Clinical trial NCT02494778
Conditions: Huntington's Disease
Keywords: Huntington's disease, pridopidine
Sponsor: Prilenia
Start date: 2015-09-24; Completion date: 2018-01-12
Enrollment: 248 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study is to collect and assess long term data on the safety, tolerability, and efficacy of pridopidine in patients with Huntington's disease (HD).

Detailed description:

Arms: arm 1: The mode of administration is oral. Capsules will be swallowed whole with water. One capsule should be taken in the morning and 1 in the afternoon, 7 to 10 hours after the morning dose. Study drug can be taken irrespective of meals.
Interventions: intervention 1: Pridopidine
Intervention descriptions: intervention 1: 45 mg BID

Protocol documents:
Prot_000.pdf: 
Official Title: A Multi-Center, Open-Label Study Evaluating the Safety, Tolerability, 
and Efficacy of Pridopidine in Patients with Huntington’s Disease (Open PRIDE-HD) 
NCT Number: NCT02494778 
Document Date: 31 Mar 2016 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
1
TITLE PAGE
Clinical Study Protocol
Study Number TV7820-CNS-20016
A Multi-Center, Open-Label Study Evaluating the Safety, Tolerability, and Efficacy of 
Pridopidine in Patients with Huntington’s Disease (Open PRIDE-HD)
(Open PRIdopidine Dose Evaluation in Huntington's Disease)
Phase 2
IND number: 77,419
EudraCT number: 2015-000904-24
Protocol Approval Date: 31 March 2016
Sponsor (and Monitor)
Teva Branded Pharmaceutical 
Products R&D, Inc.
Authorized Representative
VP Global Head, Neurodegeneration, Clinical Development
Teva Branded Pharmaceutical Products R&D, Inc.
Sponsor’s Medical Expert
Sponsor’s Safety Representative
Senior Director, Clinical Development
Leader NDD
Teva Branded Pharmaceutical 
Products R&D, Inc.
Director, PhV Safety Physician
Global Patient 
Safety & Pharmacovigilance 
Teva Pharmaceutical Industries, Ltd.
Confidentiality Statement
This clinical study will be conducted in accordance with current Good Clinical Practice (GCP) as directed 
by the provisions of the International Conference on Harmonisation (ICH); United States (US) Code of 
Federal Regulations (CFR) and European Union (EU) Directives (as applicable in the region of the 
study); local country regulations; and the sponsor’s Standard Operating Procedures (SOPs). 
This document contains confidential and proprietary information (including confidential commercial 
information pursuant to 21CFR§20.61) and is a confidential communication of Teva Branded 
Pharmaceutical Products R&D, Inc. The recipient agrees that no information contained herein may be 
published or disclosed without written approval from the sponsor.
© 2016 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
2
AMENDMENT HISTORY
The protocol for study TV7820-CNS-20016 (original protocol dated 26 March 2015) has been 
amended and reissued as follows:
Global Protocol Amendment 02
31 March 2016
(94 patients enrolled to date)
Administrative Letter 02
03 February 2016
Global Protocol Amendment 01
30 June 2015
(0 patients enrolled to date)
Administrative Letter 01
05 May 2015
(0 patients enrolled to date)
 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
3
INVESTIGATOR AGREEMENT


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
4
CLINICAL LABORATORY AND OTHER DEPARTMENTS AND 
INSTITUTIONS
Central Clinical Laboratory
 
 
 
 
 
 
 
 
 
 
 
 
Electronic Data Capture
Central Electrocardiogram Evaluation
Web and Phone Integrated Interactive Response Technology
 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
5
Bioanalytical Pharmacokinetics Evaluation
Computer-Based Rating System
Digital Health Sub-Study 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
6
CLINICAL STUDY PERSONNEL CONTACT INFORMATION
For medical issues, contact the physician listed below: 
EU Sites:
Australian Sites:
US and Canadian Sites:
In a study-related medical emergency situation, when assigned Medical Monitors for a study 
cannot be reached, an on-call Physician can be reached 24 hours per day, 7 days per week via an 
 [Toll (not free of charge) telephone number 
allowing a global reach from both landlines and mobile phones]
On the following internet page
 a list of country-specific toll-free 
telephone numbers is provided. It should be noted that not all countries globally have access to 
toll-free numbers as indicated on the “24/7 Medical Help desk” index. Countries without toll-free 
numbers need to dial the toll (not free of charge) number as indicated above. Toll-free numbers 
are unfortunately not available from mobile phones. 
For operational issues, contact the operational lead listed below: 
For serious adverse events:
Send by e mail to the local safety officer/contract research organization (LSO/CRO). The email 
address will be provided in the serious adverse event (SAE) report form. In the event of 
difficulty transmitting the form, contact the sponsor’s study personnel identified above for 
further instruction.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
7
CLINICAL STUDY PROTOCOL SYNOPSIS
Study TV7820-CNS-20016
Title of Study: A Multi-Center, Open-Label Study Evaluating the Safety, Tolerability, and Efficacy of Pridopidine 
in Patients with Huntington’s Disease (Open PRIDE-HD- Open PRIdopidine Dose Evaluation in Huntington's 
Disease)
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
IND Number: 77,419
EudraCT Number: 2015-000904-24
Name of Active Ingredient: 4-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride (pridopidine) 
Name of Investigational Product: Pridopidine capsules
Phase of Clinical Development: 2 
Number of Investigational Centers Planned: Up to 54
Countries Planned: Australia, Austria, Canada, Denmark, France, Germany, Italy, Netherlands, Poland, Russia, 
United Kingdom (UK), United States (US)
Planned Study Period: First Patient First Visit in Q3 2015. Enrollment will continue until the last patient from the 
TV7820-CNS-20002 study (PRIDE-HD) has entered the study. Treatment duration will be extended for an 
additional 52 weeks (ie, total of 104 weeks), until approximately Q3 2017 (last patient last visit for the extended 
study period).
Number of Patients Planned: Up to 300 
Study Population: Male and female patients, aged ≥21 years and with body weight ≥50 kg with HD who completed 
the double-blind, randomized phase in PRIDE-HD study, including the follow-up period, or who participated in the 
open-label ACR16C015 (Open-HART) extension study. 
Primary Objective: The primary objective of this study is to evaluate safety and tolerability of pridopidine in 
patients with HD.
Secondary Objectives: The secondary objectives of the study are to assess the effects of long-term, open-label 
dosing with pridopidine on motor symptom severity, overall patient function, physical performance, and health-
related quality of life.
Study Endpoints:
Safety endpoints:
Safety measures will include the following: 

adverse events (AEs)

vital signs assessments

concomitant medication usage 

physical examination findings 

clinical laboratory evaluations (hematology, clinical chemistry, and urinalysis)


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
8

Electrocardiography (ECG) findings 

Suicidality [using the Columbia-Suicide Severity Rating Scale (C-SSRS)] and Problem Behaviors 
Assessment-Short form (PBA-s)_
Tolerability endpoints: 

Proportion of subjects (%) who prematurely discontinued from the study

Proportion of subjects (%) who prematurely discontinued from the study due to AEs 
Efficacy endpoints:
Long-term efficacy evaluations are the secondary objective of this study. Efficacy endpoints include the following

Unified Huntington’s Disease Rating Scale – Total Motor Score (UHDRS-TMS)

Modified Physical Performance Test (mPPT)

Unified Huntington’s Disease Rating Scale - Total Functional Capacity (UHDRS-TFC)

Short Form 12 (SF-12) questionnaire (acute version)

Problem Behaviors Assessment-Short form (PBA-s) (also part of safety assessments)

Quantitative motor (Q-motor) assessment
General Design and Methodology:
This is an open-label, multi-center study to evaluate the safety, tolerability, and efficacy of pridopidine 45 mg twice-
daily (bid) in patients with HD.
It is planned to enroll up to 300 patients from the PRIDE-HD and Open-HART studies. 
The following titration scheme will be followed:

Week 1: Patients will receive 1 capsule of 22.5 mg pridopidine bid (22.5 mg bid, total daily dose of 45 
mg pridopidine). 

Week 2 to study completion: Patients will receive 1 capsule of 45 mg pridopidine bid (total daily dose 
of 90 mg pridopidine).
Upon meeting eligibility criteria, patients who transition from the ACR16C015 (Open-HART) study may perform 
the baseline visit assessments and procedures. They do not have to undergo titration as they will continue taking the 
same dose as in Open-HART (45 mg bid).
Patients will be treated with study drug for 104 weeks. Safety will be assessed after 4, 12, 26, 52, 78, and 104 weeks 
of treatment and at the follow-up End-of-study (EoS) visit (Week 106). Safety evaluation telephone calls will be 
performed at weeks 18 and 38. During these phone calls, inquiries about adverse events, concomitant medication 
(including changes in use of benzodiazepines and antidepressants), changes in use of alcohol and illicit drugs, C-
SSRS, and an abbreviated PBA-s (a subset of PBA-s questions on depressed mood, suicidal ideation, anxiety, 
irritability, loss of motivation, and obsessive-compulsive behaviors) will be conducted.
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.
Doses of up to 112.5 mg bid are currently being investigated in the ongoing PRIDE-HD study. Upon completion of 
PRIDE-HD and following analysis of safety, tolerability, and efficacy data the dose administered in this study may
be adjusted to a maximum of 112.5mg bid after a titration period at the discretion of the sponsor. 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
9
During the study, an independent Data and Safety Monitoring Board (DSMB) will review accumulating safety data. 
The DSMB will meet as detailed in the charter. In case of a significant emerging safety concern the DSMB will have 
the authority to discontinue enrolled patients from study drug administration, and stop enrollment of new patients. 
Thereafter, the DSMB will decide whether there is a need for additional meetings, and, if needed, will determine 
when these will take place.
Digital Health Sub-study (optional participation):
Motor symptoms can be objectively assessed in Huntington’s disease patients using different quantitative motor 
assessments.
Objective motor assessments aim at improving the limited sensitivity observed with categorical clinical rating 
scales, and reducing the intra- and inter-rater variability, as well as potential placebo effect observed in scales such 
as the UHDRS. Improved sensitivity for early-stage clinical studies of efficacy of a new drug on motor dysfunction 
is expected with objective assessments and may support early go/no go decisions in smaller cohorts of patients 
(Reilmann et al. 2001; Reilmann et al. 2011).
A feasibility sub-study including up to 60 patients with chorea will be conducted to collect accelerometry data using 
a wearable sensor-mobile application tool. The overall objective of the sub-study is to test the hypothesis of using 
wearable sensor data to estimate clinically relevant measures of HD in patients while on their medication regimen, 
which includes pridopidine. The aim is to develop algorithms to objectively quantify chorea by analyzing the data 
from the wearable sensors. The application will also include a simple diary to track medication use during the study. 
Patients enrolled in the sub-study will be provided with a commercial grade wearable digital sensor (Pebble watch), 
an android smartphone and will be granted access to the accompanying mobile application. The mobile application 
will collect accelerometry and medication data and transmit for storage and processing. Participating subjects will be 
asked to continuously wear the digital sensor for a period of 6 months. Participation in the sub-study will be 
optional. The accelerometry data collection will be performed on the wrist of the non-dominant limb. A training 
session will be done at screening for the sub-study. Assessments will be done at times specified in the Schedule of 
Activities section of the protocol. A separate user’s manual and training on the tool will be provided to sites. This 
system of data collection will allow researchers and clinicians to gather detailed patient data outside of the clinical 
setting. The data analysis is expected to facilitate future research and clinical studies on the effectiveness of new 
interventions in HD.
Method of Blinding and Randomization: 
This is a nonrandomized, open-label study with no blinding.
Study Drug Dose, Mode of Administration, and Administration Rate:
Pridopidine will be provided as a white hard gelatin capsule, size 2 containing 45 mg pridopidine and a white hard 
gelatin capsule, size 4 containing 22.5 mg pridopidine or a light pink/white hard gelatin capsule, size 2 with black 
color imprinting containing 45 mg pridopidine and a white hard gelatin capsule, size 4, with black imprinting 
containing 22.5 mg pridopidine.
The mode of administration is oral. Capsules will be swallowed whole with water. One capsule should be taken in 
the morning and 1 in the afternoon, 7 to 10 hours after the morning dose. Study drug can be taken irrespective of 
meals.
Each medication pack will contain distinct labeled bottles in accordance with the associated dose strength. The 
capsules will be provided in 2 configurations: Each bottle will contain 30 capsules (of 22.5 mg or 45 mg white 
capsules; or 22.5 mg white imprinted capsules) or 60 capsules (of 45 mg light pink/white imprinted capsules). 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
10
Bottles will be used to accomplish the dosing of possible treatment options including possible dose escalation and 
de-escalation. Each bottle will be labeled with a unique pack number.
All medication supplied in connection with this study must be used only for this study and no other purpose.
Duration of Patient Participation: Treatment duration is 104 weeks. Study participation will be 108 weeks, 
including a screening period of up to 2 weeks and an end-of-study (EoS) follow-up visit. 
Criteria for Inclusion: Patients may be included in the study only if they meet all of the following criteria: 
a.
[Revision 1] Patient has completed the PRIDE-HD trial within the last 6 months, including the follow-
up period, or transitioned from Open-HART.
For patients that have failed to complete PRIDE-HD or those who completed the PRIDE-HD study 
over 6 months prior to the screening visit, and meet all other inclusion criteria, eligibility should be 
discussed with the Open-PRIDE medical monitor and clinician on a case-by-case basis
b.
[Revision 1] For patients that experienced a drug-related serious adverse event (SAE) or had a major 
compliance violation during PRIDE-HD or Open-HART, eligibility approval should be discussed with 
PRIDE-HD’s or Open-HART's medical monitor and clinician. Patients that experienced an adverse 
event/serious adverse event of suicidal ideation/behavior will be excluded without discussion.
c.
Able and willing to provide written informed consent prior to any study related procedure being 
performed. Patients with a legal guardian should be consented according to local requirements.
d.
Females of child bearing potential have to be compliant in using adequate birth control throughout the 
duration of the study. Adequate birth control is defined as consistent practice of an effective and 
accepted method of contraception according to local regulations (hormone-based, intrauterine device, 
or double barrier contraception, i.e., condom and diaphragm). Abstinence is an acceptable method of 
contraception only when this is the preferred and usual lifestyle of the subject. Periodic abstinence 
(calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), and lactational 
amenorrhoea method (LAM) are not acceptable methods of contraception. Male study participants 
have to be compliant in using adequate birth control with their partners (as defined above) throughout 
the duration of the study.
e.
Body weight ≥50 kg. Patients that meet this criterion at screening but fail to meet it at a subsequent 
visit may be discontinued based on Investigator or Sponsor discretion. It is allowed to repeat the 
weight measurement once, if clinically appropriate. 
f.
Willing and able to take oral medication and able to comply with the study specific procedures. 
g.
Ambulatory, being able to travel to the study center, and judged by the investigator as likely to be able 
to continue to travel for the duration of the study.
h.
The patient is in good health as determined by medical examination, ECG, serum chemistry, 
hematology, and urinalysis. 
i.
The patient must be willing and able to comply with study restrictions and to remain at the clinic for 
the required duration during the study period, and willing to return to the clinic for evaluation as 
specified in this protocol.
Criteria for Exclusion: Patients will be excluded from participating in this study if they meet any of the following 
criteria:


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
11
a.
A prolonged Fridericia-corrected QT (QTcF) interval (defined as a QTcF interval of >450 msec) at the 
screening visit. ECGs will be performed in triplicate during the screening visit, and the mean of the 3 
QTcF measurements will be used to determine whether or not the patient is suitable for inclusion in the 
study.
b.
Patients with clinically significant heart disease at the screening visit, defined as follows: (i) significant 
cardiac event (eg, myocardial infarction), angina pectoris or episode of congestive heart failure with 
symptoms >Grade 2 New York Heart Association classification within 12 weeks before 
randomization, or presence of cardiac disease that in the opinion of the investigator increased the risk 
of ventricular arrhythmia, (ii) history of arrhythmia (multifocal premature ventricular contractions, 
bigeminy, trigeminy, ventricular tachycardia) that was symptomatic or required treatment (Common 
Terminology Criteria for Adverse Events Grade 3), symptomatic or uncontrolled atrial fibrillation 
despite treatment, or asymptomatic sustained ventricular tachycardia, (iii) presence of left bundle 
branch block.
c.
Patients with serum potassium, magnesium, and/or calcium levels outside of the central laboratory’s 
reference range at the screening visit and considered clinically significantly abnormal by the 
investigator. Repeat testing is allowed (up to a maximum of 3 tests) if required to establish whether 
values are within normal range or clinically significantly abnormal.
d.
Patients receiving medications (within the last 6 weeks prior to baseline) other than pridopidine that 
have been proven to prolong QT interval or who may require such medications during the course of the 
study such as but not limited to non-allowed anti-psychotic medications, tricyclic antidepressants,
and/or Class I antiarrhythmics.
e.
Patients receiving medications (within the last 6 weeks prior to baseline) other than pridopidine that 
are metabolized by Cytochrome P450 (CYP) 2D6 and have the potential of reducing seizure threshold.
f.
Patients with a history of epilepsy or of seizures within the last 5 years.
g.
Creatinine clearance <60 mL/min at screening, calculated using the Cockcroft-Gault equation: 
(140 - age) × mass (kg) × [0.85 if female] / 72 × serum creatinine (mg/ dL). It is allowed to repeat the 
test once, if clinically appropriate.
h.
Any clinically significant, abnormal, screening laboratory result which in the opinion of the 
investigator, affects the patients’ suitability for the study or puts the patient at risk if he/she enters the 
study.
i.
[Revision 1] Patients with adverse events of suicidal ideation or attempt at any time in the past or as 
measured by suicide ideation score of ≥3on the C-SSRS, or 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 the attempt or acts were performed at any time in the past, or patients 
who, in the opinion of the investigator, present a risk of suicide.
j.
Females who are pregnant or breastfeeding.
k.
Treatment with any investigational product other than pridopidine within 6 weeks of screening or 
patients planning to participate in another clinical study assessing any investigational product during 
the study.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
12
Measures and Time Points: 
The following assessments will be performed at the specified time points: 

Eligibility criteria will be reviewed and confirmed at screening and baseline.

Vital signs will be measured at each study visit. Vital signs include the following: pulse, blood 
pressure (supine and standing), body temperature.

A brief (symptom-directed) physical examination will be performed at each study visit. 

Serum chemistry tests will be performed at each study visit.

Hematology tests will be performed at each visit;

Urinalysis will be performed at each visit;

Human chorionic gonadotropin (HCG) serum test will be performed for all women of childbearing age 
at screening. HCG urine tests will be performed for all women of childbearing age at all subsequent 
visits, and if clinically indicated at any other time.

