missing values will not be imputed.
8.4
Sample Size and Power Considerations
As this is an open-label extension study, no sample size calculations have been performed.
8.5
Disposition of Patients
The number of patients who entered the study, who completed, and who discontinued 
prematurely will be tabulated.
Discontinuation will also be summarized by appropriate intervals (every 6 months).
8.6
Demographics and Other Baseline Characteristics
Demographics and baseline characteristics will be tabulated.
8.7
Concomitant Medication During the Study
Concomitant medication during the study will be listed.
8.8
Efficacy Set
Descriptive statistics of each of the efficacy variables for the efficacy analysis set will be 
presented by yearly intervals. Changes in efficacy parameters will be calculated both from 
baseline (in main study) and from start of this extension part. 
The efficacy parameters will also be presented graphically.
Efficacy data will be presented for all patients combined.
8.9
Assessments and Analysis of Safety and Tolerability
8.9.1
Exposure
The overall exposure in terms of patient-years will be presented by treatment. The number 
of patients who had a dosage reduction and who had a suspension of IMP will be presented.
8.9.2
Adverse Events
All AEs starting either after the first dose and until 2 weeks after the last dose (scheduled 
follow-up period) in Open-HART, or Open-PRIDE-HD and continuing in the virtualized Open-
HART or starting after the first dose in the Open-HART virtualization will be reported and 
regarded as treatment-emergent.
Separate displays will be presented for events starting in the Open-HART virtualization. In 
these displays, only an overall pridopidine treatment group will be presented. Both crude 
incidences and incidence rates (patients with events per exposure) will be presented.


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Combined AEs from HART and Open-HART (ACR16C009 and ACR16C015, respectively) will 
be reported through an Integrated Summary of Safety.
The following displays will be generated:

A brief summary of AEs will be tabulated.

AEs will be summarized by system organ class and preferred term, severity, and 
relationship to IMP. 

Separate displays of SAEs and AEs leading to discontinuation will be produced. 

All AEs will be listed.
8.9.3
Other Safety Parameters
Changes in other safety parameters (e.g. QTcF, vital signs, and body weight) will be 
presented by yearly intervals overall.
9
ETHICAL AND REGULATORY CONSIDERATIONS
This study will be conducted in accordance with the current FDA and International Council of 
Harmonisation - Good Clinical Practice (ICH-GCP) guidelines and applicable regulatory
requirements.
ICH-GCP
is the international ethical
and scientific quality standard for
designing, conducting, recording, and reporting studies that involve the participation of
patients. The investigator (or qualified designee) will ensure that this study is conducted in
full conformance with ethical principles which have their origin in the Declaration of Helsinki,
or with the laws and regulations of the country in which the research is conducted,
whichever affords greater protection to the individual.
9.1
Indemnity, Insurance, and Compensation
 


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9.2
Informed Consent
Written informed consent in compliance with FDA/competent authority regulations and ICH-
GCP guidelines shall be obtained from each patient prior to entering the study.
If any institution-specific modifications to study-related procedures are proposed or made
by the site, the consent should be reviewed by the
and/or the Sponsor, if appropriate,
prior to IRB/REB submission. Once reviewed, the Informed Consent Form (ICF) will be
submitted by the investigator (or qualified designee) to his/her IRB/REB (or to the central 
IRB by the Contract Research Organization [CRO]) for review and approval and to the 
insurance broker contracted by Teva.
An IRB/REB–approved ICF, providing a written summary of all relevant information, will be
given to the patient prior to written informed consent being obtained. Informed consent can
only be obtained after a full explanation of the aims, methods, anticipated benefits, and all
potential hazards of the study have been given to the patient by the investigator (or 
qualified designee) and when the investigator (or qualified designee) is assured that the
patient fully understands the implications of participating in the study.
At all centers the ICF will be signed and dated by the patient and the investigator (or 
qualified designee). The investigator (or qualified designee) must store the original signed
ICF. A copy should be given to the patient.
If the ICF is revised during the course of the study, all active participating patients must
sign the revised ICF.
It is recognized that patients enrolled in OPEN-HART may experience progressive cognitive 
impairment, potentially involving loss of capacity to provide continued consent throughout 
the study. To ensure ongoing enrollment is appropriate under these circumstances, patients 
will appoint a research proxy.
During the VTV, the patient will be asked to identify their research proxy. At this visit, 
patients will provide written consent to allow their research proxy involvement in decisions 
regarding study participation if the investigator (or qualified designee) determines at some 
point the patient is no longer able to make decisions independently. In advance of this visit, 
patients will be encouraged to thoroughly discuss and document their future study 
participation wishes with the designated research proxy before reviewing their preferences 
with the investigator (or qualified designee). 
Throughout the study, the investigator (or qualified designee) will be responsible for 
regularly determining the patient’s mental capacity and considering if the research proxy
should be contacted to discuss the risks and benefits of continued enrollment. The research 
proxy will be contacted by telephone during study visits, if he/she is not already present, if 
the investigator (or qualified designee) determines that this is needed.
At follow-up visits for patients who lose capacity to provide ongoing consent, study staff 
who are qualified to obtain consent will document lost capacity. Discussions with the 
patient’s designated research proxy at each visit and notation of the patient’s completion of 
a research proxy form will also be documented.
On a state-by-state/provincial basis, the accepted term for the designated research proxy 
may vary, as will the specific consent format, but the specific objective of this plan is for the 
investigator (or qualified designee) to 1) continually assess the patient’s capacity to make 


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decisions and 2) ensure the patient’s wishes with respect to participation in the study are 
respected.
9.3
Approvals
9.3.1
Institutional Review Board/Research Ethics Boards Approval
Federal regulations and the ICH guidelines require that approval be obtained from an
IRB/REB prior to participation of human patients in research studies. The protocol, ICF,
advertisements to be used for patient recruitment and any other written information
regarding this study to be provided to the patient must be approved by the IRB/REB prior to
commencement of the study. Documentation of all IRB/REB approvals and of the IRB/REB
compliance with ICH Guideline E6 will be maintained by the center (a copy will be provided
to the
and will be available for review by the Sponsor or its designee.
All IRB/REB approvals should be signed by the IRB/REB Chairman or designee and must
identify the IRB/REB name and address, the clinical protocol by title and/or protocol number
and the date approval and/or favorable opinion was granted.
Where an investigator (or qualified designee) or other staff member is a serving member of
the Ethics Committee, he should take no part in the protocol approval process other than to
provide additional information to the committee, if requested.
The investigator (or qualified designee) is responsible for obtaining continued review of the
research at intervals on an annual basis or otherwise specified by the IRB/REB. The
investigator (or qualified designee) must supply the
and the Sponsor with written
documentation of continued review of the clinical research. For sites using the central IRB, 
the CRO will complete continuing review submissions at intervals specified by the central 
IRB. The CRO must supply 
 and the Sponsor with written documentation of the 
continued review of the clinical research.
The IRB/REB will be notified by the investigator (or qualified designee) within 90 days the
end of the clinical study (last patient, last visit). The investigator (or qualified designee) will
also inform the IRB/REB within 15 days should the study be terminated early and the
reasons why.
9.3.2
Regulatory Approval
Teva will
be
responsible
for
ensuring
that
the
relevant
regulatory approval
(US
IND/Canadian CTA) is obtained prior to study start. Documentation regarding regulatory
approval will be provided to the investigator (or qualified designee).
Teva will forward any protocol amendments to regulatory authorities and will ensure that
progress reports and details of any serious protocol violations are provided as required by
each regulatory authority.
The regulatory authorities will be informed should the study be terminated early.
The regulatory authorities will be notified within 90 days of the end of the clinical study (last
patient, last visit). The FDA/Health Canada will also be informed within 15 days should the
study be terminated early and the reasons why.