ECG will be performed at every visit and will be centrally evaluated at a core lab. 

Adverse Events (AEs) will be monitored throughout the study.

Suicidality will be monitored throughout the study through administration of the C-SSRS and PBA-s.

Concomitant medications will be monitored throughout the study.

Motor function evaluations (UHDRS Total Motor Score) will be performed at all visits

Modified physical performance test (mPPT) will be performed at baseline, week 12, week 26, week 
52, week 78, week 104 and week 106.

Functional capacity evaluation (UHDRS-Total Functional Capacity) will be performed at baseline, 
week 26, week 52, week 78, week 104 and week106.

SF-12 evaluation will be performed at baseline, week 26, week 52, week 78, week 104 and week 106.

The PBA-s will be performed at all study visits.

Q-motor assessment will be performed at baseline, week 52, week 78, week 104 and week 106.
Pharmacokinetics Measures and Time Points:
Pharmacokinetic (PK) samples will be aimed to be drawn, to the extent possible, in the event of a SAE, an AE 
leading to discontinuation, or for patients who withdrew prematurely because of lack of efficacy
Allowed and Disallowed Medications Before and During the Study: 
Medications that are CYP2D6 substrates and have a narrow safety margin, eg, class I antiarrythmics and tricyclic 
antidepressants, will be administered according to the list of permitted and prohibited concomitant medications. 
Disallowed CYP2D6 substrates can be administered only 1 week after the discontinuation of pridopidine (i.e., 1-
week washout), to allow enzyme recovery. CYP2D6 inhibitors can be administered to study patients.
The concomitant use of medications that are known to have a profound effect on QT interval should be avoided 
according to the list of permitted and prohibited concomitant medications.
 
concomitant treatment with tetrabenazine 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
13
is disallowed. Medications that are CYP2D6 substrates and have the potential to reduce the seizure threshold will 
not be permitted during the study.
Statistical Considerations:
Sample Size Rationale:
This is an open-label study. The sample size for this study is not based on statistical considerations; hence, only 
descriptive statistics will be presented. Up to 300 subjects who completed the PRIDE-HD or transitioned from the 
ongoing Open-HART study and met patient exclusion/inclusion criteria will be enrolled.
Analysis of Efficacy Endpoints: No formal inferential statistics will be applied to the efficacy endpoints. Efficacy 
analyses will be considered exploratory. Comparisons will generally be made to baseline, as appropriate. Descriptive 
statistics over time will be presented to detect trends via changes from baseline.
Multiple Comparisons and Multiplicity: Not applicable.
Safety and Tolerability Analyses: 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Each patient will be 
counted only once in each preferred term or system organ class (SOC) category for the analyses of safety. 
Summaries will be presented for all AEs (overall and by severity), AEs determined by the investigator to be related 
to study treatment (defined as related or with missing relationship) (overall and by severity), serious AEs, and AEs 
causing withdrawal from the study. Summaries will be presented by treatment group and for all patients. Patient 
listings of SAEs and AEs leading to withdrawal will be presented.
Changes in laboratory and vital signs measurement data will be summarized descriptively. All values will be 
compared with pre-specified boundaries to identify potentially clinically significant changes or values, and such 
values will be listed.
The use of concomitant medications will be summarized by therapeutic class using descriptive statistics. 
Concomitant medications will include all medications taken while the patient is treated with study drug.
Descriptive summaries of SAEs, patient withdrawals due to AEs, and potentially clinically significant abnormal 
values (clinical laboratory or vital signs) based on predefined criteria will also be provided.
If any patient dies during the study, a listing of deaths will be provided and all relevant information will be discussed 
in the patient narrative included in the clinical study report.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
14
TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
AMENDMENT HISTORY .............................................................................................................2
INVESTIGATOR AGREEMENT...................................................................................................3
CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS ..............4
CLINICAL STUDY PERSONNEL CONTACT INFORMATION ...............................................6
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................7
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................22
1.
BACKGROUND INFORMATION...........................................................................25
1.1.
Introduction.................................................................................................................25
1.1.1.
Huntington’s Disease..................................................................................................25
1.1.2.
Pridopidine..................................................................................................................25
1.2.
Name and Description of Investigational Product......................................................25
1.3.
Findings from Nonclinical and Clinical Studies.........................................................26
1.3.1.
Nonclinical Studies.....................................................................................................26
1.3.2.
Clinical Studies...........................................................................................................27
1.3.2.1.
Clinical Pharmacology Studies...................................................................................27
1.3.2.2.
Clinical Safety and Efficacy Studies ..........................................................................28
1.4.
Known and Potential Risks and Benefits to Human Patients.....................................29
1.4.1.
Risks of Pridopidine ...................................................................................................29
1.4.1.1.
Drug Interactions ........................................................................................................30
1.4.1.2.
Carcinogenesis, Mutagenesis, Impairment of Fertility...............................................30
1.4.1.3.
Pregnancy ...................................................................................................................31
1.4.1.4.
Pharmacological Class Events....................................................................................31
1.4.2.
Benefits of Pridopidine...............................................................................................31
1.4.3.
Overall Risk and Benefit Assessment for This Study ................................................31
1.5.
Selection of Drugs and Dosages.................................................................................33
1.5.1.
Justification for Dosage of Active Drug.....................................................................33
1.6.
Compliance Statement................................................................................................33
1.7.
Population To Be Studied and Justification................................................................34
1.8.
Location and Timing of Study....................................................................................34
2.
PURPOSE OF THE STUDY AND STUDY OBJECTIVES.....................................35


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
15
2.1.
Purpose of the Study...................................................................................................35
2.2.
Study Objectives.........................................................................................................35
2.2.1.
Primary Objective.......................................................................................................35
2.2.2.
Secondary Objectives .................................................................................................35
2.3.
Study Endpoints..........................................................................................................35
2.3.1.
Safety and Tolerability Endpoints ..............................................................................35
2.3.1.1.
Safety Endpoints:........................................................................................................35
2.3.1.2.
Tolerability Endpoints: ...............................................................................................35
2.3.2.
Efficacy Endpoints......................................................................................................36
3.
STUDY DESIGN .......................................................................................................37
3.1.
General Design and Study Schema.............................................................................37
3.2.
Justification for Study Design ....................................................................................39
3.3.
Efficacy Measures and Time Points ...........................................................................39
3.4.
Safety and Tolerability Measures and Time Points....................................................39
3.5.
Pharmacokinetic Measures and Time Points..............................................................40
3.6.
Randomization and Blinding......................................................................................40
3.6.1.
Data and Safety Monitoring Board.............................................................................40
3.7.
Drugs Used in the Study.............................................................................................40
3.7.1.
Investigational Product ...............................................................................................40
3.8.
Drug Supply and Accountability ................................................................................41
3.8.1.
Drug Storage and Security..........................................................................................41
3.8.2.
Drug Accountability ...................................................................................................41
3.9.
Duration of Patient Participation and Justification.....................................................41
3.10.
Stopping Rules and Discontinuation Criteria .............................................................41
3.10.1.
Discontinuation of Individual Patients .......................................................................42
3.11.
Source Data Recorded on the Case Report Form .......................................................42
3.12.
Study Procedures ........................................................................................................43
3.12.1.
Procedures for Screening and Enrollment (Visit 1)....................................................47
3.12.2.
Procedures Before Study Drug Treatment (Baseline [Visit 2])..................................48
3.12.3.
Procedures During Study Drug Treatment – Open Label Treatment Period..............49
3.12.3.1.
Weeks 4 and 12 [Visits 3 and 4].................................................................................49
3.12.3.2.
Telephone Contact at Week 18 and Week 38.............................................................50


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
16
3.12.3.3.
Week 26 (Visit 5), Week 52 (Visit 6), Week 78 (Visit 7) and Week 104 (End 
Of Treatment, Visit 8).................................................................................................50
3.12.3.4.
Week 106 (Visit 9) - End of Study / Early Termination Visit....................................51
3.12.4.
Procedures After Study Drug Treatment ....................................................................51
3.12.5.
Unscheduled Visits .....................................................................................................52
4.
SELECTION AND WITHDRAWAL OF PATIENTS..............................................53
4.1.
Patient Inclusion Criteria ............................................................................................53
4.2.
Patient Exclusion Criteria...........................................................................................54
4.3.
Justification for Key Inclusion and Exclusion Criteria...............................................55
4.4.
Withdrawal Criteria and Procedures...........................................................................55
5.
TREATMENT OF PATIENTS..................................................................................57
5.1.
Drugs Administered During the Study .......................................................................57
5.2.
Restrictions .................................................................................................................57
5.3.
Prior and Concomitant Therapy or Medication..........................................................57
5.3.1.
Permitted Medication..................................................................................................58
5.3.2.
Prohibited Medication ................................................................................................59
5.3.2.1.
Antipsychotic Medication...........................................................................................59
5.3.2.2.
Antidepressant Medication.........................................................................................59
5.3.2.3.
Antiarrhythmic Medication ........................................................................................59
5.3.2.4.
Medications Lowering Seizure Thresholds ................................................................59
5.4.
Procedures for Monitoring Patient Compliance .........................................................60
5.5.
Temporary Study Drug Discontinuation ....................................................................60
5.6.
Total Blood Volume ...................................................................................................60
6.
ASSESSMENT OF EFFICACY ................................................................................62
6.1.
Efficacy Measures and Justification ...........................................................................62
6.1.1.
UHDRS-TMS .............................................................................................................63
6.1.2.
Modified Physical Performance Test..........................................................................63
6.1.3.
UHDRS Total Functional Capacity............................................................................63
6.1.4.
Short Form 12 (SF-12) Health Survey........................................................................63
6.1.5.
Problem Behaviors Assessment-Short Form..............................................................64
6.1.6.
Quantitative Motor (Q-Motor) Assessment................................................................65
6.1.6.1.
Digitomotography (Speeded Index Finger Tapping)..................................................65
6.1.6.2.
Dysdiadochomotography (Pronation/Supination Hand Tapping) ..............................65


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
17
6.1.6.3.
Manumotography and Choreomotography (Grip Force and Chorea Analysis) .........65
6.1.6.4.
Pedomotography (Speeded Foot Tapping) .................................................................66
6.2.
Methods and Timing of Assessing, Recording, and Analyzing Efficacy Data ..........66
7.
ASSESSMENT OF SAFETY.....................................................................................67
7.1.
Adverse Events ...........................................................................................................67
7.1.1.
Definition of an Adverse Event..................................................................................67
7.1.2.
Recording and Reporting Adverse Events..................................................................68
7.1.3.
Severity of an Adverse Event .....................................................................................69
7.1.4.
Relationship of an Adverse Event to the Study Drug.................................................70
7.1.5.
Serious Adverse Events..............................................................................................70
7.1.5.1.
Definition of a Serious Adverse Event .......................................................................70
7.1.5.2.
Expectedness...............................................................................................................71
7.1.5.3.
Reporting a Serious Adverse Event............................................................................71
7.1.6.
Protocol-Defined Adverse Events for Expedited Reporting ......................................73
7.1.7.
Withdrawal Due to an Adverse Event ........................................................................73
7.1.8.
Overdose of Study Drug .............................................................................................74
7.1.9.
Protocol Deviations Because of an Adverse Event ....................................................74
7.2.
Pregnancy ...................................................................................................................74
7.3.
Clinical Laboratory Tests ...........................................................................................75
7.3.1.
Serum Chemistry ........................................................................................................75
7.3.2.
Hematology.................................................................................................................76
7.3.3.
Urinalysis....................................................................................................................76
7.3.4.
Other Clinical Laboratory Tests .................................................................................77
7.3.4.1.
Human Chorionic Gonadotropin Tests.......................................................................77
7.4.
Vital Signs ..................................................................................................................77
7.5.
Electrocardiography....................................................................................................77
7.6.
Physical Examinations................................................................................................78
7.7.
Concomitant Therapy or Medication..........................................................................78
7.8.
Other Safety Measures and Variables.........................................................................78
7.8.1.
Columbia Suicide Severity Rating Scale....................................................................78
7.9.
Methods and Timing of Assessing, Recording, and Analyzing Safety Data..............79
8.
ASSESSMENT OF PHARMACOKINETICS/ PHARMACODYNAMICS 
BIOMARKERS/ PHARMACOGENOMICS/ IMMUNOGENICITY ......................80


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
18
9.
STATISTICS ..............................................................................................................81
9.1.
Sample Size and Power Considerations .....................................................................81
9.2.
Analysis Sets...............................................................................................................81
9.2.1.
Intent-to-Treat Analysis Set........................................................................................81
9.2.2.
Safety Analysis Set.....................................................................................................81
9.2.3.
Full Analysis Set.........................................................................................................81
9.3.
Data Handling Conventions........................................................................................81
9.4.
Study Population.........................................................................................................81
9.4.1.
Patient Disposition......................................................................................................81
9.4.2.
Demographic and Baseline Characteristics ................................................................82
9.5.
Efficacy Analysis........................................................................................................82
9.5.1.
Efficacy Endpoint .......................................................................................................82
9.5.2.
Planned Method of Analysis.......................................................................................82
9.6.
Multiple Comparisons and Multiplicity......................................................................82
9.7.
Safety Endpoints and Analysis ...................................................................................82
9.7.1.
Safety Endpoints.........................................................................................................82
9.7.2.
Safety Analysis ...........................................................................................................82
9.8.
Tolerability Variables and Analysis ...........................................................................83
9.8.1.
Tolerability Variables .................................................................................................83
9.8.2.
Tolerability Analysis ..................................................................................................83
9.9.
Planned Interim Analysis............................................................................................83
9.10.
Reporting Deviations from the Statistical Plan ..........................................................83
10.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................84
11.
QUALITY CONTROL AND QUALITY ASSURANCE .........................................85
11.1.
Protocol Amendments and Protocol Deviations and Violations ................................85
11.1.1.
Protocol Amendments ................................................................................................85
11.1.2.
Protocol Violations.....................................................................................................85
11.2.
Information to Study Personnel..................................................................................85
11.3.
Study Monitoring........................................................................................................86
11.4.
Clinical Product Complaints.......................................................................................86
11.4.1.
Product Complaint Information Needed from the Investigational Center..................87
11.4.2.
Handling the Study Drug at the Investigational Center..............................................87


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
19
11.4.3.
Adverse Events or Serious Adverse Events Associated with a Product 
Complaint ...................................................................................................................88
11.4.4.
Documenting a Product Complaint ............................................................................88
11.5.
Audit and Inspection...................................................................................................88
12.
ETHICS ......................................................................................................................89
12.1.
Informed Consent .......................................................................................................89
12.2.
Health Authorities and Independent Ethics Committees/Institutional Review 
Boards.........................................................................................................................89
12.3.
Confidentiality Regarding Study Patients ..................................................................89
12.4.
Declaration of the End of the Clinical Study..............................................................90
12.5.
Registration of the Clinical Study...............................................................................90
13.
DATA HANDLING, DATA QUALITY CONTROL, AND RECORD 
KEEPING ...................................................................................................................91
13.1.
Data Collection...........................................................................................................91
13.2.
Data Quality Control...................................................................................................91
13.3.
Archiving of Case Report Forms and Source Documents..........................................92
13.3.1.
Sponsor Responsibilities.............................................................................................92
13.3.2.
Investigator Responsibilities.......................................................................................92
14.
FINANCING AND INSURANCE.............................................................................94
15.
REPORTING AND PUBLICATION OF RESULTS................................................95
16.
REFERENCES ...........................................................................................................96


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
20
LIST OF TABLES
Table 1:
Study Procedures and Assessments............................................................................44
Table 2:
Blood Volumes...........................................................................................................61


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
21
LIST OF FIGURES
Figure 1:
Overall Study Schema ................................................................................................38


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
22
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
Arc mRNA
activity-regulated cytoskeleton-associated protein messenger ribonucleic acid
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
β-HCG
beta human chorionic gonadotropin
bid
twice daily
BUN
blood urea nitrogen
CAG
cytosine-adenosine-guanine
CBC
Complete blood count
CDMS
clinical data management system 
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences 
Cmax
maximum observed plasma drug concentration
CNS
central nervous system
CPK
creatine phosphokinase
CRF
case report form
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
cytochrome P450
DSMB
Data and Safety Monitoring Board
ECG
electrocardiogram
EM
extensive metabolizers
EoS
End-of-Study
EU
European Union
FDA
US Food and Drug Administration
GCP
Good Clinical Practice
GGT
gamma-glutamyl transpeptidase
HART
Huntington’s disease ACR16 Randomized Trial (ACR16C009)


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
23
Abbreviation
Term
HD
Huntington’s disease
HDL
high-density lipoprotein
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IND
Investigational New Drug Application
IOI
inter onset intervals
IPI
inter peak intervals
IRB
Institutional Review Board
IRT
interactive response technology
ITI
inter tap intervals
ITT
intent-to-treat 
LAM
Lactational amenorrhea method
LCM
Local clinical management
LDH
lactic dehydrogenase
LDL
low-density lipoprotein
LSO
Local safety officer 
MAD
Multiple ascending dose
MedDRA
Medical Dictionary for Regulatory Activities 
MermaiHD
Multinational European Multicentre ACR16 study in Huntington’s Disease
(ACR16C008)
mMS
Modified Motor Score
mPPT
Modified Physical Performance Test
MTD
maximum tolerated dose
NMDA
N-methyl-D-aspartate
NOAEL
no observed adverse effect level
OTC
Over the counter
PBA-s
Problem Behaviors Assessment-Short form
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PM
poor metabolizer
Q-motor
Quantitative motor


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
24
Abbreviation
Term
qd
once daily
QTcF
Fridericia-corrected QT interval
ΔΔQTcF
placebo-corrected change from baseline in QTcF
RBC
red blood cell
RSI
Reference Safety Information
SAE
serious adverse event
SD
standard deviation
SF-12
Short Form 12 
SOC
system organ class/standard of care
SOP
standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
t½
half life
TC
telephone contact
TD
tap durations
TF
tapping forces
TFC
Total Functional Capacity
TMS
Total Motor Score
UHDRS
Unified Huntington’s Disease Rating Scale
UK
United Kingdom
ULN
upper limit of the normal range
USA
United States of America
WBC
white blood cell
WHO
World Health Organization
WHO Drug
World Health Organization (WHO) drug dictionary