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9.3.3
Protocol Amendments
The investigator (or qualified designee) should not implement any deviation from, or
changes to, the protocol without agreement by Teva and the investigator (or qualified 
designee) and prior review and documented favorable opinion from the IRB/REB and
FDA/Health
Canada,
if
required,
except
where
necessary
to
eliminate
an
immediate
hazard(s) to the study patients.
Urgent Amendments
A protocol change intended to eliminate an apparent immediate hazard to patients may be
implemented immediately provided FDA/Health Canada and the reviewing IRB/REB is
notified in accordance with applicable regulations.
Amendments Requiring Notification to the FDA
Any changes to the protocol that significantly affects the safety of patients, the scope of the
investigation or the scientific quality of the study must be notified to the FDA and the IRB
responsible for the review and approval of the study. The amendment(s) should then be
forwarded to the FDA and IRB in accordance with FDA 21 CFR (Code of Federal Regulation)
Part 312.30 (Protocol Amendments).
Changes to the protocol which meet the above criteria may be implemented provided
2 conditions are met:
(a) Teva has submitted the change to FDA for its review; and
(b) The change has been approved by the IRB with responsibility for review and
approval of the study.
Teva may comply with these 2 conditions in either order.
A protocol amendment must be submitted to the FDA when a new investigator is to be
added to the protocol. Teva shall notify the FDA of the new investigator(s) within 30 days of
the investigator being added.
Amendments Requiring Approval of Health Canada
The following amendments to the protocol must be notified to Health Canada:
(a) affecting the selection, the criteria for selection, monitoring, or dismissal of a clinical
study patient;
(b) affecting the evaluation of the clinical efficacy of the IMP;
(c) altering the risk to health of a clinical study patient;
(d) affecting the safety evaluation of the IMP; or
(e) extending the duration of the clinical study.
The protocol amendment may not be implemented until approved by Health Canada.
Teva and the investigator (or qualified designee) reserve the right to terminate the study at
any time for safety, clinical, and/or ethical reasons. The procedures for termination will be
arranged after review and consultation by both parties. In the case of early termination the
Sponsor will notify the competent authority(ies) concerned within 15 days.


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9.4
Study Documentation and Study Confidentiality
9.4.1
eCRF and Data Collection
The investigator (or qualified designee) must generate and maintain adequate records
(patient medical records, eCRFs, e-source documents) to enable the conduct of this study to
be fully documented.
It is the investigator’s (or qualified designee’s) responsibility to ensure that entries are
proper
and
complete.
Data Management is responsible for the accuracy, quality, 
completeness, and internal consistency of the data from this study. Data handling, including 
data quality control, will comply with international regulatory guidelines, including ICH-GCP 
guidelines. Data management and control processes specific to this study, along with all 
steps and actions taken regarding data management and data quality control, will be 
described in a data management plan and/or equivalent document.
At the conclusion of the study, the site will be provided with a portable document format
(pdf) file on electronic media depicting eCRFs for their site.
Teva’s policy is that study data on the eCRFs must be verifiable to the source data, which
necessitates access to all original recordings, laboratory reports, and patients’ records (as 
applicable). The investigator (or qualified designee) must therefore agree to allow direct
access to patients’ records, and source data must be made available for all study data. The
patients must also allow access to the patients’ research records, and they will be informed
of this and will be confirming their agreement when giving informed consent. The only 
exception is when study data is recorded directly into the eCRF.
The patients participating in the study will not be identified by name on any study
documents to be collected by the Sponsor (or designee), but will be identified by their
patient ID Number and initials.
The nature and location of all source documents will be identified to ensure that all sources
of
original
data
required
to
complete
the
eCRF
are
known
to
the
company
and
investigational staff and are accessible for verification by the study monitor. If electronic
records
are
maintained,
the
method
of
verification
must
be
discussed
with
the
investigational staff.
9.4.2
Data Management
Data for this study will be managed using the clinical database management system from
Medidata. This is an internet accessible electronic data capture (EDC) application. The EDC
application is designed to ensure timeliness and accuracy of data, as well as the prompt
reporting of data from the study on an ongoing basis to the investigator (or qualified 
designee) and to the clinical monitor. The application is compliant with relevant US FDA
regulatory requirements including 21 CFR Part 11.
Sponsor will have overall responsibility for the data.
Creation of the analytical database will be covered in the statistical analysis plan.
The investigator (or qualified designee) must be aware of his responsibility to retain patient
identification codes in line with regulatory requirements after completion or discontinuation
of the study.


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If a patient ceases treatment prematurely, then the reason must be noted in the eCRF. If a
patient ceases treatment because of an AE, reasonable efforts must be made to clearly
document the outcome.
The investigator (or qualified designee) will allow authorized Sponsor personnel, auditors,
and regulatory authorities direct access to the patients’ research records.
The investigator (or qualified designee) must make study data accessible to the clinical 
monitor, other authorized representatives of the Sponsor (or designee), and Regulatory
Agency (e.g. FDA, Health Canada) inspectors upon request.
Patient identity information will be recorded on the Confidential Patient Identification Code
List and maintained for at least 15 years. Research proxy identity information will be 
recorded on a Confidential Log and maintained for at least 15 years.
Investigators (or qualified designees) must maintain all study documentation for a period of
2 years following the approval date of the drug, or until 2 years after the investigational
drug program is discontinued. In the event of an audit or regulatory authority inspection,
access to the eCRFs will be provided. Teva will notify the
and the investigators (or 
qualified designees) when any records may be discarded.
A record must be kept of all patients who signed consent and were considered for the study
and subsequently excluded. The reason for non-participation in the study should be
recorded.
9.4.3
Confidentiality of Study Documents and Patient Records
The investigator (or qualified designee) must ensure the patients’ anonymity is maintained.
Patients must NOT be identified by their name on documents submitted to
/the
Sponsor/third party contractor but by a Patient ID Number and by their initials. The
investigator (or qualified designee) will be responsible for maintaining a separate log of
patients’ codes, names, and unique identifiers. This log will be maintained as required by
applicable
regulatory
requirements.
Documents
not
for
submission
to
/the
Sponsor/third party contractor, e.g. patients’ written consent forms, must be maintained by
the investigator (or qualified designee) in strict confidence.
Upon a patient’s request and written permission, medical information may be given to
his/her personal physician or other appropriate medical personnel responsible for the
patient’s welfare.
The
patient
and physician
must
be
aware
that
the information
is
considered research information.
Data generated for this study must be available for inspection on request to representatives
of the FDA, other national or local health authorities, associated IRBs/REBs, the Sponsor
and third party contractors.
Additional patient confidentiality issues are covered in the Clinical Study Agreement and in
the ICF signed by the patient.
9.4.4
Confidentiality of Proprietary Information
All study related documentation is confidential, whether obtained by the investigator (or 
qualified designee) or provided by
/the Sponsor. Disclosure of such information is
restricted to those involved in the scientific, ethical, and clinical study procedures.


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9.4.5
Financial Disclosure
To meet the requirements of the FDA, all clinical investigators are required to disclose any
interests in Teva, the parent company of the Sponsor Company, that they have directly or
through close family members. The investigator’s disclosable financial interests must be
collected during study initiation, following completion of the study at the investigational site,
and 1 year following study completion. The investigator should promptly update this
information if any relevant changes occur during this period. Disclosable financial interests
will be recorded on the Investigator Financial Disclosure Form.
Any investigator (or qualified designee) added as investigational staff must complete the
Investigator Financial Disclosure Form at the beginning of their participation in the study.
For any investigator(s) leaving the site before study completion, an Investigator Financial
Disclosure Form should be obtained at the end of their participation.
10 PUBLICATION OF DATA
10.1
Publication
Teva acknowledges that the community of investigators is dedicated to free scholarly
exchange and to public dissemination of the results of its scholarly activities. Therefore, the
community of investigators or delegated individual investigators shall have the right to
publish, either orally or in writing, results arising from the study. The previously appointed 
HART publication committee (which includes
representatives
from
the
community
of
investigators, a representative of Teva, and the study statistician) will serve as the 
publication committee for ACR16C015 as well. The publication committee will write and
implement a publication plan for the study. The publication committee will, unless otherwise
specified in the agreements with the investigators, set the rules for appointing and appoint
the primary authors for the planned articles. The rules for appointing authors shall be in
conformity with the contract between the
and Teva.
The authors shall furnish Teva with a copy of any proposed written publication or all other
material for any other presentation at least 30 days prior to the submission for publication
or presentation for review and commenting. In the event that the proposed publication or
oral presentation contains patentable patient matter or other confidential information that
needs protection, the community of investigators or delegated individual investigators shall,
upon written request from Teva within the 30-day review period, delay the publication or
presentation for up to an additional 60 days (which is a maximum of 90 days from the date
of submission to Teva) to allow Teva to file a patent application.
Any Teva required modifications or delay will not result in withholding any study results
from academic publication.
Authorship of publications arising from this study should be awarded according to the
Uniform Requirements for Manuscripts Submitted to Biomedical Journals, issued by the
International Committee of Medical Journal Editors, and community of investigators or
delegated individual investigators agree to allow personnel from Teva to be authors when
deemed appropriate by said rules.
The investigators acknowledge that the results of the study have to be reported internally
within Teva and submitted to the regulatory authorities and the IRB/REB, irrespective of
whether the study was terminated prematurely or completed as planned. The investigators
also acknowledge that Teva may use data from this study as part of a drug application
and/or as part of meta-analyses.


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11 ADMINISTRATIVE PROCEDURES
The study will be carried out in accordance with the study protocol, ICH-GCP guidelines,
appropriate FDA-CFRs, and local regulatory requirements.
CROs and/or independent contract personnel may be contracted, subject to approval by 
Teva, to manage and monitor the study, to provide services for data management and
statistical analysis, to provide regulatory advice and services, to handle the reporting of
SAEs, to provide services for laboratory analysis, to package and distribute the clinical study
supplies, and to provide advice on ICH-GCP and quality, and to audit the investigational
centers/contractors involved in the conduct of the study.
A full statistical analysis plan will be written in conjunction with the protocol and finalized
before database lock. A statistical report will be produced and a final integrated clinical and
statistical report will be written in accordance with ICH-GCP by an appropriately qualified
individual.
For the purposes of notification to regulatory authorities and ethics committees the end of
the study will be defined as being the date of the last visit of the last patient undergoing the
study.
11.1
Quality Assurance
Audits may be undertaken by the Sponsor, an independent auditor, and/or regulatory
authority. Audits may take place at a investigational center, at the offices of
during
the study or up to a number of years after study closure.
11.2
Monitoring
This study will be monitored by the Sponsor (or designee) in accordance with current GCP.
By signing this protocol, the investigator (or qualified designee) grants permission to the
Sponsor (or designee), and appropriate regulatory authorities to conduct remote and on-site
monitoring of all appropriate study documentation and/or direct data entry into the eCRF. In
order
to
assure
the
accuracy
of
data
collected
in
the
eCRFs,
it
is
mandatory
that
representatives of the Sponsor or designee have access to original source documents
(e.g. patient research records, patient research charts, and laboratory reports). During the
review of these documents, the anonymity of the patient will be respected with strict
adherence to professional standards of confidentiality.
The study monitor will contact and visit the site regularly or remotely and will be allowed,
on request at a mutually acceptable time, to inspect the various records of the study. It will
be the monitor’s responsibility to inspect the eCRFs at regular intervals throughout the
study, to verify the adherence to the protocol and the completeness, correctness and
accuracy of all eCRF entries as compared to source documents. The study monitor should
have access to laboratory test results and any other source records and data needed to
verify the entries and/or direct data entries on the eCRFs. The investigator (or qualified 
designee) agrees to cooperate with the study monitor to ensure that any problems detected
in the course of these monitoring visits are resolved.
11.3
Clinical Study Agreement
Agreed costs for each participating center will be met by the Sponsor. For each center, an
agreement
will
be
prepared
and
signed
off
by
the
investigator 
(or 
qualified 
designee)/institution and by the
before the clinical phase of the
study commences.