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
25
1.
BACKGROUND INFORMATION
1.1.
Introduction 
1.1.1.
Huntington’s Disease
Huntington’s disease (HD) is a fatal neurodegenerative disorder with an autosomal dominant 
mode of inheritance. The disease is associated with a triad of motor, behavioral, and cognitive 
symptoms. Motor disturbances are the defining feature of the disease and, with chorea the most 
evident motor symptom. Although useful for diagnosis, chorea is a poor marker of disease 
severity. Rather, disability and disease severity best correlate with negative motor features such 
as impairment in fine motor skills, bradykinesia, and gross motor coordination skills, including 
speech difficulties, gait, and postural dysfunction (Mahant et al 2003).
Dopamine is widely regarded as an important neurotransmitter modulating several aspects of 
brain functions including motor function (Nieoullon and Coquerel, 2003). A disrupted 
dopaminergic signaling has been implicated in a number of neurological and psychiatric 
conditions, (Zhan et al 2011; Dunlop and Nemeroff, 2007) and there is considerable clinical and 
preclinical evidence suggesting that dopaminergic functions are also compromised in HD (Kung 
et al 2007; Huot et al 2007). 
A number of medications are prescribed to ameliorate the motor and emotional problems 
associated with HD; however, the scientific evidence for the usefulness of various drugs in HD is 
poor (Mestre et al 2009a; Mestre et al 2009b). Only 1 drug, tetrabenazine, which reduces 
dopamine availability and transmission, is registered specifically for the treatment of patients 
with HD for the management of chorea. No registered drugs are available for the management of 
the multifaceted motor symptoms. As such, there is a significant unmet medical need to develop 
medications to ameliorate symptoms of HD.
1.1.2.
Pridopidine
 
 
 
 
1.2.
Name and Description of Investigational Product
The investigational product is pridopidine (TV-7820), and the active ingredient is 
4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride.
Pridopidine will be provided as a white hard gelatin capsule, size 2 containing 45 mg pridopidine 
and a white hard gelatin capsule, size 4 containing 22.5 mg pridopidine or a light pink/white hard 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
26
gelatin capsule, size 2, with black color imprinting containing 45 mg pridopidine and a white 
hard gelatin capsule, size 4, with black imprinting containing 22.5 mg pridopidine.
A more detailed description of the product is given in Section 5.1. 
1.3.
Findings from Nonclinical and Clinical Studies
1.3.1.
Nonclinical Studies
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
27
1.3.2.
Clinical Studies
To date, 20 clinical studies have been completed or are ongoing with pridopidine, comprising 
9 studies in healthy subjects (of which 1 study also included patients with schizophrenia), 1 study 
in patients with Parkinson’s disease, 2 studies in patients with schizophrenia (including the study 
mentioned above), and 9 studies in patients with HD (including 3 open-label extension studies). 
In addition, a compassionate use program for pridopidine in patients with HD is ongoing in 
Europe (ACR16CU014), and an open-label, long term safety study is ongoing in the United 
States (US) and Canada (ACR16C015, Open-HART). 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 (bid) for symptomatic treatment in 
patients with HD (TV7820-CNS-20002, PRIDE-HD) was initiated in February 2014 and is 
currently ongoing (Zielonka et al, 2015). Patients who complete the PRIDE-HD study may be 
eligible to enroll into the open-label extension study, outlined in this protocol. 
As per 14 February 2016, 866 patients with HD have been enrolled in clinical studies with 
pridopidine, with 634 patients receiving pridopidine in doses ranging from 20 to 90 mg daily. 
The ongoing Phase 2 TV7820-CNS-20002 (PRIDE-HD) study is blinded; therefore, patient 
exposure from this study is not included in the above total.
1.3.2.1.
Clinical Pharmacology Studies
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                
1 Exploratory Population Pharmacokinetic Modeling and Simulations with Pridopidine (Report CP-13-013). 
Pharsight Consulting Services, 10 July 2013.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
28
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.3.2.2.
Clinical Safety and Efficacy Studies
Three randomized, double-blind, placebo-controlled, parallel-group clinical studies investigating 
the efficacy and safety of pridopidine in patients with HD have been conducted. 
Study ACR16C007 explored the efficacy of 44 mg pridopidine once daily (qd) in 58 patients. 
Subsequently, the “Huntington’s disease ACR16 Randomized Trial” (HART) study 
(ACR16C009) was designed to explore the dose-response of pridopidine looking at 3 different 
daily doses (10, 22.5, and 45 mg bid) in 227 patients during 12 weeks of treatment. In parallel, 
the “Multinational European Multicentre ACR16 study in Huntington’s Disease” (MermaiHD) 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
29
study (ACR16C008) investigated the efficacy and safety of 45 mg given qd and bid over 
26 weeks of treatment in 437 patients.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.4.
Known and Potential Risks and Benefits to Human Patients 
1.4.1.
Risks of Pridopidine
The following are general risks considered to be associated with pridopidine administration:

 
 
 
 
 
 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
30

 
 
 
 
 
 
 and to ensure a reasonable minimum
clearance in all patients through the renal pathway, patients with a creatinine clearance 
(calculated by the Cockcroft-Gault formula) <60 mL/min will be excluded from the study.
; therefore, patients with body weight 
below 50 kg will be excluded from the study.
1.4.1.1.
Drug Interactions
 
 
. Patients on stable treatment with CYP2D6 inhibitors may be 
included in the study, since drug-induced inhibition of CYP2D6 metabolism is considered as 
functionally similar to genetic poor CYP2D6 metabolism.
, medications that are CYP2D6 substrates 
and have a narrow safety margin, eg, class I antiarrythmics and tricyclic antidepressants, will be 
administered according to the list of permitted and prohibited concomitant medications. 
Disallowed CYP2D6 substrates can be administered only 1 week after the discontinuation of 
pridopidine (i.e., 1-week washout), to allow enzyme recovery.
The concomitant use of medications that are known to have a profound effect on QT interval 
should be avoided according to the list of permitted and prohibited concomitant medications.
 
 concomitant treatment with tetrabenazine is disallowed.
Permitted and prohibited concomitant medications are detailed in Section 5.3.
1.4.1.2.
Carcinogenesis, Mutagenesis, Impairment of Fertility
 
 
 
 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
31
1.4.1.3.
Pregnancy
 
 
 
 care should be taken to not expose pregnant women or women of childbearing potential 
to pridopidine.
 
. Pridopidine use 
should therefore be restricted in nursing mothers.
1.4.1.4.
Pharmacological Class Events
 
 
 
 
 
1.4.2.
Benefits of Pridopidine
Results of 2 large previous clinical studies in HD patients, ACR16C009 (HART) and 
ACR16C008 (MermaiHD), suggested that pridopidine may have an effect on motor function. 
 
 
1.4.3.
Overall Risk and Benefit Assessment for This Study
The objective of the PRIDE-HD study is to investigate the safety and tolerability of pridopidine 
doses of 45-112.5 mg bid. Previously, doses up to 90 mg bid have been investigated in healthy 
volunteers (see Protocol Section 1.3.2.2 and IB sections 5.4.1, 5.4.2.5). 
Although the results of the efficacy, safety and tolerability analyses of the PRIDE-HD study are 
not yet available, several measures have been implemented in this open-label extension study to 
ensure patient safety and to improve tolerability:


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
32
1. The present study design includes a 1-week titration period (see section 5.1 of the 
protocol) following the PRIDE-HD 2-week washout period, prior to administration of the 
45 mg bid dose.
A robust set of relevant inclusion/exclusion criteria have been implemented, similar to those 
in PRIDE-HD:
○
Patients with a clinically significant heart disease will be excluded;
○
Patients with a QTcF interval of >450 msec at screening will be excluded;
○
Patients with a known history of Long QT Syndrome will be excluded;
○
Patients with serum potassium, magnesium and/or calcium levels outside of 
the central laboratory’s reference range at the screening will be excluded;
○
Patients receiving medications that have been proven to prolong QT interval 
will be excluded;
○
Patients with a history of epilepsy or of seizures will be excluded;
○
Patients receiving medications (that are metabolized by CYP2D6 (and hence 
are influenced by pridopidine treatment) and have the potential of reducing 
seizure threshold will be excluded;
○
Patients are followed closely and monitored for suicidality and AE recording;
○
In addition, a number of precautions are taken to exclude patients who might 
experience high exposures to pridopidine, i.e. patients with a body weight 
below 50 kg, and patients with renal impairment;
○
Finally, the investigator will terminate the patient’s participation in the study, 
should a QTc prolongation or a seizure occur, as defined in Section 3.6.1 of 
the protocol.
2. A monitoring plan has been implemented. Concomitant medication will be monitored 
throughout the study; ECG will be performed at every visit and will be centrally 
evaluated at a core lab. 
3. During the study, an independent Drug Safety Monitoring Board (DSMB) will be
responsible for reviewing accumulating unblinded safety data. The DSMB will meet on a 
regular basis (at least every 3 months) to ensure the continuing safety of the study 
patients and study conduct issues (see Section 3.6.1).
 
 
 
 
 
 
 
 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
33
 
 
 
 
 
Therefore, all treatment arms in the study will be continued with updated informed consent and 
an amended protocol with additional increased precautionary safety measures (eg Section 3.1),
including updated individual patient stopping rules (see Section 3.10.1) while the sponsor closely 
monitors psychiatric AEs in all pridopidine studies for emergence of any potential safety signal
identified.
No new significant information or safety signal has been identified or obtained for the previously 
identified risks associated with use of pridopidine.
Taken collectively, the sponsor believes that the study is well equipped, as described above, to 
adequately investigate the long term safety and tolerability profile of pridopidine, while caring 
for the individual patient’s safety.
Additional information regarding risks and benefits to human patients may be found in the 
current IB.
1.5.
Selection of Drugs and Dosages 
A detailed description of study drug administration is presented in Section 5.1.
1.5.1.
Justification for Dosage of Active Drug
The dosages to be administered in this open-label extension study [i.e., 22.5 mg for 1 week and 
45 mg bid from Week 2 onwards] were selected on the basis of previous doses investigated in 
clinical studies with pridopidine.
Studies MermaiHD (ACR16C008) and HART (ACR16C009) have shown that a pridopidine 
45 mg bid dose is associated with improvement in UHDRS-TMS (of approximately 3 points 
relative to placebo) and motor subscores, with no aggravation in other domains of the disease 
(cognition, behavior). 
Pridopidine has been shown to have a benign safety profile, similar to placebo, in 45 mg bid 
doses so far tested in patients with HD. Hence it was perceived as relevant to investigate higher 
doses, with the potential to increase the beneficial effects of pridopidine. Consequently, doses of 
67.5, 90, and 112.5 mg bid are being explored in the ongoing PRIDE-HD study. Upon 
completion of PRIDE-HD and following analysis of safety, tolerability, and efficacy data the 
dose administered in this study may be adjusted to a maximum of 112.5mg bid after a titration 
period at the discretion of the sponsor.
1.6.
Compliance Statement
This study will be conducted in full accordance with the International Conference on 
Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any 
applicable national and local laws and regulations (eg, Title 21 Code of Federal Regulations 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
34
[21CFR] Parts 11, 50, 54, 56, 312, and 314, European Union [EU] Directive 2001/20/EC on the 
approximation of the laws, regulations and administrative provisions of the Member States 
relating to the implementation of GCP in the conduct of clinical trials on medicinal products for 
human use). Any episode of noncompliance will be documented.
The investigator is responsible for performing the study in accordance with this protocol and the 
applicable GCP guidelines referenced above for collecting, recording, and reporting the data 
accurately and properly. Agreement of the investigator to conduct and administer this study in 
accordance with the protocol will be documented in separate study agreements with the sponsor 
and other forms as required by national authorities in the country where each investigational 
center is located.
The investigator is responsible for ensuring the privacy, health, and welfare of the patients during 
and after the study and must ensure that trained personnel are immediately available in the event 
of a medical emergency. The investigator and the applicable study staff must be familiar with the 
background to, and requirements of, the study and with the properties of the study drug(s) as 
described in the IB or prescribing information. 
The principal investigator at each investigational center has the overall responsibility for the 
conduct and administration of the study at that center and for contacts with study management, 
with the Independent Ethics Committee/Institutional Review Board (IEC/IRB), and with local 
authorities.
1.7.
Population To Be Studied and Justification
The study population will consist of male or female patients aged ≥21 years and with body 
weight ≥50 kg, with diagnosis of HD, who completed the double-blind, randomized phase of the 
TV7820-CNS-20002 (PRIDE-HD) study, including the 2-week follow-up period, or patients 
who transitioned from the ACR16C015 (Open-HART) study. Eligible patients will be allowed to 
enter this open-label extension study to continue to receive treatment with pridopidine. Patients 
should be in good general health, ambulatory and have the capacity to travel to the clinic visits.
1.8.
Location and Timing of Study 
This study is planned to be conducted in Australia, Austria, Canada, Denmark, France, Germany, 
Italy, Netherlands, Poland, Russia, UK, and the USA at up to 54 centers. It is expected to start in 
Q3 2015. Enrollment will continue until the last patient from the TV7820-CNS-20002 study 
(PRIDE-HD) has entered the study. Treatment duration will be extended for an additional 
52 weeks (ie total of 104 weeks), until approximately Q3 2017 (last patient last visit for the 
extended study period). 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
35
2.
PURPOSE OF THE STUDY AND STUDY OBJECTIVES
2.1.
Purpose of the Study
The present clinical study is planned as an open-label extension of the TV7820-CNS-20002 
(PRIDE-HD) study, in order to collect and assess long term data on the safety, tolerability, and 
efficacy of pridopidine in patients with Huntington's disease (HD).
2.2.
Study Objectives
2.2.1.
Primary Objective
The primary objective of this study is to evaluate safety and tolerability of pridopidine in patients 
with HD.
2.2.2.
Secondary Objectives
The secondary objectives of the study are to assess the effects of long-term, open-label dosing 
with pridopidine on motor symptom severity, overall patient function, physical performance, and 
health-related quality of life in patients with HD.
2.3.
Study Endpoints 
2.3.1.
Safety and Tolerability Endpoints
2.3.1.1.
Safety Endpoints:
The safety endpoints for this study are as follows:

adverse events (AEs) throughout the study

vital signs assessments

concomitant medication usage throughout the study

physical examination findings 

clinical laboratory evaluations (hematology, clinical chemistry, and urinalysis)

ECG findings 

Suicidality [using the Columbia-Suicide Severity Rating Scale (C-SSRS)] and 
Problem Behaviors Assessment-Short form (PBA-s)
2.3.1.2.
Tolerability Endpoints: 
The tolerability endpoints for this study are as follows:

Proportion of subjects (%) who prematurely discontinued from the study

Proportion of subjects (%) who prematurely discontinued from the study due to AEs


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
36
2.3.2.
Efficacy Endpoints
Long-term efficacy evaluations are the secondary objective of this study. Efficacy endpoints 
include the following:

Unified Huntington’s Disease Rating Scale – Total Motor Score (UHDRS-TMS)

Modified Physical Performance Test (mPPT)

Unified Huntington’s Disease Rating Scale - Total Functional Capacity (UHDRS-
TFC)

Short Form 12 (SF-12) questionnaire (acute version)

Problem Behaviors Assessment-Short form (PBA-s) (also part of safety assessments)

Quantitative motor (Q-motor) assessments


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
37
3.
STUDY DESIGN
3.1.
General Design and Study Schema
This is a multicenter, open-label study to evaluate the safety, tolerability, and efficacy of 
pridopidine treatment at a dosage of 45 mg bid in adults with HD. The study will consist of a 
screening period up to 2 weeks, followed by an open-label treatment period.
The assessments and procedures performed during each study visit are detailed in Table 1 and 
Section 3.12.
Up to 300 patients from the PRIDE-HD and the Open-HART studies are planned to be enrolled 
to receive a total daily dose of 90 mg pridopidine (45 mg bid) for the duration of the study.
If medically necessary (e.g. following discussion with the medical monitor), the patient may be 
allowed to de-escalate to a dose of 22.5 mg bid. The start date and reason for de-escalation will 
be entered into the electronic case report form (eCRF). 
Upon meeting eligibility criteria, patients who transition from the ACR16C015 (Open-HART) 
study may perform the baseline visit assessments and procedures. They do not have to undergo 
titration as they will continue taking the same dose as in Open-HART (45 mg bid).
Upon completion of the PRIDE-HD study and analysis of the efficacy, safety, and tolerability 
data, the dose of study drug administered to the patients in this long-term study may be adjusted.
After the 1 week titration period, patients will be seen at Weeks 4, 12, 26, 52, 78, and 104. An 
EoS follow-up visit will take place at Week 106. Safety evaluation telephone calls will be 
performed at weeks 18 and 38. During these phone calls, inquiries about adverse events, 
concomitant medication (including changes in use of benzodiazepines and antidepressants), 
changes in use of alcohol and illicit drugs, C-SSRS, and an abbreviated PBA-s (a subset of PBA-
s questions on depressed mood, suicidal ideation, anxiety, irritability, loss of motivation, and 
obsessive-compulsive behaviors) will be conducted.
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.
Patients who withdraw from the study will have the early termination procedures and 
assessments performed at their final visit. 
An independent DSMB will oversee the study (see Section 3.6.1).
The study schema is presented in Figure 1. 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
38
Figure 1:
Overall Study Schema
Abbreviations: EoS=end of study; ET=early termination; FU=follow up; PRIDE-HD=PRIdopidine Dose Evaluation 
in Huntington's Disease (Study TV7820-CNS-20002); T=titration period; TDD=total daily dose; V=visit.
Digital Health Sub-study (optional participation):
Motor symptoms can be objectively assessed in Huntington’s disease patients using different 
quantitative motor assessments.
Objective motor assessments aim at improving the limited sensitivity observed with categorical 
clinical rating scales, and reducing the intra- and inter-rater variability, as well as potential 
placebo effect observed in scales such as the UHDRS. Improved sensitivity for early-stage 
clinical studies of efficacy of a new drug on motor dysfunction is expected with objective 
assessments and may support early go/no go decisions in smaller cohorts of patients (Reilmann 
et al. 2001; Reilmann et al. 2011).
A feasibility sub-study including up to 60 patients with chorea will be conducted to collect 
accelerometry data using a wearable sensor-mobile application tool. The overall objective of the 
sub-study is to test the hypothesis of using wearable sensor data to estimate clinically relevant 
measures of HD in patients while on their medication regimen, which includes pridopidine. The 
aim is to develop algorithms to objectively quantify chorea by analyzing the data from the 
wearable sensors. The application will also include a simple diary to track medication use during 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
39
the study. Patients enrolled in the sub-study will be provided with a commercial grade wearable 
digital sensor (Pebble watch), an android smartphone and will be granted access to the 
accompanying mobile application. The mobile application will collect accelerometry and 
medication data and transmit for storage and processing. Participating subjects will be asked to 
continuously wear the digital sensor for a period of 6 months. Participation in the sub-study will 
be optional. The accelerometry data collection will be performed on the wrist of the non-
dominant limb. A training session will be done at screening for the sub-study. Assessments will 
be done at times specified in the Schedule of Activities section of the protocol. A separate user’s 
manual and training on the tool will be provided to sites. This system of data collection will 
allow researchers and clinicians to gather detailed patient data outside of the clinical setting. The 
data analysis is expected to facilitate future research and clinical studies on the effectiveness of 
new interventions in HD.
3.2.
Justification for Study Design
The open label study design is considered standard practice to gain additional experience in the 
clinical setting, to increase exposure, and to enhance understanding of the safety, tolerability, and 
efficacy profile of the drug. 
3.3.
Efficacy Measures and Time Points
Efficacy analyses will be considered exploratory. Comparisons will generally be made to 
baseline, as appropriate. Efficacy endpoints include the following:

UHDRS-TMS - will be performed at all visits during the Open-PRIDE study.

mPPT - will be performed at baseline and at weeks 12, 26, 52, 78, 104 and 106. 