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11.4
Investigator (or Qualified Designee) Responsibilities
The investigator will have overall responsibility for the conduct of the study at his/her
center. The investigator may delegate specific duties to appropriately trained qualified
members of his/her research team or to other hospital staff e.g. mobile nurses, pharmacy, 
etc. Any delegation must be clearly documented in a center specific delegation list.
11.5
Clinical Product Complaints
A clinical product complaint is defined as a problem or potential problem with the physical 
quality or characteristics of clinical drug supplies and/or clinical device supplies used in a 
clinical research study sponsored by Teva. Examples of a product complaint include but are 
not limited to the following:

suspected contamination

questionable stability (e.g. color change, flaking, crumbling, etc.)

defective components

missing or extra units (e.g. primary container is received at the site with more or less 
than the designated number of units inside)

incorrect packaging or incorrect or missing labeling/labels

unexpected or unanticipated taste or odor or both

device not working correctly or appears defective in some manner
Each investigational center will be responsible for reporting a possible clinical product 
complaint by completing the Product Complaint Form provided by Teva and emailing it to 
 within 48 hours of becoming aware of the issue.
For complaints involving a device or other retrievable item, it is required that the device (or 
item) be sent back to the Sponsor for investigative testing whenever possible. For 
complaints involving a drug product, all relevant samples (e.g. the remainder of the 
patient’s drug supply) should be sent back to the Sponsor for investigative testing whenever 
possible. 
11.5.1
Product Complaint Information Needed from the Investigational Center
In the event that the Product Complaint Form cannot be completed, the investigator (or 
qualified designee) will obtain the following information, as available:

investigational center number and investigator (or qualified designee) name

name, phone number, and address of the source of the complaint 

clinical protocol number

patient identifier (patient study number) and corresponding visit numbers, if applicable

product name and strength for open-label studies

patient number, bottle, and kit numbers (if applicable) for double-blind or open-label 
studies

product available for return Yes/No

product was taken or used according to protocol Yes/No

description or nature of complaint

associated SAE Yes/No

clinical supplies unblinded (for blinded studies) Yes/No

date and name of person receiving the complaint 
Note: Reporting a complaint must not be delayed because not all the required information 
can be immediately obtained. Known information must be immediately reported. The 


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sponsor will collaborate with the investigator (or qualified
designee)
to obtain any 
outstanding information.
11.5.2
Handling the IMP at the Investigational Center
The investigator (or qualified designee) is responsible for retaining the product in question 
in a location separate from the investigator’s (or qualified designee’s) clinical study supplies. 
The Sponsor may request that the investigator (or qualified designee) return the product for 
further evaluation and/or analysis. If this is necessary, the mobile nurse or designee will 
provide the information needed for returning the IMP.
If it is determined that all of the IMP must be returned, the Sponsor will provide the 
information needed to handle the return by the mobile nurse.
11.5.3
Adverse Events or Serious Adverse Events Associated with a Product 
Complaint
If there is an AE or SAE associated with a product complaint, the protocol should be 
followed (see Section 11.5.4).
11.5.4
Documenting a Product Complaint
The investigator (or qualified designee) will record a description of the product complaint in 
the source documentation as well as any actions taken to resolve the complaint and to 
preserve the safety of the patient. Once the complaint has been investigated by the Sponsor 
and the investigator (or qualified designee), if necessary, an event closure letter may be 
sent to the investigational center where the complaint originated or to all investigational 
centers using the product.


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SIGNATURE SHEET
I agree to the conditions relating to this study as set out in this protocol and fully
understand that any changes instituted by me without previous discussion with the Sponsor,
constitute a violation of the protocol. I agree to adhere to the protocol in all circumstances
other than where necessary to protect the well-being of the patient.
I will ensure that the drugs supplied by the Sponsor will be used only for administration to
patients included in this study protocol and for no other purpose.
_______________________________________________ _______________
Responsible Principal Investigator                                       (Print Name)
_______________________________________________ _______________
(Signature)                                                                       (Date)


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DSM-IV TR CRITERIA FOR SUBSTANCE ABUSE 
DIAGNOSIS – CRITERIA FOR SUBSTANCE ABUSE
A. A maladaptive pattern of substance use leading to clinically significant impairment or 
distress, as manifested by 1 (or more) of the following, occurring within a 12-month period:
(1) recurrent substance use resulting in a failure to fulfill major role obligations at work, 
school, or home (e.g. repeated absences or poor work performance related to substance 
use; substance-related absences, suspensions, or expulsions from school; neglect of 
children or household)
(2) recurrent substance use in situations in which it is physically hazardous (e.g. driving an 
automobile or operating a machine when impaired by substance use)
(3) recurrent substance-related legal problems (e.g. arrests for substance-related disorderly 
conduct)
(4) continued substance use despite having persistent or recurrent social or interpersonal 
problems caused or exacerbated by the effects of the substance (e.g. arguments with 
spouse about consequences of intoxication, physical fights)
The symptoms have never met the criteria for Substance Dependence for this class of 
substance


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Kingma EM, van Duijn E, Timman R, van der Mast RC, Roos RA. Behavioural problems in 
Huntington's disease using the Problem Behaviours Assessment. Gen Hosp Psychiatry. 
2008;30(2):155-61.
Paulsen JS, Long JD. Onset of Huntington's disease: can it be purely cognitive? Mov Disord 
2014 Sep 15;29(11):1342-50.
Ponten H, Kullingsjö J, Lagerkvist S,Martin P, Pettersson F, Sonesson C, et al.In vivo 
pharmacology of the dopaminergic stabilizer pridopidine. Eur J Pharmacol 2010;644:88–95.
Quinn N, Schrag A. Huntington's disease and other choreas. J Neurol 1998 
Nov;245(11):709-16.
Ross CA, Tabrizi SJ. Huntington's disease: from molecular pathogenesis to clinical 
treatment. Lancet Neurol 2011;10(1):83-98.
Ross CA, Pantelyat A, Kogan J, Brandt J. Determinants of functional disability in 
Huntington's disease: role of cognitive and motor dysfunction. Mov Disord 2014 Sep 
15;29(11):1351-8.
Rung JP, Rung E, Helgeson L, Johansson AM, Svensson K, Carlsson A, et al. Effects of (-)-
OSU6162 and ACR16 on motor activity in rats, indicating a unique mechanism of 
dopaminergic stabilization. J Neural Transm (Vienna) 2008;115(6):899-908.
Sahlholm K, Århem P, Fuxe K, Marcellino D. The dopamine stabilizers ACR16 and (-) 
OSU6162 display nanomolar affinities at the σ-1 receptor. Mol Psychiatry 2013;18(1):12-4.
Sahlholm K, Sijbesma JW, Maas B, Kwizera C, Marcellino D, Ramakrishnan NK, et al. 
Pridopidine selectively occupies sigma-1 rather than dopamine D2 receptors at behaviorally 
active doses. Psychopharmacology (Berl) 2015;232(18):3443-53.


Trial Code: ACR16C015
IND Number: IND 77,419
Protocol Version: FINAL 6.0
Date: 29 June 2017
Page 179 of 179
Open-HART Protocol with Amendment 05
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among patients with Huntington's disease. J Neurol Neurosurg Psychiatry 
1984;47(12):1283-7.
Smith A. The Symbol Digit Modalities Test: a neuropsychologic test for economic screening 
of learning and other cerebral disorders. Learning Disorders. 1968;3:83-91.
Stroop JR. Studies of interference in serial verbal reactions. J Exp Psychol. 1935;18:643-62.