UHDRS-TFC - will be performed at baseline and at weeks 26, 52, 78, 104 and 106.

SF-12 (acute version) - will be administered at baseline and at weeks 26, 52, 78, 104 
and 106.

PBA-s – will be performed at all visits during the Open-PRIDE study (also part of 
safety assessments).

Q-motor – will be performed at baseline and at weeks 52, 78, 104 and 106.
3.4.
Safety and Tolerability Measures and Time Points
The following safety and tolerability measures will be assessed during the study:

AEs – will be monitored at every study visit.

Vital signs assessments – will be monitored at every study visit.

Concomitant medication usage - will be monitored at every study visit.

Physical examination findings – brief physical examination will be performed at 
every study visit.

Clinical laboratory evaluations (hematology, clinical chemistry, and urinalysis) - will 
be performed at each study visit


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
40

ECG findings – ECG will be performed at every study visit (in triplicate at baseline; 
single measurement at all subsequent visits)

Suicidality (C-SSRS and PBA-s) will be assessed throughout the study.
Tolerability endpoints: 

Proportion of subjects (%) who prematurely discontinued from the study

Proportion of subjects (%) who prematurely discontinued from the study due to AEs 
A description of the safety measures is provided in Section 7.
3.5.
Pharmacokinetic Measures and Time Points
Pharmacokinetics is not evaluated in this open-label study. Pharmacokinetic samples will be 
aimed to be drawn, to the extent possible, in the event of a SAE, an AE leading to 
discontinuation, or for patients who withdrew prematurely because of lack of efficacy.
3.6.
Randomization and Blinding
This is a non-randomized, open-label study and there is no blinding.
3.6.1.
Data and Safety Monitoring Board
During the conduct of this study, a DSMB will review accumulating safety data on a regular 
basis (as detailed in the DSMB charter) to ensure the continuing safety of the study patients and 
study conduct issues.
The DSMB will be comprised of the same members as that of the PRIDE-HD study. It is 
composed of independent physicians with expertise in the relevant therapeutic field and other 
relevant experts, such as a statistician. The DSMB will receive safety data periodically in an 
unblinded fashion. They will have the right to recommend discontinuation of the study for safety 
reasons. 
All DSMB sessions will be open. During open sessions, representatives of the sponsor may be 
present and information is provided and discussed in an unblinded fashion. 
The DSMB chairperson will communicate with the sponsor in regard to issues resulting from the 
conduct and clinical aspects of the study. The sponsor will work closely with the committee to 
provide the necessary data for review.
The conduct and specific details regarding the DSMB sessions are outlined in the DSMB charter.
3.7.
Drugs Used in the Study 
3.7.1.
Investigational Product 
A more detailed description of pridopidine administration procedures is given in Section 5.1.
This is an uncontrolled study with no other study drug. 
Additional details may also be found in the current version of the IB for pridopidine. 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
41
3.8.
Drug Supply and Accountability
3.8.1.
Drug Storage and Security
All medication supplied in connection with this study must be used only for this study and no 
other purpose.
Study drug supplies will be stored securely according to the manufacturer’s drug product 
stipulation in a temperature-controlled storage area (a locked cupboard or pharmacy with limited 
access). Only authorized personnel will have access to the study drug. The study site personnel at 
each site will be responsible for correct storage and handling of the study drug.
All study drug supplies must be stored in a dry place, at room temperature (15°C to 25°C/59°F to 
77°F). Medication must not be refrigerated.
Any actual or suspected theft or diversion must be reported to the sponsor immediately.
3.8.2.
Drug Accountability
Each study drug shipment will include a packing slip listing the contents of the shipment, drug 
return instructions, and any applicable forms. Distribution of study drugs will be performed 
under the sponsor's responsibility.
The investigator is responsible for ensuring that deliveries of study drug and other study 
materials from the sponsor are correctly received, recorded, handled and stored safely and 
properly in accordance with the CFR or local regulations, and used in accordance with this 
protocol.
If the study drug supplies appear to be damaged or missing upon arrival at the investigational 
site, the sponsor should be contacted immediately.
Patients will be instructed to return all used empty bottles and unused study drug at each visit.
A record of study drug accountability (i.e., study drug and other materials received, used, 
retained, returned, or destroyed) must be prepared and signed by the principal investigator or 
designee, with an account given for any discrepancies. Empty, partially used, and unused bottles 
of study drug will be destroyed or returned to the sponsor or its designee. The Monitor is 
responsible for the accountability of the returned study drugs.
3.9.
Duration of Patient Participation and Justification
This study will consist of an up to 2-week screening period, an open-label treatment period of 
104 weeks and an end-of-study visit (at week 106). Patients are expected to participate in this 
study for its entire duration. See Section 12.4 for the definition of the end of the study.
3.10.
Stopping Rules and Discontinuation Criteria
There are no formal rules for early termination of this study. 
During the conduct of the study, SAEs will be reviewed (see Section 7.1.5) as they are reported 
from the investigational center to identify safety concerns. The study may be terminated by the 
sponsor at any time.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
42
A patient may discontinue participation in the study at any time for any reason (eg, lack of 
efficacy, consent withdrawn, and adverse event). The investigator and/or sponsor can withdraw a 
patient from the study at any time for any reason (eg, protocol violation or deviation as defined 
in Section 11.1.2, noncompliance, or adverse event).
3.10.1.
Discontinuation of Individual Patients
If hypokalemia is observed, dosing will be interrupted and should not be started again until 
normal electrolyte values are confirmed and maintained for 7 days. Patients needing more than 
14 days to reach stable potassium levels, without study drug, should be withdrawn from the 
study drug. The patient will be asked to continue in the study and follow the visit schedule as 
outlined in the protocol. 
At any visit, if a QTcF of >500 msec is recorded in a single measurement, 2 additional 
measurements will be performed and the mean value will be calculated. If the mean value is 
above >500 msec, the patient should be withdrawn from the study.
If the local ECG reading results at the site match the above criterion, the patient should stop 
taking study medication until the central ECG reader’s report is received. If the central reader 
does not report a QTcF interval that would lead to discontinuation according to the above, then 
the patient should restart study medication.
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
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 adverse event/serious adverse event of suicide ideation or attempt; or 

they have a C-SSRS suicidal ideation score >2 (ie, 3, 4 and 5); or

they have a C-SSRS report of suicidal act; or 

they have a PBA-s suicidal ideation item score >2 (ie, 3, 4, 5) . 
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.
In case the 45 mg bid treatment arm in PRIDE-HD is discontinued for safety reasons, the Open-
PRIDE-HD study (utilizing the same 45 mg bid dose) will be stopped. 
3.11.
Source Data Recorded on the Case Report Form
All patient data must have supportive original source documentation in the medical records, or 
equivalent, before they are transcribed onto the case report form (CRF). Data may not be 
recorded directly onto the CRF and considered as source data unless the sponsor provides written 
instructions specifying which data are permitted to be recorded directly onto the CRF. 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
43
If data are processed from other institutions (eg, clinical laboratory, central image center, 
electronic diary data), the results will be sent to the investigational center, where they will be 
retained but not entered into the CRF unless otherwise noted in the protocol. These data may also 
be sent electronically to the sponsor (or organization performing data management) for direct 
entry into the clinical database (see Section 13.1). All data from other institutions will be 
available to the investigator.
The CRFs are filed in the sponsor’s central file. 
3.12.
Study Procedures
Study procedures and assessments with their timing are summarized in Table 1.
Detailed by-visit information is provided in the sections following the table. Detailed 
descriptions of each assessment are provided in Section 6 (efficacy assessments), Section 7
(safety assessments), and Section 8 (pharmacokinetic and other assessments).


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
44
Table 1:
Study Procedures and Assessments
Study period
Open label treatment period
Follow Up
Visit number
V1
V2
V3
V4
TC
V5
TC
V6
V7
V8
End-Of-
Treatment 
Visit
V9
End–Of –
Study / ET 
Visit
Procedures and assessments
Screening a b
Baselinec
Week 4d
Week 12d
Week 18
Week 26 d
Week 38 Week 52 d Week 78
Week 104
Week 106 d
Allowed time windows
Up to 2 weeks
±3 days
±4 days
±14 days
±14 days
±14 days
±14 days
±14 days
±14 days
±14 days
On-site visit
X
X
X
X
X
X
X
X
X
Telephone call
X
X
Informed consent
X
Medical and psychiatric historye
X
Prior medication historye
X
Inclusion and exclusion criteria
X
X
Clinical laboratory tests
(Clinical chemistry, hematology 
and urinalysis)
X
X
X
X
X
X
X
X
X
Brief physical examination f g
X
X
X
X
X
X
X
X
X
Electrocardiography
Xh
X
X
X
X
X
X
X
X
Vital signs measurementi
X
X
X
X
X
X
X
X
X
Serum/urine β-HCG test for 
women of childbearing potential
Xj
Xk
X
X
X
X
X
X
X
C-SSRS
Xl
X
Xm
Xm
X
Xm
X
Xm
X
X
Xm
UHDRS-TMS
X
X
X
X
X
X
X
X
X
UHDRS-TFC
X
X
X
X
X
X
mPPT
X
X
X
X
X
X
X
SF-12
X
X
X
X
X
X
PBA-s
X
X
X
X
X
X
X
X
X


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
45
Study period
Open label treatment period
Follow Up
Visit number
V1
V2
V3
V4
TC
V5
TC
V6
V7
V8
End-Of-
Treatment 
Visit
V9
End–Of –
Study / ET 
Visit
Procedures and assessments
Screening a b
Baselinec
Week 4d
Week 12d
Week 18
Week 26 d
Week 38 Week 52 d Week 78
Week 104
Week 106 d
Allowed time windows
Up to 2 weeks
±3 days
±4 days
±14 days
±14 days
±14 days
±14 days
±14 days
±14 days
±14 days
On-site visit
X
X
X
X
X
X
X
X
X
Telephone call
X
X
Abbreviated PBA-s
Xn
Xn
Q-motoro
X
X
X
X
X
Adverse event inquiry
X
X
X
X
X
X
X
X
X
X
X
PK samplingp
Dispense/collect study drug
X
X
X
X
X
X
Xq
Dosage review and adjustment 
(titration)
Xr
Concomitant medication inquiry
X
X
X
X
X
X
X
X
X
X
X
Benzodiazepines and 
antidepressants inquirys
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
Inform patients of study 
restrictions and compliance 
requirements
X
X
Review of study compliance and 
adherence
X
X
Xt
X
Xt
X
X
X
X
a The screening visit of the Open-PRIDE study may coincide with the follow-up visit of PRIDE-HD. If found operationally convenient and effective for a site, 
the screening visit may take place over the course of more than 1 day; however, the allowed 2-week screening period may not be exceeded.
b If a certain procedure or assessment was completed for the PRIDE-HD study, which took place on the same day as the Open-PRIDE screening visit, this 
procedure or assessment does not need to be repeated for Open-PRIDE.
c All baseline (Visit 2) assessments must take place on the same day.
d If found operationally convenient and effective for a site, the procedure and assessment visits (V3 through End of Study/ ET) may be performed over several 
days, as long as they are completed within the defined visit window. 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
46
eA gap of up to 3 months is allowed between the patient's completion of the PRIDE-HD study and the Open-PRIDE screening visit. If less than 3 months have 
passed, and there are no changes to psychiatric, medical, or medication history since completion of the PRIDE-HD study, these data do not have to be re-
captured in the eCRF. If the gap is between 3-6 months, the information has to be re-captured.
f Weight will be measured at the screening visit and at baseline (for study eligibility) and at week 26, 52 78, 104 and 106.
g Brief physical exam will be focused on general appearance, the cardiovascular, pulmonary, abdominal exams, as well as directed towards any patient-reported 
symptoms. The brief neurological exam includes observation for cerebellar (intention) tremor and for non-cerebellar tremors (eg, resting or positional), finger-
nose, heel-shin, Romberg, tandem walking, positional, and gaze-evoked nystagmus.
h ECGs will be performed in triplicate at screening.
i Vital signs include pulse, blood pressure (supine and standing), body temperature.
j Serum B-HCG test will be performed for all women of childbearing potential at screening.
k Urine HCG tests will be performed for all women of childbearing potential at all subsequent visits.
l If less than 3 months have passed since the patient's completion of the PRIDE-HD protocol and the Open-PRIDE screening visit, the "since last visit" version 
of the scale can be used. If 3-6 months have passed, the screening/baseline version of the scale should be administered.
m The "Since Last Visit" version will be administered at all subsequent visits.
n The safety telephone calls will include an abbreviated PBA-s (a subset of PBA-s questions on depressed mood, suicidal ideation, anxiety, irritability, loss of 
motivation, and obsessive-compulsive behaviors).
o Including digitomotography (speeded index finger tapping), dysdiadochomotography (pronation/supination hand tapping), manumotography and 
choreomotography (grip force and chorea analysis) and pedomotography (speeded foot tapping).
p PK samples will be aimed to be drawn, to the extent possible, in the event of a SAE, an AE leading to discontinuation, or for patients who withdrew 
prematurely because of lack of efficacy.
q At the end-of-treatment (EoT) visit (Visit 8), study drug will only be collected.
r Patients will undergo a 1-week titration in which a pridopidine dose of 22.5 mg bid (total daily dose 45 mg) will be taken. From week 2 onwards, patients will 
receive a pridopidine dose of 45 mg bid (total daily dose 90 mg). Doses up to 112.5 mg bid are currently being investigated in the ongoing PRIDE-HD study. 
Following availability of PRIDE-HD results, the dose administered in this study may be adjusted.
s This information will be collected as part of concomitant medication inquiry.
t Study adherence will be reviewed during the safety telephone calls.
Abbreviations: bid=twice daily; β-HCG=beta human chorionic gonadotropin ; C-SSRS=Columbia-Suicide Severity Rating Scale; ET=Early Termination; 
mPPT=Modified Physical Performance Test; PBA-s=Problem Behaviors Assessment-Short form; PK=pharmacokinetic(s); Q26=every 26 weeks after the Month 
12 visit; TC=telephone contact; TFC=Total Functional Capacity; TMS=Total Motor Score; SAE=serious adverse event; SF-12=Short Form 12; 
Q-motor=Quantitative motor; UHDRS=Unified Huntington’s Disease Rating Scale; V=Visit


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
47
3.12.1.
Procedures for Screening and Enrollment (Visit 1)
A signed and dated informed consent form will be obtained before screening procedures 
commence (see Section 12.1). Evaluations obtained as part of routine medical care and 
performed during the screening period may be used in place of the protocol-specific evaluations. 
In addition, disease-specific assessments performed within a specified time frame before
informed consent may be used for the study. Patients will acknowledge and agree to the possible 
use of this information for the study by giving informed consent. 
After informed consent is obtained, patients will be enrolled into the Open-PRIDE study and will 
continue with their assigned subject identification number from the PRIDE-HD study. 
The screening visit of the Open-PRIDE study may coincide with the follow-up visit of the 
PRIDE-HD study. If the Open-PRIDE screening visit occurs on the same day as the last visit of 
the PRIDE-HD study, procedures or assessments completed for the PRIDE-HD study do not 
need to be repeated for Open-PRIDE.
A patient who is screened but not enrolled, eg, because entry criteria were not met or enrollment 
did not occur within the specified time, or other logistical or operational issues occurred, may be 
considered for screening again if, eg, there is a change in the patient’s medical background or a 
modification of study entry criteria. 
The screening visit (Visit 1) will take place not more than 2 weeks before the baseline visit. If 
found operationally convenient and effective for a site, the screening visit may take place over 
the course of more than 1 day; however, the allowed 2-week screening period may not be 
exceeded.
The following procedures will be performed at Visit 1:

obtain written informed consent before any other study-related procedures are 
performed

review inclusion/exclusion criteria 

review medical, medication and psychiatric history
○
If less than 3 months have passed between the patient's completion of the 
PRIDE-HD study and the Open-PRIDE screening visit, and there are no 
changes to medical, medication, or psychiatric history since completion of the 
PRIDE-HD study, these data do not have to be re-captured in the eCRF. 
○
If the gap is between 3-6 months, the information has to be re-captured.

perform clinical laboratory tests

perform vital signs measurements

perform ECG (in triplicate)

perform brief physical examination (including weight)

serum β-HCG test for women of childbearing potential


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
48

C-SSRS
o
If less than 3 months have passed between the patient's completion of the 
PRIDE-HD study and the Open-PRIDE screening visit, the "Since Last Visit" 
version of the scale may be administered. 
o
If the gap is between 3-6 months, the screening/baseline version of the scale 
will be administered.