SAP_001.pdf: 
Official Title: A multi-center, North American, open-label extension study of 
pridopidine (ACR16) in the symptomatic treatment of Huntington’s Disease (Open-
HART). 
NCT Number: NCT01306929 
Document Date: 11 Jan 2018 


Uncontrolled Open-Label Study-Huntington’s Disease
Statistical Analysis Plan   
Study ACR16C015
1
TITL
TITLE PAGE
Statistical Analysis Plan
Study Number ACR16C015
A multi-center, North American, open-label extension study of pridopidine (ACR16) in the 
symptomatic treatment of Huntington’s Disease (Open-HART)
Phase 2
IND number: 77,419
Approval Date: 11 January 2018
Sponsor
Teva Branded Pharmaceutical 
Products R&D, Inc.
United States
Prepared by:
Global Statistics


Statistical Analysis Plan 
Uncontrolled Open-Label Study-Huntington's Disease 
Study ACR16COI5 
STATISTICAL ANALYSIS PLAN APPROVAL 
Study No.: 
A multi-center, North American, open-label extension study ofpridopidine 
(ACR16) in the symptomatic treatment ofHuntington's Disease (Open-HART) 
Study Title: ACR16COJ5 
Statistical Analysis Plan for: 
Version: 
Date: 
Author: 
0 Interim Analysis 
181 Final Analysis 
Final 
08- Jan-20 18 
Global Statistics 
Approver: 
Global Statistics 
Approver: 
0 Integrated Summary of Efficacy 
0 Integrated Summary ofSafety 
//11/1'0/1 
Date 
Senior Director, Clinical Development, Movement Disorders 
GOP _RD_702_FRM_OI 
Effective Date:27-Nov-20 14 
2 
Version2.0 
Page I of I 


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TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................................6
INTRODUCTION ...........................................................................................................................7
1.
STUDY OBJECTIVES ................................................................................................8
2.
STUDY DESIGN .........................................................................................................9
2.1.
General Design .............................................................................................................9
2.2.
Efficacy Measures ......................................................................................................11
2.3.
Safety Measures..........................................................................................................11
2.4.
Randomization and Blinding......................................................................................11
2.5.
Sample Size and Power Considerations .....................................................................11
2.6.
Sequence of Planned Analyses ...................................................................................11
2.6.1.
Planned Interim Analyses...........................................................................................11
2.6.2.
Final Analyses and Reporting.....................................................................................11
3.
ANALYSIS SETS ......................................................................................................12
3.1.1.
Intent-to-Treat Analysis Set........................................................................................12
3.1.2.
Safety Analysis Set.....................................................................................................12
3.1.3.
Full Analysis Set.........................................................................................................12
4.
GENERAL ISSUES FOR DATA ANALYSIS..........................................................13
4.1.
General........................................................................................................................13
4.2.
Specification of Baseline Values................................................................................13
4.3.
Scoring for Rating Scales ...........................................................................................13
4.4.
Handling Withdrawals and Missing Data...................................................................13
4.5.
Study Days and Visits.................................................................................................14
5.
STUDY POPULATION.............................................................................................15
5.1.
General........................................................................................................................15
5.2.
Patient Disposition......................................................................................................15
5.3.
Demographics and Baseline Characteristics...............................................................15
5.4.
Medical History ..........................................................................................................15
5.5.
Prior Therapy and Medication....................................................................................15
5.6.
Electrocardiography....................................................................................................16
5.7.
Physical Examinations................................................................................................16


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5.8.
Study Protocol Violations...........................................................................................16
6.
EFFICACY ANALYSIS ............................................................................................17
6.1.
General........................................................................................................................17
6.2.
Efficacy Endpoint and Analysis .................................................................................17
7.
SAFETY ANALYSIS ................................................................................................18
7.1.
General........................................................................................................................18
7.2.
Duration of Exposure to Study Drug..........................................................................18
7.3.
Adverse Events ...........................................................................................................18
7.4.
Vital Signs ..................................................................................................................18
7.5.
Electrocardiography....................................................................................................19
7.6.
Physical Examinations................................................................................................19
7.7.
Concomitant Medications or Therapies......................................................................19
7.8.
Other Safety Assessments...........................................................................................20
8.
STATISTICAL SOFTWARE ....................................................................................21
9.
CHANGES TO ANALYSES SPECIFIED IN THE STUDY PROTOCOL..............22


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LIST OF TABLES
Table 1:
Criteria for Potentially Clinically Significant Vital Signs..........................................19


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
BMI
body mass index
CAG
Cytosine-Adenosine-Guanine
CRF
case report form
C-SSRS
Columbia-Suicide Severity Rating Scale
ECG
electrocardiogram
FA
Functional Assessment
IS
Independence Scale
ITT
intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
PBA-s
Problem-Behaviors Assessment-Short Form
PT
preferred term
R&D
Research and Development
SAP
statistical analysis plan
SD
Standard Deviation
SE
Standard Error
SOC
system organ class
SOP
standard operating procedure
TFC
Total Functional Capacity
TMS
Total Motor Score
UHDRS
Unified Huntington’s Disease Rating Scale
WHO
World Health Organization


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INTRODUCTION
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for Teva 
Branded Pharmaceutical Products R&D, Inc. study ACR16C015, (A multi-center, open-label 
extension study of pridopidine (ACR16) in the symptomatic treatment of Huntington’s Disease 
(Open-HART)), and was written in accordance with SOP GBP_RD_702 (Statistical Analysis 
Plan).
The reader of this SAP is encouraged to read the study protocol for details on the conduct of this 
study, the operational aspects of clinical assessments, and the timing for completing the 
participation of a patient in this study. 
The SAP is intended to be in agreement with the protocol, especially with regards to the primary 
and all secondary endpoints and their respective analyses. However, the SAP may contain more 
details regarding these particular points of interest, or other types of analyses (e.g. other 
endpoints).When differences exist in descriptions or explanations provided in the study protocol 
and this SAP, the SAP prevails; the differences will be explained in the Clinical Study Report.
 


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1.
STUDY OBJECTIVES
The objective is to access the long-term safety of pridopidine and to analyze treatment affects 
during long-term, open-label treatment.
The primary objective of this study is to evaluate the long-term safety of pridopidine treatment 
and to collect information on Unified Huntington’s Disease Rating Scale (UHDRS) development 
during long-term, open-label treatment.


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2.
STUDY DESIGN
2.1.
General Design
Note: the SAP is based on Protocol Am 04 (dated 25 August 2016), and that Protocol Am 05 
was issued (on 29 June 2017) for study virtualization but was not implemented.
This is a multi-center open-label study of pridopidine 45mg bid for patients who completed the 
ACR16C009 (HART) or TV7820-CNS-20002 (PRIDE-HD) studies.
At the Baseline Visit the following tests will be performed and documented: review and 
completion of informed consent; review of inclusion and exclusion criteria; pregnancy test (for 
females of childbearing potential); review of (baseline) adverse events (AEs), concomitant 
medication and medical history. All patients will be assessed for suicidality using the Columbia-
Suicide Severity Rating Scale (C-SSRS). Evaluation for Research Study Consent and blood draw 
(calcium, magnesium, potassium, and creatinine for creatinine clearance calculation) will be 
performed for patients from the PRIDE-HD study. 
The following assessments will be performed: physical examination including vital signs (heart 
rate and blood pressure) and weight; review of concomitant medication; (including inquiry about 
changes in use of benzodiazepines and antidepressants); inquiry about changes in use of alcohol 
and illicit drugs; UHDRS (including motor assessment, cognitive assessment, behavioral 
assessment, functional capacity, independence scale, functional assessment); 12-lead 
electrocardiogram (ECG) (single). 
Trial medication will be dispensed and an appointment made for the next visit.
At Telephone Visit 1 (T1, Week 1) an evaluation for research study consent will be conducted, 
any AEs will be collected and reported, compliance will be confirmed, concomitant medication 
reviewed (including inquiry about changes in use of benzodiazepines and antidepressants); 
inquiry about changes in use of alcohol and illicit drugs, C-SSRS, abbreviated Problem-
Behaviors Assessment-Short Form (PBA-s), and an appointment for next contact will be made. 
Evaluation for Research Study Consent will be performed for patients from the PRIDE-HD 
study.
At Visit 1 (1 Month) the following will be documented: an evaluation for research study 
consent, review of concomitant medications (including inquiry about changes in use of 
benzodiazepines and antidepressants); inquiry about changes in use of alcohol and illicit drugs, 
AEs, C-SSRS, PBA-s, vital signs and drug compliance. Evaluation for Research Study Consent, 
ECG and blood draw (calcium, magnesium, potassium, and creatinine for creatinine clearance 
calculation) will be performed for patients from the PRIDE-HD study.
Subsequently, the patient will be contacted every 3 months as per below: 
At Telephone or in-person Visits [Safety Visit (SV)] (eg after 3, 9, 15 months etc.) the 
following will be documented: an evaluation for research study consent, review of concomitant 
medication (including inquiry about changes in use of benzodiazepines and antidepressants); 
inquiry about changes in use of alcohol and illicit drugs, C-SSRS and PBA-s assessment, review 
of AEs, and assessment of compliance with trial medication. A 12-lead ECG will be obtained, 
vital signs will be assessed and calcium, magnesium and potassium level and creatinine for 


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creatinine clearance calculation will be drawn [hypokalemia is defined as a potassium level less 
than 3.5 mEq/L)]. If less than 3.5 mEq/L, patient’s study drug will be suspended until normal 
(greater than or equal to 3.5mEq/L). Participants can choose to have the assessments of vital 
signs, ECG and blood draw for calcium, magnesium, potassium, and creatinine for creatinine 
clearance calculation performed by their GP and/or local cardiologist or schedule a visit with site
but the site must have a telephone contact with the participant to review concomitant medication, 
AEs and assess compliance with trial medication.
At Telephone contacts [C] (eg once a month between on-site visits) the following will be 
documented: an evaluation for research study consent, review of concomitant medication 
(including inquiry about changes in use of benzodiazepines and antidepressants); inquiry about 
changes in use of alcohol and illicit drugs, review of adverse events, C-SSRS and an abbreviated 
PBA-s assessment. 
At Clinic Visits (eg 6, 12, 18 months etc.) the following tests will be performed and 
documented: an evaluation for research study consent, brief physical examination including vital 
signs and weight, calcium, magnesium, and potassium levels and creatinine for creatinine 
clearance calculation  will be drawn [hypokalemia is defined as a potassium level less than 3.5 
mEq/L)]. If less than 3.5 mEq/L, patient’s study drug will be suspended until normal (greater 
than or equal to 3.5mEq/L), review of concomitant medication (including inquiry about changes 
in use of benzodiazepines and antidepressants); inquiry about changes in use of alcohol and illicit 
drugs, review of AEs, C-SSRS, PBA-s, 12-lead ECG and assessment of compliance with trial 
medication. On a yearly basis, UHDRS (including motor assessment, cognitive assessment, 
behavioral assessment, functional capacity, independence scale, functional Assessment) and a 
pregnancy test (for females of childbearing potential) should be done. The PBA-s will be 
collected at all safety and clinic visits except on those at which the UHDRS is performed.
Withdrawal from treatment
If the patient wishes to stop the drug, or is judged by the investigator to not be suitable for 
continued therapy, or the study is discontinued, a clinic visit ("withdrawal visit", end of study 
drug visit) should be performed and the patient withdrawn from the study. A (telephone) follow-
up visit (30 d TC F/U) to collect and report AEs (as well as inquiry about changes in use of 
benzodiazepines and antidepressants, and inquiry about changes in use of alcohol and illicit 
drugs), C-SSRS and an abbreviated PBA-s assessment should take place one month after the 
actual discontinuation of study drug took place.
Patients who discontinue study medication due to safety or tolerability reasons may continue in 
the study off drug and perform the scheduled visits and assessments.
Unscheduled Visit(s)
If a patient has tolerability problems, or has to de-escalate the investigational treatment, the 
investigator can decide to call the patient to an unscheduled study visit at the study center. Where 
a patient attends an Unscheduled Visit between the scheduled visits they should be instructed to 
attend their next visit according to the study schedule as planned.
Schedule of assessments are outlined in Table 1.2 of the protocol.


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2.2.
Efficacy Measures

Unified Huntington’s Disease Rating Scale – Total Motor Score (UHDRS-TMS)

Unified Huntington’s Disease Rating Scale – Total Functional Capacity         
(UHDRS-TFC)

Unified Huntington’s Disease Rating Scale – Functional Assessment (UHDRS-FA)

Unified Huntington’s Disease Rating Scale – Independence Scale (UHDRS-IS)

UHDRS Behavioral Assessment

UHDRS Cognitive Assessment

PBA-s (also part of safety measures)
2.3.
Safety Measures

AEs

Vital signs assessments

ECG findings

Concomitant medication usage. 