UHDRS-TMS

PBA-s

inquire about AEs

concomitant medication inquiry (including inquiry about changes in use of 
benzodiazepines and antidepressants)

inquiry about changes in use of alcohol and illicit drugs 

inform patients of study restrictions and compliance requirements
3.12.2.
Procedures Before Study Drug Treatment (Baseline [Visit 2])
Patients who meet the inclusion/exclusion criteria at Visit 1 will continue to Visit 2, when 
baseline evaluations will be conducted. All baseline (Visit 2) assessments must take place on the 
same day.
The following procedures will be performed at Visit 2:

review inclusion/exclusion criteria

perform clinical laboratory tests

perform brief physical examination

perform ECG

perform vital signs measurements

urine β-HCG test for women of childbearing potential

C-SSRS ("Since Last Visit" version)

UHDRS-TMS

mPPT

UHDRS-TFC

SF-12 questionnaire

PBA-s

Q-motor

inquire about AEs


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
49

concomitant medication inquiry (including inquiry about changes in use of 
benzodiazepines and antidepressants)

inquiry about changes in use of alcohol and illicit drugs 

dispense study drug

inform patients of study restrictions and compliance requirements
A patient who is not enrolled in the study on the basis of results of baseline assessments (eg, 
because entry criteria were not met or enrollment did not occur within the specified time) may be 
considered for screening again if there is a change in the patient’s medical background, a 
modification of study entry criteria, or other relevant change. 
Patients who continue to meet the inclusion/exclusion criteria may be enrolled into the study, and 
study drug will be dispensed.
3.12.3.
Procedures During Study Drug Treatment – Open Label Treatment Period
If found operationally convenient and effective for a site, the procedure and assessment visits 
(V3 through End of Study/ ET) may be performed over several days, as long as they are 
completed within the defined visit window. 
3.12.3.1.
Weeks 4 and 12 [Visits 3 and 4]
The following procedures/assessments will be performed at weeks 4 and 12 (visits 3 and 4):

perform clinical laboratory tests

perform brief physical examination

perform ECG

perform vital signs measurements

urine β-HCG test for women of childbearing potential

C-SSRS ("Since Last Visit" version)

UHDRS-TMS 

mPPT - at Week 12 only 

PBA-s

inquire about AEs

concomitant medication inquiry (including inquiry about changes in use of 
benzodiazepines and antidepressants)

inquiry about changes in use of alcohol and illicit drugs 

dispense/collect study drug

review study compliance


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
50
3.12.3.2.
Telephone Contact at Week 18 and Week 38
Patients will be contacted by telephone at week 18 and week 38 to evaluate safety and 
tolerability to the study drug through the following:

assessment of adverse events 

use of concomitant medications (including inquiry about changes in use of 
benzodiazepines and antidepressants)

inquiry about changes in use of alcohol and illicit drugs 

C-SSRS ("Since Last Visit" version)

abbreviated PBA-s (a subset of PBA-s questions on depressed mood, suicidal ideation, 
anxiety, irritability, loss of motivation, and obsessive-compulsive behaviors)

review of study adherence
3.12.3.3.
Week 26 (Visit 5), Week 52 (Visit 6), Week 78 (Visit 7) and Week 104 (End Of 
Treatment, Visit 8)
The following procedures/assessments will be performed at Weeks 26, 52, 78, and 104 (s
Visits 5-8):

perform clinical laboratory tests

perform brief physical examination

perform ECG

perform vital signs measurements

urine β-HCG test for women of childbearing potential

C-SSRS ("Since Last Visit" version)

UHDRS-TMS 

mPPT 

UHDRS-TFC 

SF-12 questionnaire 

PBA-s

Q-motor assessments – at Visits 6, 7, and 8 only

inquire about AEs

concomitant medication inquiry (including inquiry about changes in use of 
benzodiazepines and antidepressants)

inquiry about changes in use of alcohol and illicit drugs 

dispense study drug – only at Visits 5, 6, and 7

collect study drug – at Visits 5, 6, 7, and 8


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
51

review study compliance
3.12.3.4.
Week 106 (Visit 9) - End of Study / Early Termination Visit
The following procedures/assessments will be performed at the end-of-study visit:

perform clinical laboratory tests

perform brief physical examination

perform ECG

perform vital signs measurements

urine β-HCG test for women of childbearing potential

C-SSRS ("Since Last Visit" version)

UHDRS-TMS 

mPPT

UHDRS-TFC 

SF-12 questionnaire 

PBA-s

Q-motor

inquire about AEs

concomitant medication inquiry (including inquiry about changes in use of 
benzodiazepines and antidepressants)

inquiry about changes in use of alcohol and illicit drugs 

PK sampling
o
PK samples will be aimed to be drawn, to the extent possible, in the event of 
an AE leading to discontinuation, or for patients who withdrew prematurely 
because of lack of efficacy.

collect study drug

review study compliance
3.12.4.
Procedures After Study Drug Treatment
For patients who complete the study or withdraw prematurely, final evaluations will be 
performed at an end-of treatment visit or on the last day the patient receives the study drug, or as 
soon as possible thereafter. Procedures for patients who withdraw prematurely from the study are 
described in Section 4.4. As appropriate, patients should be treated with standard of care (SOC) 
following termination of the study.
Patients with ongoing adverse events or clinically significant abnormal laboratory test results (as 
interpreted by the investigator) will be monitored as described in Section 7.1.2.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
52
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.
3.12.5.
Unscheduled Visits
An unscheduled visit may be performed at any time during the study at the patient’s request or as 
deemed necessary by the investigator. The date and reason for the unscheduled visit will be 
recorded on the CRF as well as any other data obtained (eg, adverse events, concomitant 
medications and treatments, and results from procedures or tests).
Procedures performed during unscheduled visits include the following:

concomitant medication review (including inquiry about changes in use of 
benzodiazepines and antidepressants)

inquiry about changes in use of alcohol and illicit drugs 

vital signs measurements

AE inquiry

review of study drug accountability

collect study drug

study compliance review

C-SSRS ("Since Last Visit" version) and PBA-s (if visit scheduled to assess 
psychiatric adverse events)
Other procedures may be performed at the discretion of the investigator.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
53
4.
SELECTION AND WITHDRAWAL OF PATIENTS
Prospective waivers (exceptions) from study eligibility criteria to allow patients to enter a study 
are not granted by Teva (see Section 11.1.2).
4.1.
Patient Inclusion Criteria
Patients may be included in this study only if they meet all of the following criteria:
a.
[Revision 1] Patient has completed the PRIDE-HD trial within the last 6 months, 
including the follow-up period, or transitioned from Open-HART. 
For patients that have failed to complete PRIDE-HD or those who completed the 
PRIDE-HD study over 6 months prior to the screening visit, and meet all other 
inclusion criteria, eligibility should be discussed with the Open-PRIDE medical 
monitor and clinician on a case-by-case basis.
b. [Revision 1] For patients that experienced a drug-related SAE or had a major 
compliance violation during PRIDE-HD or Open-HART, eligibility approval should 
be discussed with PRIDE-HD’s or Open-HART's medical monitor and clinician.
Patients that experienced an adverse event/serious adverse event of suicidal 
ideation/behavior will be excluded without discussion.
c.
Able and willing to provide written informed consent prior to any study related 
procedure being performed. Patients with a legal guardian should be consented 
according to local requirements.
d. Females of child bearing potential have to be compliant in using adequate birth 
control throughout the duration of the study. Adequate birth control is defined as 
consistent practice of an effective and accepted method of contraception according to 
local regulations (hormone-based, intrauterine device, or double barrier
contraception, i.e., condom and diaphragm). Abstinence is an acceptable method of 
contraception only when this is the preferred and usual lifestyle of the subject. 
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), and lactational amenorrhoea method (LAM) are not acceptable 
methods of contraception. Male study participants have to be compliant in using 
adequate birth control with their partners (as defined above) throughout the duration 
of the study.
e. Body weight ≥50 kg. Patients that meet this criterion at screening but fail to meet it at 
a subsequent visit may be discontinued based on Investigator or Sponsor discretion. It 
is allowed to repeat the weight measurement once, if clinically appropriate.
f. Willing and able to take oral medication and able to comply with the study specific 
procedures. 
g. Ambulatory, being able to travel to the study center, and judged by the investigator as 
likely to be able to continue to travel for the duration of the study.
h. The patient is in good health as determined by medical examination, ECG, serum 
chemistry, hematology, and urinalysis. 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
54
i. The patient must be willing and able to comply with study restrictions and to remain 
at the clinic for the required duration during the study period, and willing to return to 
the clinic for evaluation as specified in this protocol.
4.2.
Patient Exclusion Criteria
Patients will be excluded from participating in this study if they meet any of the following 
criteria: 
a.
A prolonged QTcF interval (defined as a QTcF interval of >450 msec) at the 
screening visit. ECGs will be performed in triplicate during the screening visit, and 
the mean of the 3 QTcF measurements will be used to determine whether or not the 
patient is suitable for inclusion in the study.
b. Patients with clinically significant heart disease at the screening visit, defined as 
follows: (i) significant cardiac event (eg, myocardial infarction), angina pectoris or 
episode of congestive heart failure with symptoms >Grade 2 New York Heart 
Association classification within 12 weeks before randomization, or presence of 
cardiac disease that in the opinion of the investigator increased the risk of ventricular 
arrhythmia, (ii) history of arrhythmia (multifocal premature ventricular contractions, 
bigeminy, trigeminy, ventricular tachycardia) that was symptomatic or required 
treatment (Common Terminology Criteria for Adverse Events Grade 3), symptomatic 
or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained 
ventricular tachycardia, (iii) presence of left bundle branch block.
c.
Patients with serum potassium, magnesium, and/or calcium levels outside of the 
central laboratory’s reference range at the screening visit and considered clinically 
significantly abnormal by the investigator. Repeat testing is allowed (up to a 
maximum of 3 tests) if required to establish whether values are within normal range 
or clinically significantly abnormal.
d. Patients receiving medications (within the last 6 weeks prior to baseline) other than 
pridopidine that have been proven to prolong QT interval or who may require such 
medications during the course of the study such as but not limited to non-allowed 
anti-psychotic medications, tricyclic antidepressants, and/or Class I antiarrhythmics.
e.
Patients receiving medications (within the last 6 weeks prior to baseline) other than 
pridopidine that are metabolized by CYP2D6 and have the potential of reducing 
seizure threshold.
f.
Patients with a history of epilepsy or of seizures within the last 5 years.
g. Creatinine clearance <60 mL/min at screening, calculated using the Cockcroft-Gault 
equation: (140 - age) × mass (kg) × [0.85 if female] / 72 × serum creatinine (mg/ dL). 
It is allowed to repeat the test once, if clinically appropriate.
h. Any clinically significant, abnormal, screening laboratory result which in the opinion 
of the investigator, affects the patients’ suitability for the study or puts the patient at 
risk if he/she enters the study.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
55
i.
[Revision 1] Patients with adverse events of suicidal ideation or attempt at any time in 
the past or as measured by suicide ideation score of ≥3on the C-SSRS, or 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 the 
attempt or acts were performed at any time in the past, or patients who, in the opinion 
of the investigator, present a risk of suicide.
j.
Females who are pregnant or breastfeeding.
k. Treatment with any investigational product other than pridopidine within 6 weeks of 
screening or patients planning to participate in another clinical study assessing any 
investigational product during the study. 
4.3.
Justification for Key Inclusion and Exclusion Criteria
The key inclusion criteria are:

PRIDE-HD completion, (Note: The follow up period in the PRIDE-HD trial is 2 weeks 
(± 1 week). As long as the protocol visit windows are adhered to, a patient may perform 
baseline activities upon meeting all inclusion criteria) or transition from the ACR16C015 
(Open-HART) study;

Weight ≥50 kg at screening;

Women of child-bearing potential or male participants: Adequate contraception and birth 
control;

Good general health;
The key exclusion criteria include:

Similar baseline criteria for ECG, vital signs, cardiovascular system, and renal function to 
PRIDE-HD;

Similar concomitant medication restrictions to PRIDE-HD.
The justification for the key inclusion and exclusion criteria are to maintain the stringent safety-
related characteristics from the PRIDE-HD study, which may influence patient safety during 
participation in this open-label study, and allow transition of patients from the Open-HART 
study. 
4.4.
Withdrawal Criteria and Procedures
In accordance with the Declaration of Helsinki (in accordance with the applicable country’s 
acceptance), each patient is free to withdraw from the study at any time. The investigator also 
has the right to withdraw a patient from the study in the event of intercurrent illness, adverse 
events, pregnancy (see Section 7.2), or other reasons concerning the health or well-being of the 
patient, or in the event of lack of cooperation. In addition, a patient may be withdrawn from the 
study as described in Sections 3.10, 3.12.4, 5.4, and 7.1.7. 
Should a patient decide to withdraw after administration of study drug(s), or should the 
investigator decide to withdraw the patient, all efforts will be made to complete and report all 
observations up to the time of withdrawal. A complete final evaluation at the time of the 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
56
patient’s withdrawal should be made and an explanation given as to why the patient is 
withdrawing or being withdrawn from the study.
The reason for and date of withdrawal from the study must be recorded on the source 
documentation and transcribed onto the CRF. If a patient withdraws consent, every attempt will 
be made to determine the reason. If the reason for withdrawal is an adverse event or a potentially 
clinically significant abnormal laboratory test result, monitoring will be continued at the 
discretion of the investigator (eg, until the event has resolved or stabilized, until the patient is 
referred to the care of a health care professional, or until a determination of a cause unrelated to 
the study drug or study procedure is made). The specific event or test result must be recorded on 
the source documentation and transcribed onto the CRF. 
In addition, a blood sample will be obtained for the measurement of study drug concentrations. 
The sample date and time will be recorded on the source documentation and transcribed onto the 
CRF. 
All evaluations should be performed according to the protocol on the last day the patient takes 
study drug, or as soon as possible thereafter.
If the final visit is conducted more than 7 days after the final dose of study drug, all safety 
evaluations will be performed, but efficacy evaluations will not be made (see Section 3.12.4). 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
57
5.
TREATMENT OF PATIENTS
5.1.
Drugs Administered During the Study 
Following the baseline visit, patients will be assigned to receive pridopidine 22.5 mg bid 
(45 mg). Capsules will be swallowed whole with water. One capsule should be administered 
orally once each day in the morning, and 1 in the afternoon, 7 to 10 hours after the morning dose.
Study drug can be taken irrespective of meals. Study drug will be titrated for 1 week up to the 
dosage of 90 mg/day (45 mg bid). Following titration, patients will remain at their dosage (45 mg 
bid) for the duration of the study.
If medically necessary (e.g. following discussion with the medical monitor), the patient may be 
allowed to de-escalate to a dose of 22.5 mg bid. The start date and reason for de-escalation will 
be entered into the eCRF. 
Pridopidine will be provided as a white hard gelatin capsule, size 2 containing 45 mg pridopidine 
and a white hard gelatin capsule, size 4 containing 22.5 mg pridopidine or a light pink/white hard 
gelatin capsule, size 2, with black color imprinting containing 45 mg pridopidine and a white 
hard gelatin capsule, size 4, with black imprinting containing 22.5 mg pridopidine.
An Interactive Response Technology (IRT) system will be used to manage the Pridopidine 
supply at the depots and sites. 
Each medication pack will contain distinct labeled bottles in accordance with the associated dose 
strength. The capsules will be provided in 2 configurations: Each bottle will contain 30 capsules 
(of 22.5 mg or 45 mg white capsules; or 22.5 mg white imprinted capsules) or 60 capsules (of 45 
mg light pink/white imprinted capsules). Bottles will be used to accomplish the dosing of 
possible treatment options including possible dose escalation and de-escalation. Each bottle will 
be labeled with a unique pack number.
All medication supplied in connection with this study must be used only for this study and no 
other purpose.
Study drug will be packaged in bottles and provided for patients to take at home (see
Section 3.7). Study drug exposure will be measured and compliance to study drug administration 
will be monitored.
5.2.
Restrictions
Medications prohibited before and/or during the study are described in Section 5.3. 
Restrictions in regard to sexual activity and required laboratory values are provided in the 
inclusion and exclusion criteria. 
There are no additional restrictions in this study.
5.3.
Prior and Concomitant Therapy or Medication
Any prior or concomitant therapy, medication, or procedure a patient has had within 2 weeks
prior to screening and up to the end of the study period will be recorded on the CRF. Generic or 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
58
trade name, indication, and dosage will be recorded. The sponsor will encode all therapy and
medication according to the World Health Organization (WHO) drug dictionary (WHO Drug).
Medications that are not prohibited during the study (see Section 5.3.1) are allowed at the
discretion of the investigator and will be documented in the CRF. To the extent possible, patients
should continue on medications already prescribed at enrollment; dose modifications and
introduction of new medications should be avoided unless deemed necessary for optimal patient
care by the investigator.
Disallowed CYP2D6 substrates can be administered only 1 week after the discontinuation of
pridopidine (i.e., 1-week washout), to allow enzyme recovery. CYP2D6 inhibitors can be 
administered to study patients. The concomitant use of medications that are known to have a 
profound effect on QT interval should be avoided according to the list of permitted and 
prohibited concomitant medications.
 
 concomitant treatment with tetrabenazine is disallowed.
Medications that are CYP2D6 substrates and have the potential to reduce the seizure threshold 
will not be permitted during the study.
Any changes to an existing concomitant medication or any new medication started during the
study should be recorded in the CRF. 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 CRF.
If a patient receives a prohibited treatment during the randomized phase of the study, he/she will
be encouraged to continue in the study and complete the study visits in accordance with the study
visit schedule; however, the patient may need to be withdrawn from study treatment (see
Section 4.4). If the patient refuses to be seen for further visits, the assessments for End-of-Study 
(EoS)/Early Termination should be performed, as far as possible (at least attempts to capture 
information on AEs and concomitant medication).
At each clinic visit after the screening visit, the investigator will ask patients whether they have 
taken any medications (other than study drug), including over-the-counter (OTC) medications, 
vitamins, or herbal or nutritional supplements, since the previous visit. Indication, dosage, and 
start and end dates should be entered on the CRF. 
5.3.1.
Permitted Medication
For patients taking allowed antipsychotic, antidepressant, antiarrhythmic, or other medication, 
the dosing of medication must have been kept constant for at least 6 weeks before baseline and 
must be kept constant during the study.
If the dose was adjusted during the PRIDE-HD study, but less than 6 weeks prior to the Open-
PRIDE screening visit, the patient's eligibility to participate in the study will be assessed on a 
case-by case basis.
Allowed antipsychotic medications are olanzapine, quetiapine, thiothixene, acetophenazine, 
triflupromazine, loxapine, tiapride, chlorprothixene, and bromperidol. Aripiprazole, risperidone, 
and perphenazine are permitted, at no more than usual recommended doses in the approved 
labeling. If, according to investigator judgment, a change of usage or dosage of antipsychotic 
medication is required during the study, this should be recorded in the CRF and discussed with 
the medical monitor.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
59
Allowed antidepressant medications are venlafaxine, paroxetine, duloxetine, sertraline, 
omipramol (opipramol), moclobemide, tranylcypromine, buspiron, bupropion, reboxetine, and 
dibenzepin. Fluvoxamine is permitted, at no more than usual recommended doses in the 
approved labeling. 
Bupropion is an antidepressant drug potentially administered to study patients. Although no PK 
interactions are expected between bupropion and pridopidine, bupropion is associated with 
seizures in approximately 0.4% (4/1000) of patients treated at doses up to 450 mg/day. This 
incidence of seizures may exceed that of other marketed antidepressants by as much as 4-fold 
(Wellbutrin label, 2014). Retrospective analysis of clinical experience gained with bupropion 
suggests that the risk of seizure may be minimized if the total daily dose of bupropion does not 
exceed 450 mg, the daily dose is administered 3 times daily (with each single dose not to exceed 
150 mg, and the rate of incrementation of dose is very gradual (Wellbutrin label, 2014). 
Mexiletine and tocainide are allowed antiarrhythmic medications, at no more than usual 
recommended doses in the approved labeling. 
Allowed medications with lowering seizure thresholds but for which no PK interactions are 
expected are baclofen, bupropion, ciprofloxacin, cyclosporine, isoniazid, lindane, 
methylphenidate, metronidazole, penicillins, theophylline, amantadine, morphine, 
buprenorphine, diphenoxylate, alfentanil, fentanyl, remifentanil, meptazinol, and pethidine.
5.3.2.
Prohibited Medication
5.3.2.1.
Antipsychotic Medication
Ziprasidone, clozapine, haloperidol, mesoridazine, thioridazine, pimozide, zuclopenthixol, 
chlorpromazine, paliperidone, iloperidone, fluphenazine, prochlorperazine, 
trifluoperazine/trifluroperazine, flupentixol, benperidol, amisulpride, and sulpiride are not 
allowed within 6 weeks of baseline (Visit 1) and during the study.
5.3.2.2.
Antidepressant Medication
Lithium, the tricyclic/tetracyclic antidepressants trazodone, amitriptyline, nortriptyline, 
imipramine, desipramine, maprotiline, doxepin, clomipramine, protriptyline, and amoxapine, and 
the serotonin–norepinephrine reuptake inhibitors citalopram, escitalopram, and fluoxetine are not 
allowed within 6 weeks of baseline (Visit 1) and during the study.
5.3.2.3.
Antiarrhythmic Medication
Disopyramide, procainamide, quinidine, flecainide, propafenone, amiodarone, dofetilide, 
ibutilide, and sotalol are not allowed within 6 weeks of baseline (Visit 1) and during the study.
5.3.2.4.
Medications Lowering Seizure Thresholds
Maprotiline, dipipanone, dihydrocodeine, methadone, oxycodone, papaveretum, pentazocine, 
and tramadol are not allowed within 6 weeks of baseline (Visit 1) and during the study