Physical examination findings 

Suicidality (C-SSRS and PBA-s)
2.4.
Randomization and Blinding
This is a non-randomized, open-label study and there is no blinding.
2.5.
Sample Size and Power Considerations
As this is an open-label extension study, no sample size calculations have been performed.
Patients who completed the HART or the PRIDE-HD study and met patient exclusion/inclusion 
criteria will be enrolled.
2.6.
Sequence of Planned Analyses
2.6.1.
Planned Interim Analyses
There will be no formal interim analysis for this study.
2.6.2.
Final Analyses and Reporting
All analyses identified in this SAP will be performed after the end of study as defined in the 
study protocol.
This SAP and any corresponding amendments will be approved before database lock, in 
accordance to SOP GBP_RD_702 (Statistical Analysis Plan).


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3.
ANALYSIS SETS
3.1.1.
Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set will include all enrolled patients, regardless of whether or 
not a patient took any study drug. 
3.1.2.
Safety Analysis Set
The safety analysis set will include all patients who receive at least 1 dose of study drug. 
3.1.3.
Full Analysis Set 
The full analysis set will include all patients in the ITT analysis set who receive at least 1 dose of 
study drug and have a baseline and at least 1 post-baseline UHDRS-TMS assessment.


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4.
GENERAL ISSUES FOR DATA ANALYSIS
4.1.
General
Descriptive statistics for continuous variables include n, mean, standard deviation (SD), standard 
error (SE), median, minimum, and maximum. Descriptive statistics for categorical variables 
include patient counts and percentages, missing category will be displayed as appropriate.
4.2.
Specification of Baseline Values
The baseline value is the last observed data prior to the first dose of study drug in this study.                                
4.3.
Scoring for Rating Scales
A detailed description for all rating scales below can be found in the protocol.
The UHDRS comprises a broad assessment of features associated with HD. It is a research tool 
which has been developed to provide a uniform assessment of the clinical features and course of 
HD. The TMS component of UHDRS comprises 31 assessments from the 15 items of the 
UHDRS. The UHDRS-TMS is calculated as the sum of the 31 motor assessments.
The TFC scale of the UHDRS assesses 5 functional domains associated with disability 
(occupation, finances, domestic chores, activities of daily living, and care level). The      
UHDRS-TFC is calculated as the sum of the 5 functional capacity items.
The FA component of the UHDRS assesses 25 items associated with functional problems. The 
UHDRS-FA is calculated as the sum of the 25 items.
The behavioral assessment of the UHDRS comprises 11 items that measures the frequency and 
severity of symptoms related to affect, thought content and coping styles. Severity and frequency 
scores are multiplied (after setting all values outside the range of 0-4 to missing) to produce an 
overall score for each item. The total behavioral score is the sum of the overall scores across the 
11 items.
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. Each symptom is 
rated for severitiy and for frequency. Severity and frequency scores are multiplied (after setting 
all values outside the range of 0-4 to missing) to produce an overall ‘PBA score’ for each 
symptom. The PBA total score is the sum of all PBA scores across the 11 symptoms.
4.4.
Handling Withdrawals and Missing Data
For all variables, only the observed data from the patients will be used in the statistical analyses, 
ie, there is no plan to estimate missing data.
For the TMS component of the UHDRS, if responses to 1 assessment up to 25% of assessments
are missing, the missing responses will be replaced by the average of the remaining responses 
within the TMS component. If responses to more than 25% of the assessments are missing, the 
missing responses will not be replaced and the UHDRS-TMS will be set to missing.


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For the TFC scale of the UHDRS, if responses to 1 item up to 25% of items are missing, the 
missing responses will be replaced by the average of the remaining responses within the TFC 
scale. If responses to more than 25% of the assessments are missing, the missing responses will 
not be replaced and the UHDRS-TFC will be set to missing.
For the FA component of the UHDRS, if responses to 1 assessment up to 25% of assessments are 
missing, the missing responses will be replaced by the average of the remaining responses within 
the FA component. If responses to more than 25% of the assessments are missing, the missing 
responses will not be replaced and the UHDRS-FA will be set to missing.
For the behavioral assessment of the UHDRS and the PBA-s, the severity x frequency items need 
to be calculated before calculating the total score. If either the severity or frequency value is 
missing then the item will be equal to the nonmissing value. After calculating the items, if 
responses to 1 item up to 25% of items are missing, the missing responses will be replaced by the 
average of the remaining responses. If responses to more than 25% of the items are missing, the 
missing responses will not be replaced and the total score will be set to missing.
4.5.
Study Days and Visits
Study days are numbered relative to the first day of study drug administration. The start of 
treatment (Day 1) is defined as the date on which a patient takes the first dose of study drug, as 
recorded on the study drug diary. Days will be numbered relative to treatment start (ie, ..., –2, –1, 
1, 2, ...; with day 1 being the first day of study drug administration and day –1 being the day 
before the first day of study drug administration).
For efficacy and safety by-visit analyses, data collected at postbaseline scheduled visits will be 
included using their scheduled visit, data collected at postbaseline unscheduled visits will be 
included and assigned to their corresponding scheduled visit, and data collected at early 
termination visits will be included and assigned to the next scheduled visit. After the assignments 
are made, if there is a scheduled and unscheduled visit at the same visit, the scheduled visit will 
be used in the analysis.       
            
                                                                                  


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5.
STUDY POPULATION
5.1.
General
The ITT analysis set will be used for all study population summaries. Summaries will be 
presented for all patients.
5.2.
Patient Disposition
Patient screened, patients screened but not in the ITT analysis set (and reason not in the ITT 
analysis set) will be summarized using patient counts. Patients in the ITT analysis set, patients in 
the ITT analysis set but not treated, patients in the safety and full analysis sets, patients who 
completed treatment and completed study, and patients who withdraw from the treatment and 
study (and reasons for withdrawing) will be summarized using descriptive statisitcs.
5.3.
Demographics and Baseline Characteristics
For demographics, the continuous variables of patient age, weight, height, and body mass index 
(BMI) will be summarized using descriptive statistics. The categorical variables of patient sex, 
race, and ethnicity will be summarized using descriptive statistics for each category. Missing 
categories will be presented if necessary.                            
For baseline characteristics, the categorical variables of CYP2D6 metabolizer genotype (poor, 
extensive, intermediate or ultra-rapid metabolizer), neuroleptic use, and number of  Cytosine-
Adenosine-Guanine (CAG) repeats, all determined from baseline in the PRIDE-HD or HART
studies, will be summarized using descriptive statistics for each category. Missing categories will 
be presented if necessary.                      
For socio-economics, the continuous variables of year of education, years in occupation most of 
career, years in current occupation, and number of times married will be summarized using 
descriptive statistics. The categorical variables of occupation most of career, current occupation, 
marital status, and handedness will be summarized using descriptive statistics for each category. 
Missing categories will be presented if necessary.                      
5.4.
Medical History
All medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The incidence of medical history abnormalities will be summarized using 
descriptive statistics by system organ class (SOC) and preferred term (PT). Patients are counted 
only once in each SOC category, and only once in each PT category.
5.5.
Prior Therapy and Medication
Any prior therapy or medication a patient has had prior to screening will be recorded on the case 
report form (CRF). The sponsor will encode all therapy and medication according to the World 
Health Organization (WHO) drug dictionary (WHO Drug).
The incidence of prior therapies and medications will be summarized using descriptive statistics 
by therapeutic class and PT. Patients are counted only once in each therapeutic class category, 


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Study ACR16C015
16
and only once in each PT category. Prior therapies and medications will include all medications 
taken and therapies administered before the first day of study drug administration.
5.6.
Electrocardiography
ECG findings (normal and abnormal) at baseline will be summarized using descriptive statistics.
5.7.
Physical Examinations
Physical examination abnormal findings at baseline will be summarized using descriptive 
statistics.
5.8.
Study Protocol Violations
Data from patients with any protocol violations (as recorded in protocol violation CRF) during 
the study will be summarized overall and for each category using descriptive statistics.


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6.
EFFICACY ANALYSIS
6.1.
General
The full analysis set analysis set will be used for all study population summaries unless 
otherwise noted. Summaries will be presented for all patients.
6.2.
Efficacy Endpoint and Analysis
The efficacy endpoints are as follows:

UHDRS-TMS change from baseline to each visit that this is measured.

UHDRS-TFC change from baseline to each visit that this is measured.

UHDRS-FA change from baseline to each visit that this is measured.

UHDRS-IS change from baseline to each visit that this is measured.

UHDRS Behavioral total score change from baseline to each visit that this is 
measured.

UHDRS Cognitive tests change from baseline to each visit that this is measured.

PBA-s total score change from baseline to each visit that this is measured.
All efficacy endpoints wll be summarized for actual values and changes from baseline to each 
visit using descriptive statistics. 
UHDRS Behavioral domain scores and the PBA-s domain scores will also be summarized for 
actual values and changes from baseline of this study to each visit using descriptive statistics.
No formal inferential statistics will be applied to the efficacy endpoints. Efficacy analyses will 
be considered exploratory.


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7.
SAFETY ANALYSIS
7.1.
General
The safety analysis set will be used for all study population summaries unless otherwise noted. 
Summaries will be presented for all patients.
7.2.
Duration of Exposure to Study Drug
Duration of exposure to study drug (days) for individual patients is the number of days patient 
received drug (last day of study drug – first day of study drug + 1).  Duration of treatment (days) 
will be summarized using descriptive statistics. Years on treatment using the categories ≤1 year, 
>1 to ≤2 years, >2 to ≤3 years, >3 to ≤4 years, >4 to ≤5 years, >5 to ≤6 years, and >6 years will 
also be summarized using descriptive statistics.
7.3.
Adverse Events
All AEs will be coded using the MedDRA. AEs occurring on or after the first day of study drug 
administration will be included in the summaries. Summaries will be presented for all AEs
(overall and by severity), AEs determined by the investigator to be related to study drug (overall 
and by severity), serious AEs, AEs leading to withdrawal from the study, and non-serious AEs.
The incidence and total number of AEs will be summarized using descriptive statistics by SOC 
and PT (all AEs overall will also be presented by just PT category). For the incidence of AEs, 
patients are counted only once in each SOC category, and only once in each PT category. The 
exposure adjusted incidence rate will also be presented and is defined as the number of patients 
with an AE divided by patient-years of treatment. For calculating patient-years, patients with an 
AE contribute with treatment exposure up to the day of their first AE, and patients without an AE 
contribute with the entire treatment exposure. For the summary by severity, patients are counted 
at the greatest severity. AEs missing relationship to study drug will be included in the study drug 
related summary.
In addition, a summary of AEs by time period of treatment will be presented.
7.4.
Vital Signs
Summary statistics for pulse, blood pressure, body temperature, and weight will be presented at 
baseline and each visit. Vital signs values and changes from baseline to each visit will by 
summarized using descriptive statistics.
The incidence of potentially clinically significant abnormal values will be summarized for vital 
signs using descriptive statistics with the criteria specified in Table 1. These summaries willl 
include all postbaseline values (including scheduled, unscheduled, and withdrawal visits). Note 
that in order to qualify as potentially clinically significant abnormal, a value needs to meet both 
criteria below: ie, have a value beyond the criterion value and a change of at least the magnitude 
specified in the change relative to baseline column.


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Table 1:
Criteria for Potentially Clinically Significant Vital Signs
Vital Sign
Criterion value
Change relative to baseline
Pulse
120 bpm
Increase of 15
50 bpm
Decrease of 15
Systolic blood pressure
180 mm Hg
Increase of 20
90 mm Hg
Decrease of 20
Diastolic blood pressure
105 mm Hg
Increase of 15
50 mm Hg
Decrease of 15
Body temperature
≥38.3C
Change of 1.1C
7.5.
Electrocardiography
Shifts (normal and abnormal) from baseline to overall finding and each visit willl be summarized 
using patient counts. For overall finding, the summary will use the worst postbaseline finding for 
the patient (the abnormal finding if there are both normal and abnormal findings). Summary 
statistics for ECG variables will be presented at baseline and each visit. Actual values and 
changes from baseline to each visit will be summarized using descriptive statistics.
The incidence of potentially clinically significant abnormal values for ECG variables will be 
summarized using descriptive statistics with the criterian specified below.

QTcF values >450 ms or >480 ms or >500 ms.

QTcF change from baseline values >30 or >60.

PR change from baseline 25% and value >200.

QRS change from baseline 25% and value >110.

Heart rate value <60 bpm or >100 bpm.
7.6.
Physical Examinations
Shifts (normal and abnormal) from baseline to each visit for each category will be summarized 
using patient counts. 
7.7.
Concomitant Medications or Therapies 
Concomitant medications and therapies, including medications that are taken on an as needed 
basis and occasional therapies, will be monitored during the study. All concomitant medications 
will be coded using the WHO drug.
The incidence of concomitant medications and therapies will be summarized using descriptive 
statistics by therapeutic class category and PT. Patients are counted only once in each therapeutic 
class, and only once in each PT category. Concomitant medications and therapies will include all 


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medications taken and therapies administered from the first day of study drug administration up 
to the end of study as defined in the study protocol.
7.8.
Other Safety Assessments
Summary statistics for the C-SSRS baseline version will be presented at screening. Patients with 
suicidal ideation and behavior items will be summarized as categorical data using descriptive 
statistics.
Summary statistics for the C-SSRS last visit version will be presented at overall postbaseline. 
Patients with suicidal ideation and behavior items will be summarized as categorical data using 
descriptive statistics.


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8.
STATISTICAL SOFTWARE
All data listings, summaries, and statistical analyses will be generated using SAS® version 9.4 or 
later.


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9.
CHANGES TO ANALYSES SPECIFIED IN THE STUDY 
PROTOCOL
There are no changes to analyses specified in the study protocol.