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
60
5.3.2.4.1. Other Prohibited Medications
Due to either QT prolongation effects or metabolism by CYP2D6 into active metabolites, the 
following medications are not allowed within 6 weeks of baseline (Visit 1) and during the study: 
astemizole, terfenadine, azithromycin, erythromycin, moxifloxacin, pentamidine, sparfloxacin, 
clarithromycin, chloroquine, halofantrine, bepridil, cisapride, domperidone, droperidol, 
levomethadyl, methadone, codeine, tramadol, sevoflurane, and tamoxifene.
5.4.
Procedures for Monitoring Patient Compliance
The investigator will be responsible for monitoring patient compliance. A check of study drug 
compliance will be performed during each visit after the initial dispensation of study drug, and 
study drug accountability records will be completed. If the investigator or the sponsor determines 
that the patient is not in compliance with the study protocol, the investigator and the sponsor 
should determine whether the patient should be withdrawn. The IEC/IRB should be notified.
5.5.
Temporary Study Drug Discontinuation
Temporary discontinuation is defined as missing more than 5 consecutive days of the study drug.
The patient will report any temporary discontinuation to the investigator and will be instructed
by the investigator regarding continuation of treatment. The reasons for temporary study drug
discontinuation should be recorded in the appropriate section of the study drug dispensing and
compliance log in the eCRF and the local clinical management (LCM) should be notified.
Patients who discontinue study drug for less than 5 days may resume taking the study drug at the 
same dose they were taking prior to the drug discontinuation. No titration will be required for 
these patients.
Patients who discontinue study drug for 5 days or more will be required to titrate again. Sites 
should discuss the patient status with the Medical Monitor prior to dispensing a titration kit.
If a patient discontinues study drug for more than 30 days, a case-by-case review will be 
performed by the sponsor to determine whether the patient may re-start study drug treatment.
5.6.
Total Blood Volume
The total volume of blood to be collected for each patient in this study, calculated for the 
minimum study period of 52-weeks (Visits 1-8), is approximately 103.5 mL, as detailed in 
Table 2.
The total blood volume collected at the end-of-study visit (Visit 9) will be 12.5 mL.
PK samples (4 mL each) will be collected as applicable.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
61
Table 2:
Blood Volumes
Type of samples
Volume per sample (mL)
Total number of samples
Total volume
Clinical laboratory
10.5 mLa
8
84 mL
Hematology (CBC)
2 mL
8
16 mL
Serum HCG
3.5 mL
1b
3.5 mL
Pharmacokinetic sample
4 mL
As applicablec
As applicable
Total
17
103.5 mL
a The clinical laboratory tests are comprised as follows: Chemistry 3.5 mL; Creatine phosphokinase MB isoenzyme 
(CK-MB) 3.5 mL; Prolactin 3.5 mL.
b A serum HCG sample is collected at screening only for women of child-bearing potential. Urine HCG tests are 
performed during the subsequent visits.
c PK samples will be aimed to be drawn, to the extent possible, in the event of a SAE, an AE leading to 
discontinuation, or for patients who withdrew prematurely because of lack of efficacy.
Abbreviations: CBC=complete blood count; HCG=human chorionic gonadotropin.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
62
6.
ASSESSMENT OF EFFICACY 
6.1.
Efficacy Measures and Justification
The UHDRS-TMS and its subscales have been used in clinical studies for pridopidine and other 
compounds investigated in HD. 
Statistically significant findings on the UHDRS-TMS were found in both HART (ACR16C009) 
and MermaiHD (ACR16C008) studies. 
 
 
 
 

The pivotal study of tetrabenazine (103,004/TETRA-HD), the only US Food and 
Drug Administration (FDA)-approved treatment for HD-associated symptoms 
(specifically chorea), showed a borderline significant improvement of 3.3 points on 
the UHDRS-TMS (p=0.075; 45 to 47 points at baseline). The improvement induced 
by treatment with

tetrabenazine was entirely attributable to improvement of chorea and no significant 
effect was observed on other motor components. The study was powered to detect a 
2.7-point improvement in total chorea score (which constitutes the chorea items on 
the UHDRS-TMS) and a neutral effect on other UHDRS-TMS items (Huntington 
Study Group, 2006).

The RID-HD study of riluzole was powered to the same effect size (2.8 points on the 
total chorea score) (Huntington Study Group, 2003).

The TREND-HD study of ethyl-eicosapentaenoic acid used as its primary endpoint a
modified version of the UHDRS-TMS (TMS-4, encompassing chorea, dystonia, and
ocular pursuit). The study was powered to detect an effect size of 2.7 to 3.2 
(depending on cytosine-adenosine-guanine [CAG] repeat length) (Huntington Study 
Group, 2008).
The primary efficacy variable and endpoint of the PRIDE-HD study was the change from 
baseline in the UHDRS-TMS (defined as the sum of all UHDRS motor domains ratings) at 
Week 26. The secondary efficacy variable and endpoint was the change from baseline in the 
mPPT at Week 26. 
In the Open-PRIDE study, long-term efficacy evaluations are the secondary objective. Efficacy 
endpoints include the following:

UHDRS-TMS

mPPT

UHDRS-TFC


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
63

SF-12 (acute version)

PBA-s (also part of safety assessment)

Q-motor assessment
Efficacy analyses will be considered exploratory.
Except for baseline, efficacy assessments can take place before or after the afternoon dose, with 
the time of the evaluation recorded. 
UHDRS-TMS and mPPT should always be assessed in priority over other exploratory efficacy 
endpoints.
6.1.1.
UHDRS-TMS 
The UHDRS comprises a broad assessment of features associated with HD (Huntington Study 
Group, 1996). 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, 
with each assessment rated on a 5-point scale from 0 (normal) to 4 (maximally abnormal).
6.1.2.
Modified Physical Performance Test
The mPPT quantifies the patient’s performance in physical tasks (Brown et al 2000). It is a 
standardized 9-item test that measures the patient’s performance on functional tasks. Assistive 
devices are permitted for the tasks that require a standing position (items 6 to 9). Both the speed 
and accuracy at which the patients complete the items are taken into account during scoring. The 
maximum score of the test is 36, with higher scores indicating better performance.
6.1.3.
UHDRS Total Functional Capacity
The TFC scale of the UHDRS assesses 5 functional domains associated with disability 
(occupation, finances, domestic chores, activities of daily living, and care level).
6.1.4.
Short Form 12 (SF-12) Health Survey
The SF-12® is a multipurpose short-form generic measure of health status. It was developed to be 
a much shorter, yet valid, alternative to the SF-36® for use in large surveys of general and 
specific populations as well as large longitudinal studies of health outcomes. The 12 items in the 
SF-12® are a subset of those in the SF-36®; SF-12® includes 1 or 2 items from each of the 
8 health concepts. Thus, the SF-12® measures 8 concepts commonly represented in widely used 
surveys: physical functioning, role limitations due to physical health problems, bodily pain, 
general health, vitality (energy/fatigue), social functioning, role limitations due to emotional 
problems, and mental health (psychological distress and psychological well-being). Both 
standard (4-week) and acute (1-week) recall versions are available (Ware et al, 1996; Ware et al, 
2000).
The acute form of the SF-12 was created by changing the recall period for 6 SF-12 scales (Role 
Physical, Bodily Pain, Vitality, Social Functioning, Role Emotional, and Mental Health) from 
“the past four weeks” to “the past week”. Two SF-12 scales (Physical Functioning and General 
Health) do not have a recall period, so are identical across acute and standard forms. 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
64
The rationale behind the use of the 1-week recall period for the SF-12 was that shorter recall 
periods would be more sensitive than longer recall periods to recent changes in health status.
6.1.5.
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 also includes questions concerning suicidal behavior, a particular concern in 
HD. The PBA-s is based on the same set of core behavioral symptoms as the UHDRS Behavioral 
questions, which were used previously as the global psychiatric measure in most HD studies. The 
PBA-s has more detailed questions and more specific guidance on administration and scoring.
The PBA-s is a brief semi-structured interview covering the most common behavioral and 
psychiatric manifestations of HD. The interview is not restricted to a single construct, but rather 
covers several broad symptom domains relevant to HD, comprising 11 items: low mood, suicidal 
ideation, anxiety, irritability, anger/aggressive behavior, loss of motivation, perseverative 
thinking or behavior, obsessive-compulsive behaviors, paranoid thinking, hallucinations, 
behavior suggestive of disorientation. Each symptom is rated for severity on a 5-point scale 
according to detailed scoring criteria which roughly correspond to the following: 0 = “not at all”; 
1 = trivial; 2 = mild; 3 = moderate (disrupting everyday activities) and 4 = severe or intolerable. 
Each symptom is also scored for frequency on a 5-point scale as follows: 0 = symptom absent; 
1 = less than once weekly; 2 = at least once a week; 3 = most days (up to and including some 
part of every day); 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 additional safety TC. 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 medical judgment. Patients with C-SSRS or 
PBA-s suicidality scores 1 and 2 may be handled by study investigator/neurologist with a 
consultancy with psychiatrists where necessary per investigator’s medical judgement.
A referral for psychiatric evaluation is required for AE/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 or PBA-s suicidality score 3 and above. All patients with PBA-s suicidal ideation item 
score >2 (ie, 3, 4, 5) will be discontinued from treatment with study drug. Patients who are 
discontinued from treatment may continue their participation in the study and perform the 
scheduled visits and assessments, while off study drug. They will continue to be closely 
monitored by the investigator and will be referred for psychiatric evaluation per the investigator's 
medical judgment.Where possible, the same person should act as a patient’s caregiver/informant 
throughout the study. If this is not possible, a patient should have no more than 2 
caregivers/informants throughout the study. All possible attempts should be made to assure that 
the caregiver/informant will attend the clinical visits in person together with the patient. If the 
caregiver/informant is not available to attend the clinic visit, the interview can be done over the 
phone.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
65
6.1.6.
Quantitative Motor (Q-Motor) Assessment
Q-Motor assessments will be performed only in those sites that have access to the devices 
needed to perform the assessments and, where this is the case, only in those patients who are 
capable of performing the assessments.
Motor deficits can be objectively assessed using different Q-Motor assessments. All Q-Motor 
assessments are based on the application of pre-calibrated and temperature-6.1.6controlled force 
transducers and 3-dimensional position sensors with very high sensitivity and test-retest 
reliability across sessions and sites in a multicenter clinical study. Q-Motor measures thus aim to 
reduce the limited sensitivity of categorical clinical rating scales, the intra- and inter-rater 
variability, and placebo effects observed in scales such as UHDRS-TMS. In addition, Q-Motor 
assessments allow for the objective monitoring of unintended motor side effects in clinical 
studies.
Tasks detailed in the sections below have been selected for use in the current study. Data transfer 
will be performed using a secure web-based platform, allowing continuous centralized data 
monitoring and quality control. 
6.1.6.1.
Digitomotography (Speeded Index Finger Tapping)
The patient will place their hand on a hand rest with their index finger positioned above a force-
transducer. Recordings will start after practice runs. The patient will be instructed to finger tap as 
fast as possible between 2 auditory cues. The beginning of a tap is defined as a rise of the force 
by 0.05 N above maximal baseline level. The tap ends when it drops to 0.05 N before the 
maximal baseline level is reached again. The duration and variability of tap durations (TD), inter 
onset intervals (IOI), inter peak intervals (IPI), and inter tap intervals (ITI) are the exploratory 
outcome measures for speeded tapping. In addition, variability of peak tapping forces (TF) will 
be calculated as coefficient of variation, and the tapping frequency (Freq), ie, the number of taps 
between the onsets of the first and the last tap divided by the time in between, will be 
determined. Five trials of 10 seconds duration are performed with each hand.
6.1.6.2.
Dysdiadochomotography (Pronation/Supination Hand Tapping)
This task assesses the regularity of hand taps performed when alternating between the palm and 
dorsal surface of the hand performing a repetitive pronation/supination movement. The force and 
duration of the hand taps are recorded similarly to the speeded tapping task. A tone cues the start 
and end of an assessment. Five trials of 10 seconds duration are performed with each hand.
6.1.6.3.
Manumotography and Choreomotography (Grip Force and Chorea Analysis)
This task assesses the coordination of isometric grip forces in the precision grip between the 
thumb and index finger. Grip forces are assessed during grip initiation, object transport, and in a 
static holding phase. Patients are instructed to grasp and lift a device equipped with a force 
transducer and 3-dimensional position sensor in the precision grip between thumb and index 
finger and hold it stable adjacent to a marker 10-cm high. Grip forces and 3-dimensional position 
and orientation of the object are recorded. Mean isometric grip forces and grip force variability 
in the static phase (expressed as coefficient of variation = standard deviation [SD]/mean × 100) 
(GFV-C) are calculated during a 15-second period starting 8 seconds after the first cueing tone.
Five trials of 20 seconds duration are performed with each hand. Chorea is assessed calculating a 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
66
“position-index” and “orientation-index.” Start and end of assessment are signaled by a cueing 
tone.
6.1.6.4.
Pedomotography (Speeded Foot Tapping)
The patient will place a foot on the foot device such that the ball of the foot is positioned above a 
force-transducer. Recordings will start after practice runs. The patient will be instructed to tap 
with the foot as fast as possible between 2 auditory cues. The beginning of a tap is defined as a 
rise of the force by 0.05 N above maximal baseline level. The tap ends when it dropped to 0.05 N 
before the maximal baseline level is reached again. The duration and variability of TD, IOI, IPI, 
and ITI are the exploratory outcome measures for speeded tapping. In addition, variability of 
peak TF will be calculated as coefficient of variation, and the tapping Freq, ie, the number of 
taps between the onsets of the first and the last tap divided by the time in between, will be 
determined. Five trials of 10 seconds duration are performed with each foot.
6.2.
Methods and Timing of Assessing, Recording, and Analyzing 
Efficacy Data
Methods and timing of assessing efficacy data are discussed in Section 3.12. Procedures for 
recording efficacy data are discussed in Section 13.1, and methods of analyses are discussed in 
Section 9.5.2.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
67
7.
ASSESSMENT OF SAFETY
In this study, safety will be assessed by qualified study personnel by evaluating the following: 
reported adverse events, clinical laboratory test results, vital signs measurements, ECG findings, 
physical examination findings (including body weight measurements), suicidality, and 
concomitant medication usage.
7.1.
Adverse Events 
7.1.1.
Definition of an Adverse Event
An adverse event is any untoward medical occurrence in a patient administered a pharmaceutical 
product, regardless of whether it has a causal relationship with this treatment. 
In this study, any adverse event occurring after the clinical study patient has signed the informed 
consent form should be recorded and reported as an adverse event. 
An adverse event can, therefore, be any unfavorable and unintended physical sign, symptom, or 
laboratory parameter that develops or worsens in severity during the course of this study, or 
significant worsening of the disease under study or of any concurrent disease, whether or not 
considered related to the study drug. A new condition or the worsening of a pre-existing 
condition will be considered an adverse event. Stable chronic conditions (such as arthritis) that 
are present before study entry and do not worsen during this study will not be considered adverse 
events. 
New symptoms of HD or deterioration of previously existing symptoms should be recorded as an
AE only if the presentation and/or outcome is more severe than would normally be expected 
from the normal course of the disease in a particular patient.
In any event of suspected suicidality or clinical findings suggesting that the patient is dangerous 
to him or herself at the moment of evaluation or during the duration of the clinical study, the 
patient should be discontinued from treatment with study drug, referred for immediate 
psychiatric evaluation and an AE/SAE should be reported. Patients with an AE/SAE of suicide 
ideation or attempt will be discontinued from treatment with study drug. Patients who are 
discontinued from treatment may continue their participation in the study and perform the 
scheduled visits and assessments, while off study drug.
Accordingly, an adverse event can include any of the following:

intercurrent illnesses

physical injuries

events possibly related to concomitant medication

significant worsening (change in nature, severity, or frequency) of the disease under 
study or other pre-existing conditions (Note: A condition recorded as pre-existing that 
is intermittently symptomatic [eg, headache] and that occurs during this study should 
be recorded as an adverse event.)

drug interactions


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
68

events occurring during diagnostic procedures or during any washout phase of this
study

laboratory or diagnostic test abnormalities that result in the withdrawal of the patient 
from the study, are associated with clinical signs and symptoms or a SAE, or require 
medical treatment or further diagnostic work-up, or are considered by the investigator 
to be clinically significant (Note: Abnormal laboratory test results at the screening 
visit that preclude a patient from entering the study or receiving study treatment are 
not considered adverse events.)

all events of possible drug-induced liver injury with hyperbilirubinemia (defined as 
aspartate aminotransferase [AST] or alanine aminotransferase [ALT] ≥3 times the 
upper limit of the normal range [ULN], plus either bilirubin ≥2 times the ULN or 
International Normalized Ratio >1.5) or Hy’s Law events require immediate study 
treatment cessation and reporting as an SAE. Hy’s Law events are defined as follows:

The drug causes hepatocellular injury, generally shown by more frequent 3-fold 
or greater elevations above the ULN of ALT or AST than the (nonhepatotoxic) 
control agent or placebo.

Among patients showing such aminotransferase elevations, often with 
aminotransferases much greater than 3 × ULN, some patients also show elevation 
of serum total bilirubin to >2 × ULN, without initial findings of cholestasis 
(serum alkaline phosphatase activity >2 × ULN).

No other reason can be found to explain the combination of increased 
aminotransferase and serum total bilirubin, such as viral hepatitis A, B, or C, 
preexisting or acute liver disease, or another drug capable of causing the observed 
injury.
7.1.2.
Recording and Reporting Adverse Events
For adverse event recording, the study period is defined for each patient as that time period from 
signature of the informed consent form through the end of the study. 
All adverse events that occur during the defined study period must be recorded on the source 
documentation and transcribed onto the CRF, regardless of the severity of the event or judged 
relationship to the study drug. For SAEs, the SAE Form must also be completed and the SAE
must be reported immediately (see Section 7.1.5.3.1). The investigator does not need to actively 
monitor patients for adverse events once the study has ended. Serious adverse events occurring 
to a patient after the treatment of that patient has ended should be reported to the sponsor if the 
investigator becomes aware of them, following the procedures described in Section 7.1.5.3.1.
At each contact with the patient, the investigator or designee must question the patient about 
adverse events by asking an open-ended question such as, “Have you had any unusual symptoms 
or medical problems since the last visit? If yes, please describe.” All reported or observed signs 
and symptoms will be recorded individually, except when considered manifestations of a 
medical condition or disease state. A precise diagnosis will be recorded whenever possible. 
When such a diagnosis is made, all related signs, symptoms, and any test findings will be 
recorded collectively as a single diagnosis on the CRF and, if it is a SAE, on the SAE Form.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
69
The clinical course of each adverse event will be monitored at suitable intervals until resolved or 
stabilized or returned to baseline, or until the patient is referred for continued care to a another 
health care professional, or until a determination of a cause unrelated to the study drug or study 
procedure is made.
The onset and end dates, duration (in case of adverse event duration of less than 24 hours), action 
taken regarding study drug, treatment administered, and outcome for each adverse event must be 
recorded on the source documentation and transcribed onto the CRF. 
The relationship of each adverse event to study drug treatment and study procedures, and the 
severity and seriousness of each adverse event, as judged by the investigator, must be recorded 
as described below.
7.1.3.
Severity of an Adverse Event
The severity of each adverse event must be recorded as 1 of the choices on the following scale:
Mild: 
No limitation of usual activities
Moderate: Some limitation of usual activities
Severe: 
Inability to carry out usual activities


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
70
7.1.4.
Relationship of an Adverse Event to the Study Drug
The relationship of an adverse event to the study drug is characterized as follows:
Term
Definition
Clarification
No reasonable 
possibility
(not related)
This category applies to adverse 
events that, after careful 
consideration, are clearly due to 
extraneous causes (disease, 
environment, etc) or to adverse 
events that, after careful medical 
consideration at the time they are 
evaluated, are judged to be unrelated 
to the study drug.
The relationship of an adverse event may be considered 
“no reasonable possibility” if it is clearly due to 
extraneous causes or if at least 2 of the following apply:

It does not follow a reasonable temporal sequence 
from the administration of the study drug.

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 
study drug. 

It does not reappear or worsen when the study drug is 
re-administered. 
Reasonable 
possibility
(related)
This category applies to adverse 
events for which, after careful 
medical consideration at the time 
they are evaluated, a connection with 
the study drug administration cannot 
be ruled out with certainty.
The relationship of an adverse event may be considered 
“reasonable possibility” if at least 2 of the following 
apply:

It follows a reasonable temporal sequence from 
administration of the study drug.

It cannot be reasonably explained by the known 
characteristics of the patient’s clinical state, 
environmental or toxic factors or other modes of 
therapy administered to the patient.

It disappears or decreases on cessation or reduction in 
dose. There are important exceptions when an 
adverse event does not disappear upon 
discontinuation of the study drug, yet a drug 
relationship clearly exists.

It follows a known pattern of response to the study 
drug.
7.1.5.
Serious Adverse Events
7.1.5.1.
Definition of a Serious Adverse Event
A SAE is an adverse event occurring at any dose that results in any of the following outcomes or 
actions:

death

a life-threatening adverse event (i.e., the patient was at immediate risk of death from 
the event as it occurred); does not include an event that, had it occurred in a more 
severe form, might have caused death

inpatient hospitalization or prolongation of existing hospitalization, which means that 
hospital inpatient admission and/or prolongation of hospital stay were required for 
treatment of an adverse event, or that they occurred as a consequence of the event. 
Hospitalizations scheduled prior to study entry will not be considered SAEs, unless 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
71
there was worsening of the preexisting condition during the patient’s participation in 
this study.

persistent or significant disability or incapacity (refers to a substantial disruption of 
one’s ability to conduct normal life functions)

a congenital anomaly/birth defect

an important medical event that may not result in death, be life-threatening, or require 
hospitalization, but may jeopardize the patient and may require medical intervention 
to prevent one of the outcomes listed in this definition. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or the 
development of drug dependency or drug abuse. Note: Any suspected transmission of 
an infectious agent via a medicinal product is considered an important medical event.
An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a nonserious adverse event.
7.1.5.2.
Expectedness
A SAE that is not included in the Adverse Reaction section of the relevant reference safety 
information by its specificity, severity, outcome, or frequency is considered an unexpected 
adverse event. The reference safety information for this study is the IB.
A SAE that is not included in the Listing of Adverse Reactions in the IB by its specificity, 
severity, outcome, or frequency is considered an unexpected adverse event.
The sponsor’s Pharmacovigilance Department will determine the expectedness for all SAEs.
For the purpose of suspected unexpected serious adverse reaction (SUSAR)/IND safety 
reporting, the version of the reference safety information (RSI) at the moment of occurrence of
the SUSAR/IND safety report applies.
7.1.5.3.
Reporting a Serious Adverse Event
7.1.5.3.1. Investigator Responsibility
To satisfy regulatory requirements, all SAEs (as described in Section 7.1.5.1) that occur during 
the study period (including the protocol-defined follow-up period, described in Section 7.1.2), 
regardless of judged relationship to treatment with the study drug, must be reported to the 
sponsor by the investigator. The event must be reported within 24 hours of when the investigator 
learns about it. Completing the SAE form and reporting the event must not be delayed, even if 
not all the information is available. The investigator does not need to actively monitor patients 
for adverse events once this study has ended. Serious adverse events occurring to a patient after 
the treatment of that patient has ended should be reported to the sponsor if the investigator 
becomes aware of them.
The SAE form should be sent to the LSO or other designated personnel (a contract research 
organization [CRO] in a country without a sponsor LSO) (contact information is in the Clinical 
Study Personnel Contact Information section); the LSO or other designated personnel will 
forward the report to the sponsor’s Global Patient Safety & Pharmacovigilance Department.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
72
The following information should be provided to record the event accurately and completely:

Study number

investigator and investigational center identification

patient number

onset date and detailed description of adverse event

investigator’s assessment of the relationship of the adverse event to the study drug 
(no reasonable possibility, reasonable possibility)
Additional information may include the following:

age and sex of patient

date of first dose of study drug

date and amount of last administered dose of study drug

action taken

outcome, if known

severity

explanation of assessment of relatedness

concomitant therapy (including doses, routes, and regimens) and treatment of the 
event

pertinent laboratory or other diagnostic test data 

medical history

results of dechallenge/rechallenge, if known

for an adverse event resulting in death: 

cause of death (whether or not the death was related to study drug)

autopsy findings (if available)
Each report of a SAE will be reviewed and evaluated by the investigator and the sponsor to 
assess the nature of the event and the relationship of the event to the study drug, study 
procedures, and to underlying disease. 
Additional information (follow-up) about any SAE unavailable at the initial reporting should be 
forwarded by the investigational center within 24 hours of when it becomes known to the same 
address as the initial report. 
For all countries, the sponsor’s Global Patient Safety & Pharmacovigilance Department will 
distribute the Council for International Organizations of Medical Sciences (CIOMS) form/XML 
file to the LSO/CRO for local submission to the regulatory authorities, IEC/IRBs, and 
investigators, according to regulations. The investigator is responsible for ensuring that the 
IRB/EC is also informed of the event, in accordance with local regulations.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
73
Note: Although pregnancy is not a SAE, the process for reporting a pregnancy is the same as that 
for reporting a SAE, but using the pregnancy form (see Section 7.2). 
7.1.5.3.2. Sponsor Responsibility
If a serious unexpected adverse event is believed to be related to the study drug or study 
procedures, the sponsor will take appropriate steps to notify all investigators participating in 
sponsored clinical studies of pridopidine and the appropriate regulatory authorities (and 
IEC/IRB, if appropriate). 
In addition to notifying the investigators and regulatory authorities (and IEC/IRB, if appropriate), 
other measures may be required, including the following:

altering existing research by modifying the protocol

discontinuing or suspending the study

altering the process of informed consent by modifying the existing consent form and 
informing current study participants of new findings

modifying listings of expected toxicities to include adverse events newly identified as 
related to pridopidine
7.1.6.
Protocol-Defined Adverse Events for Expedited Reporting
Adverse events of suicidal ideations or attempt should be reported to the sponsor within 24 hours 
of learning of the event. The corresponding dedicated CRF should be completed, but the events 
should not be marked as serious unless deemed serious by the investigator. The words "protocol 
defined adverse event" should be added after the adverse event term. Once the adverse event of 
suicidal ideation or attempt is received, the patient should be discontinued from the study and 
from study medication, and referred to a psychiatrist for evaluation and monitoring (see 
Section 7.1.7).
7.1.7.
Withdrawal Due to an Adverse Event
Any patient who experiences an adverse event may be withdrawn from the study or from study 
treatment at any time at the discretion of the investigator. If a patient is withdrawn wholly or in 
part because of an adverse event, both the adverse events page and termination page of the CRF 
will be completed at that time.
In addition, a blood sample will be aimed to obtained, to the extent possible, for the 
measurement of study drug concentrations. The patient will be monitored at the discretion of the 
investigator (eg, until the event has resolved or stabilized, until the patient is referred to the care 
of a health care professional, or until a determination of a cause unrelated to the study drug or 
study procedure is made). The investigator must inform the Medical Monitor as soon as possible 
of all patients who are being considered for withdrawal due to adverse events. Additional reports 
must be provided when requested.
If a patient is withdrawn from the study for multiple reasons that include adverse events, the 
termination page of the CRF should indicate that the withdrawal was related to an adverse event. 
An exception to this requirement will be the occurrence of an adverse event that in the opinion of 
the investigator is not severe enough to warrant discontinuation but that requires the use of a 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
74
prohibited medication, thereby requiring discontinuation of the patient. In such a case, the reason 
for discontinuation would be need to take a prohibited medication, not the adverse event.
All patients for whom an adverse event of suicidal behavior/ideation was reported at any time 
during the study should be discontinued from study medication and the need for an evaluation by 
a psychiatrist should be assessed. Discontinued patients should attend an early termination visit 
to return study medication, perform drug accountability, and will be asked to complete all 
protocol required study procedures. Adverse events of suicidal behavior/ideation should be 
followed until resolution of the suicidal behavior/ideation.
All patients who are discontinued from the study medication due to active suicidal 
behavior/ideation should be referred to a psychiatrist and followed by the investigator until 
resolution of the suicidal behavior/ideation.
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.
7.1.8.
Overdose of Study Drug 
Any dose of pridopidine, whether taken intentionally or unintentionally, in excess of that 
prescribed must be immediately reported to the sponsor. 
7.1.9.
Protocol Deviations Because of an Adverse Event
If a patient experiences an adverse event or medical emergency, departures from the protocol 
may be allowed on a case-by-case basis. After stabilization and/or treatment has been 
administered to ensure patient safety, the investigator or other physician in attendance must 
contact the individual identified in the Clinical Study Personnel Contact Information section of 
this protocol as soon as possible to discuss the situation. The investigator, in consultation with 
the sponsor, will decide whether the patient should continue to participate in the study.
7.2.
Pregnancy 
All pregnancies of women participating in the study and partners of men participating in the 
study that occur during the study, or within 14 days of completion of the study, are to be reported 
immediately to the individual identified in the clinical study personnel contact information 
section of this protocol, and the investigator must provide the LSO/CRO with the pregnancy 
form. The process for reporting a pregnancy is the same as that for reporting a SAE (see 
Section 7.1.5.3). 
Any female patient becoming pregnant during the study will discontinue treatment. All patients 
(or partners) who become pregnant will be monitored for the outcome of the pregnancy 
(including spontaneous or voluntary termination). If the pregnancy continues to term, the 
outcome (health of the infant up to 8 weeks of age), including details of birth and presence or 
absence of any birth defect, congenital abnormalities, or maternal and newborn complications, 
will be reported to the sponsor. Any complication of pregnancy during the study and any 
complication of pregnancy that the investigator becomes aware of after termination from the 
study will be reported as an adverse event or SAE, as appropriate.
If the pregnancy does not continue to term, 1 of the following actions will be taken:


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
75

For a spontaneous abortion, report as a SAE.

For an elective abortion due to developmental anomalies, report as a SAE.

For an elective abortion not due to developmental anomalies, report on the pregnancy 
form; do not report as an adverse event.
7.3.
Clinical Laboratory Tests
All clinical laboratory test results outside of the reference range will be interpreted by the 
investigator as belonging to one of the following categories:

abnormal but not a potentially clinically significant worsening from baseline 

abnormal and a potentially clinically significant worsening from baseline 
A laboratory test result that has significantly worsened (according to medical judgment) from the 
baseline result will be recorded on the source documentation, transcribed onto the CRF as an 
adverse event, and monitored as described in Section 7.1.2. An adverse event includes a 
laboratory or diagnostic test abnormality (once confirmed by repeat testing) that results in the 
withdrawal of the patient from the study, the temporary or permanent cessation of treatment with 
study drug, or medical treatment or further diagnostic work-up.
In addition, potentially clinically significant values will be predefined by the sponsor for selected 
laboratory parameters (see Section 9.7.2) and will be detailed in the statistical analysis plan. 
Clinical laboratory tests (serum chemistry, hematology, and urinalysis) will be performed at the 
time points detailed in Table 1. Clinical laboratory tests will be performed using the central 
laboratory. Specific laboratory tests to be performed are listed below.
7.3.1.
Serum Chemistry
The following serum chemistry tests will be performed:

calcium

phosphorus

sodium

magnesium

potassium

chloride

bicarbonate or carbon dioxide

glucose

blood urea nitrogen (BUN)

creatinine

cholesterol (low-density lipoprotein (LDL)/high-density lipoprotein (HDL)/total)

uric acid


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
76

alanine aminotransferase (ALT)

aspartate aminotransferase (AST)

lactic dehydrogenase (LDH)

gamma-glutamyl transpeptidase (GGT)

alkaline phosphatase (ALP)

creatine phosphokinase (CPK) -in case of elevated creatine phosphokinase, the MB 
fraction should be measured

total protein

albumin

total bilirubin

direct bilirubin

indirect bilirubin

prolactin
7.3.2.
Hematology
The following hematology tests will be performed:

hemoglobin

hematocrit

red blood cell (RBC) count

platelet count

white blood cell (WBC) count and differential count
○
absolute neutrophil count
○
absolute lymphocyte count
○
absolute eosinophil count
○
absolute monocytes count
○
absolute basophil count
○
absolute atypical lymphocyte count
7.3.3.
Urinalysis
Urinalysis will include testing for the following:

protein

glucose

ketones


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
77

blood (hemoglobin)

pH

specific gravity

microscopic

bacteria

RBCs

WBCs

casts

crystals
7.3.4.
Other Clinical Laboratory Tests
7.3.4.1.
Human Chorionic Gonadotropin Tests 
Serum human chorionic gonadotropin (HCG) tests will be performed for all women at screening 
(visit 1). Urine HCG tests will be performed for all women of childbearing potential at all 
subsequent visits, and if clinically indicated thereafter. Any patient who becomes pregnant 
during the study will be withdrawn. Procedures for reporting the pregnancy are provided in 
Section 7.2. 
7.4.
Vital Signs
Vital signs [pulse, blood pressure (supine and standing), and body temperature] will be measured 
at the time points detailed in Table 1.
Before pulse and blood pressure are measured, the patient must be in a supine or sitting position 
and resting for at least 5 minutes. (The same position and arm should be used each time vital 
signs are measured for a given patient.) For any abnormal vital sign finding, the measurement 
should be repeated as soon as possible. Any vital sign value that is judged by the investigator as 
a potentially clinically significant change (worsening) from a baseline value will be considered 
an adverse event, recorded on the source documentation and transcribed onto the CRF, and 
monitored as described in Section 7.1.2.
7.5.
Electrocardiography
A 12-lead ECG will be conducted at every visit, at the time points detailed in Table 1. ECGs will 
be performed in triplicate at screening, and a single measurement performed at all subsequent 
visits.
A qualified physician at a central diagnostic center will be responsible for interpreting the ECG. 
Any ECG finding that is judged by the investigator as a potentially clinically significant change 
(worsening) compared with a baseline value will be considered an adverse event, recorded on the 
source documentation and transcribed onto the CRF, and monitored as described in 
Section 7.1.2.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
78
7.6.
Physical Examinations
Physical examinations and weight will be performed at the time points detailed in Table 1.
The brief (symptom-directed) physical exam will be focused on general appearance, the 
cardiovascular, pulmonary, abdominal exams, as well as directed towards any patient-reported 
symptoms. The brief neurological exam includes observation for cerebellar (intention) tremor 
and for non-cerebellar tremors (eg, resting or positional), finger-nose, heel-shin, Romberg, 
tandem walking, positional, and gaze-evoked nystagmus.
Any physical examination finding that is judged by the investigator as a potentially clinically 
significant change (worsening) compared with a baseline value will be considered an adverse 
event, recorded on the CRF, and monitored as described in Section 7.1.2.
7.7.
Concomitant Therapy or Medication
Concomitant therapy or medication usage will be monitored throughout the study. Details of 
prohibited medications are found in Section 5.3. 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 illicit drugs will also be conducted. The information collected as 
part of the safety monitoring, together with the C-SSRS and the PBA-s, will be verified with the 
patient's caregiver, spouse or other support person (where necessary)2.
7.8.
Other Safety Measures and Variables
7.8.1.
Columbia Suicide Severity Rating Scale
The C-SSRS will be used to rate the patient’s degree of suicidal ideation on a scale ranging from 
“no suicidal ideation” to “active suicidal ideation with specific plan and intent” (Posner et al 
2011). The C-SSRS Baseline version will be completed at screening (Visit 0), while the C-SSRS 
Since Last Visit version will be completed at the time points detailed in Table 1. Patients with 
active suicidal ideation, as measured by a score of 4 or 5 on the C-SSRS at the screening visit, 
will not be eligible for the study.
In any event of suspected active suicidality (e.g. active suicidal ideation or intent, significant 
suicidal behavior) or clinical findings suggesting that the patient is dangerous to himself or 
herself, the patient should be referred for immediate psychiatric evaluation. 
Patients with a positive C-SSRS suicidal ideation score of 1 and 2 will be monitored more 
closely and treated according to the investigator's medical judgment. Patients with C-SSRS or 
PBA-s suicidality scores 1 and 2 may be handled by study investigator/neurologist with a
consultancy with psychiatrists where necessary per investigator’s medical judgement. 
Patients with C-SSRS or PBA-s suicidal ideation >2 (ie, 3, 4, 5), and all patients with C-SSRS 
suicidal acts, will be discontinued from treatment with study medication. A referral for 
psychiatric evaluation is required for AE/SAE of suicidal ideation/suicidal attempt or significant 
                                                
2 In accordance with the American Psychiatric Associations 2003 Practice Guideline for the Assessment and 
Treatment of Patients with Suicidal Behaviors.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
79
increase in the suicidality scale from baseline (e.g., 2 point increase or higher) or C-SSRS or 
PBA-s suicidality score 3 and above. 
Patients who are discontinued from treatment may continue their participation in the study and 
perform the scheduled visits and assessments, while off study drug. They will continue to be 
closely monitored by the investigator and will be referred for psychiatric evaluation per the 
investigator's medical judgment.
7.9.
Methods and Timing of Assessing, Recording, and Analyzing Safety 
Data
All adverse events will be reviewed on a periodic basis by the clinical project physician/medical 
monitor according to the safety monitoring plan (eg, scheduled safety reviews for pridopidine) as 
interim/preliminary safety databases become available. Safety data will additionally be evaluated 
periodically and ad hoc (if necessary) in the Product Safety Group.
Methods and timing of assessing safety data are discussed in Section 3.12. Procedures for 
recording safety data are discussed in Section 13.1 and methods of analyses are discussed in 
Section 9.7.2. 
Information about the DSMB used for this study is provided in Section 3.6.1.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
80
8.
ASSESSMENT OF PHARMACOKINETICS/ 
PHARMACODYNAMICS BIOMARKERS/ 
PHARMACOGENOMICS/ IMMUNOGENICITY
Pharmacokinetics is not evaluated in this open-label study. Pharmacokinetic samples will be 
aimed to be drawn, to the extent possible, in the event of a SAE, an AE leading to 
discontinuation, or for patients who withdrew prematurely because of lack of efficacy.
Pharmacodynamics, pharmacogenomics, or immunogenicity will not be assessed in this open-
label study.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
81
9.
STATISTICS
This section describes the statistical analysis as foreseen at the time of planning the study. 
Changes, additions, and further details about the analyses will be described in the statistical 
analysis plan. After finalization of the statistical analysis plan, any additional analyses or 
changes to analyses that may be required will be fully disclosed in the clinical study report.
9.1.
Sample Size and Power Considerations
This is an open-label study. The sample size for this study is not based on statistical 
considerations; hence, only descriptive statistics will be presented. Up to 300 subjects who 
completed the PRIDE-HD or transitioned from the ongoing Open-HART study and met patient 
exclusion/inclusion criteria will be enrolled.
9.2.
Analysis Sets 
9.2.1.
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. A patient is considered enrolled according to the status 
reported in the database.
9.2.2.
Safety Analysis Set
The safety analysis set will include all patients who receive at least 1 dose of study drug. 
9.2.3.
Full Analysis Set 
The full analysis set will include all patients in the ITT population who receive at least 1 dose of 
study drug and have at least 1 post-baseline efficacy assessment. 
9.3.
Data Handling Conventions
For all variables, only the observed data from the patients will be used in the statistical analyses, 
i.e., there is no plan to estimate missing data.
9.4.
Study Population
The ITT analysis set (see Section 9.2) will be used for all study population summaries unless 
otherwise noted. Summaries will be presented for all patients.
9.4.1.
Patient Disposition
Data from patients in the ITT, safety, and full analysis sets will be summarized using descriptive 
statistics. Data from patients who withdraw from the study will also be summarized by reason for 
withdrawal using descriptive statistics.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
82
9.4.2.
Demographic and Baseline Characteristics 
Patient demographic and baseline characteristics, including medical history, prior medications, 
and ECG findings will be summarized using descriptive statistics. For continuous variables, 
descriptive statistics (number [n], mean, standard deviation [SD], median, minimum, and 
maximum) will be provided. For categorical variables, patient counts and percentages will be 
provided. Categories for missing data will be presented if necessary.
9.5.
Efficacy Analysis 
9.5.1.
Efficacy Endpoint 
Efficacy measures and time points are provided in Section 3.3 and in Table 1.
9.5.2.
Planned Method of Analysis
The full analysis set (see Section 9.2) will be used for all efficacy analyses. 
No formal inferential statistics will be applied to the efficacy endpoints. Efficacy analyses will 
be considered exploratory and will include descriptive statistics. Comparisons will generally be 
made to baseline, as appropriate. Descriptive statistics over time will be presented to detect 
trends via changes from baseline.
9.6.
Multiple Comparisons and Multiplicity
Not applicable. 
9.7.
Safety Endpoints and Analysis
Safety analyses will be performed on the safety analysis set (see Section 9.2).
9.7.1.
Safety Endpoints
Safety measures and time points are provided in Section 3.4 and in Table 1.
9.7.2.
Safety Analysis
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Each patient will be counted only once in each preferred term or SOC category for 
the analyses of safety. Summaries will be presented for all adverse events (overall and by 
severity), adverse events determined by the investigator to be related to study treatment (i.e., 
reasonable possibility; see Section 7.1.4) (defined as related or with missing relationship) 
(overall and by severity), SAEs, and adverse events causing withdrawal from the study. 
Summaries will be presented by treatment group and for all patients. Patient listings of SAEs and 
adverse events leading to withdrawal will be presented.
Changes in laboratory and vital signs measurement data will be summarized descriptively. All 
values will be compared with prespecified boundaries to identify potentially clinically significant 
changes or values, and such values will be listed.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
83
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics. Concomitant medications will include all medications taken while the patient is treated 
with study drug.
For continuous variables, descriptive statistics (n, mean, SD, median, minimum, and maximum) 
will be provided for actual values and changes from baseline to each time point. For categorical 
variables, patient counts and percentages will be provided. Descriptive summaries of SAEs, 
patient withdrawals due to adverse events, and potentially clinically significant abnormal values 
(clinical laboratory or vital signs) based on predefined criteria will also be provided.
If any patient dies during the study, a listing of deaths will be provided and all relevant 
information will be discussed in the patient narrative included in the clinical study report. 
9.8.
Tolerability Variables and Analysis
9.8.1.
Tolerability Variables
The tolerability variables assessed in this study are: 

Proportion of subjects (%) who prematurely discontinued from the study

Proportion of subjects (%) who prematurely discontinued from the study due to AEs 
9.8.2.
Tolerability Analysis
Number and percent of patients who prematurely discontinued from the study and patients who 
prematurely discontinued from the study due to AEs will be presented.
9.9.
Planned Interim Analysis
No interim analysis is planned for this study.
9.10.
Reporting Deviations from the Statistical Plan
Deviations from the statistical plan, along with the reasons for the deviations, will be described 
in protocol amendments, the statistical analysis plan, the clinical study report, or any 
combination of these, as appropriate, and in accordance with applicable local and regional 
requirements and regulations.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
84
10.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The medical experts, study monitors, auditors, IEC/IRB, and health authority inspectors (or their 
agents) will be given direct access to source data and documentation (eg, medical charts/records, 
laboratory test results, printouts, videotapes) for source data verification, provided that patient 
confidentiality is maintained in accordance with local requirements.
The investigator must maintain the original records (i.e., source documents) of each patient’s 
data at all times. Examples of source documents are hospital records, office visit records, 
examining physician’s finding or notes, consultant’s written opinion or notes, laboratory reports, 
drug inventory, study drug label records, diary data, protocol-required worksheets, and CRFs that 
are used as the source (see Section 3.11).
The investigator will maintain a confidential patient identification list that allows the 
unambiguous identification of each patient. All study-related documents must be kept until 
notification by the sponsor.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
85
11.
QUALITY CONTROL AND QUALITY ASSURANCE
11.1.
Protocol Amendments and Protocol Deviations and Violations
11.1.1.
Protocol Amendments
No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favorable opinion of a written amendment by the IEC/IRB and local competent 
authorities as applicable, except when necessary to address immediate safety concerns to the 
patients or when the change involves only nonsubstantial logistics or administration. Each 
investigator and the sponsor will sign the protocol amendment. 
11.1.2.
Protocol Violations
A protocol deviation is any change, divergence, or departure from the study design or procedures 
defined in the protocol.
Important protocol deviations, referred to as protocol violations, are a subset of protocol 
deviations that may significantly impact the completeness, accuracy, and/or reliability of the 
study data or that may significantly affect a patient's rights, safety, or well-being. Protocol 
violations include enrolling patients in violation of key eligibility criteria designed to ensure a 
specific subject population; failing to collect data necessary to interpret primary endpoints; 
noncompliance to study drug administration; use of prohibited medications; or any other 
deviations that may have an impact on the processes put in place for the care and safety of the 
patients or compromise the scientific value of the trial.
Protocol violations will be identified and recorded by investigational center personnel on the 
CRF. All protocol violations will be reported to the responsible IEC/IRB, as required.
When a protocol violation is reported, the sponsor will determine whether to discontinue the 
patient from the study or permit the patient to continue in the study, with documented approval 
from the medical representative. The decision will be based on ensuring the safety of the patient 
and preserving the integrity of the study. 
Deviations from the inclusion/exclusion criteria of the protocol are not prospectively granted by 
the sponsor. If investigational center personnel learn that a patient who did not meet protocol 
eligibility criteria was entered into a study, they must immediately inform the sponsor of the 
protocol violation. If such patient has already completed the study or has withdrawn early, no 
action will be taken but the violation will be recorded. If such patient is still participating in the 
study, a determination will be made by the sponsor and the investigator as to whether it is in the 
best interest of the patient to continue in the study.
11.2.
Information to Study Personnel
The investigator is responsible for giving information about the study to all staff members 
involved in the study or in any element of patient management, both before starting the study and 
during the course of the study (eg, when new staff become involved). The investigator must 
assure that all study staff members are qualified by education, experience, and training to 
perform their specific responsibilities. These study staff members must be listed on the 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
86
investigational center authorization form, which includes a clear description of each staff 
member’s responsibilities. This list must be updated throughout the study, as necessary.
The study monitor is responsible for explaining the protocol to all study staff, including the 
investigator, and for ensuring they comply with the protocol. Additional information will be 
made available during the study when new staff become involved in the study and as otherwise 
agreed upon with either the investigator or the study monitor.
11.3.
Study Monitoring
To ensure compliance with GCP guidelines, the study monitor or representative is responsible 
for ensuring that patients have signed the informed consent form and the study is conducted 
according to applicable SOPs, the protocol, and other written instructions and regulatory 
guidelines.
The study monitor is the primary association between the sponsor and the investigator. The main 
responsibilities of the study monitor are to visit the investigator before, during, and after the 
study to ensure adherence to the protocol, that all data are correctly and completely recorded and 
reported, and that informed consent is obtained and recorded for all patients before they 
participate in the study and when changes to the consent form are warranted, in accordance with 
IEC/IRB approvals.
The study monitor will contact the investigator and visit the investigational center at regular 
intervals throughout the study. The study monitor will be permitted to check and verify the 
various records (CRFs and other pertinent source data records, including specific electronic 
source documentation [see Section 3.11]) relating to the study to verify adherence to the protocol 
and to ensure the completeness, consistency, and accuracy of the data being recorded. If 
electronic CRFs are used for the study, the study monitor will indicate verification by 
electronically applying source document verification flags to the CRF and will ensure that all 
required electronic signatures are being implemented accordingly.
As part of the supervision of study progress, other sponsor personnel may, on request, 
accompany the study monitor on visits to the investigational center. The investigator and 
assisting staff must agree to cooperate with the study monitor to resolve any problems, errors, or 
possible misunderstandings concerning the findings detected in the course of these monitoring 
visits and/or provided in follow-up written communication.
11.4.
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 (eg, color change, flaking, crumbling, etc.)

defective components


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
87

missing or extra units (eg, 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 (eg, the remainder of the patient’s drug supply) 
should be sent back to the sponsor for investigative testing whenever possible. 
11.4.1.
Product Complaint Information Needed from the Investigational Center
In the event that the Product Complaint Form cannot be completed, the investigator will obtain 
the following information, as available:

investigational center number and principal investigator 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 sponsor will 
collaborate with the investigator to obtain any outstanding information.
11.4.2.
Handling the Study Drug at the Investigational Center
The investigator is responsible for retaining the product in question in a location separate from 
the investigator’s clinical study supplies. The sponsor may request that the investigator return the 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
88
product for further evaluation and/or analysis. If this is necessary, the clinical study monitor or 
designee will provide the information needed for returning the study drug.
If it is determined that the investigational center must return all of the study drug, the sponsor 
will provide the information needed to handle the return.
The integrity of the randomization code and corresponding blinded clinical supplies will be 
maintained whenever possible. A SAE or the potential for a product quality problem existing 
beyond the scope of the complaint may be a reason to unblind the clinical supplies for an
affected patient.
11.4.3.
Adverse Events or Serious Adverse Events Associated with a Product Complaint
If there is an adverse event or SAE, the protocol should be followed.
11.4.4.
Documenting a Product Complaint
The investigator 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, 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.
11.5.
Audit and Inspection
The sponsor may audit the investigational center to evaluate study conduct and compliance with 
protocols, SOPs, GCPs, and applicable regulatory requirements. The sponsor’s Global Clinical 
Quality Assurance department, independent of the Global Clinical Development department, is 
responsible for determining the need for (and timing of) an investigational center audit.
The investigator must accept that regulatory authorities and sponsor representatives may conduct 
inspections to verify compliance with GCP guidelines.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
89
12.
ETHICS
Details of compliance with regulatory guidances and applicable laws are provided in Section 1.6.
12.1.
Informed Consent
The investigator, or a qualified person designated by the investigator, should fully inform the 
patient of all pertinent aspects of the study, including the written information approved by the 
IEC/IRB. All written and/or oral information about the study will be provided in a language as 
nontechnical as practical and understood by the patient. The patient should be given ample time 
and opportunity to inquire about details of the study and to decide whether or not to participate in 
the study. The above should be detailed in the source documentation.
Written informed consent will be obtained from each patient before any study-specific 
procedures or assessments are done and after the aims, methods, anticipated benefits, and 
potential hazards are explained, according to the IEC/IRB requirements. The patient’s 
willingness to participate in the study will be documented in a consent form, which will be 
signed and personally dated by the patient and by the person who conducted the informed 
consent discussion. The investigator will keep the original consent forms, and copies will be 
given to the patients. It will also be explained to the patients that the patient is free to refuse entry 
into the study and free to withdraw from the study at any time without prejudice to future 
treatment.
Adult patients with a legal guardian should provide informed consent according to local 
requirements.
12.2.
Health Authorities and Independent Ethics Committees/Institutional 
Review Boards
Before this study starts, the protocol will be submitted to the national/local health authorities and 
to each IEC/IRB for review. As required, the study will not start at a given investigational center 
before the IEC/IRB and health authority (where applicable) for the center give written approval 
or a favorable opinion.
12.3.
Confidentiality Regarding Study Patients
The investigator must ensure that the privacy of the patients, including their identity and all 
personal medical information, will be maintained at all times. In CRFs and other documents or 
image material submitted to the sponsor, patients will be identified not by their names, but by an 
identification code (i.e., identification number).
Personal medical information may be reviewed for the purpose of patient safety and/or verifying 
data in the source and transcribed onto the CRF. This review may be conducted by the study 
monitor, properly authorized persons on behalf of the sponsor, the quality assurance unit, and/or 
regulatory authorities. Personal medical information will always be treated as confidential.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
90
12.4.
Declaration of the End of the Clinical Study
For clinical investigational centers located in the EU, a declaration of the end of the clinical 
study will be made according to the procedures outlined in Directive 2001/20/ED, Article 10(c); 
for other countries, local regulations will be followed.
12.5.
Registration of the Clinical Study
In compliance with local regulations and in accordance with Teva standard procedures, this 
clinical study may be registered on clinical trials registry websites.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
91
13.
DATA HANDLING, DATA QUALITY CONTROL, AND RECORD 
KEEPING
13.1.
Data Collection
Data will be collected using CRFs that are specifically designed for this study. The data collected 
on the CRFs will be captured in a clinical data management system (CDMS) that meets the 
technical requirements described in 21CFR Part 11. The CDMS will be fully validated to ensure 
that it meets the scientific, regulatory, and logistical requirements of the study before it is used to 
capture data from this study. Before using the CDMS, all users will receive training on the 
system and study-specific training. After they are trained, users will be provided with individual 
system access rights.
Data will be collected at the investigational center by appropriately designated and trained 
personnel, and CRFs must be completed for each patient who provided informed consent. Patient 
identity should not be discernible from the data provided on the CRF. Data will be verified using 
the data source by the study monitor, and reviewed for consistency by Data Management using 
both automated logical checks and manual review. All data collected will be approved by the 
investigator at the investigational center. This approval acknowledges the investigator’s review 
and acceptance of the data as being complete and accurate. 
If data are processed from other sources (eg, central laboratory, bioanalytical laboratory, central 
image center, electronic diary data, ePRO Tablet), the results will be sent to the investigational 
center, where they will be retained but not entered into the CRF unless otherwise specified in the 
protocol. These data may also be sent electronically to the sponsor (or organization performing 
data management) for direct entry into the clinical database. Laboratory test results will not be 
entered into the CRF unless otherwise noted in the protocol. All data from other sources will be 
available to the investigators.
For patients who enter a study but do not meet entry criteria, at a minimum, data for screen 
failure reason, demography, and adverse events from the time of informed consent will be 
entered into the CRF. 
13.2.
Data Quality Control 
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.
Case report forms received will be processed and reviewed for completeness, consistency, and 
the presence of mandatory values. Applicable terms will be coded according to the coding 
conventions for this study. Logical checks will be implemented to ensure data quality and 
accuracy. Any necessary changes will be made in the clinical database, and data review and 
validation procedures will be repeated as needed. Data from external sources will be compared 
with the information available in the CDMS. Discrepancies found will be queried.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
92
Data corrections in the CDMS will be made using the CDMS update function. The system 
requires a reason for each change and keeps a complete audit trail of the data values, dates and 
times of modifications, and authorized electronic approvals of the changes.
At the conclusion of the study, the CDMS and all other study data will be locked to further 
additions or corrections. Locking the study data represents the acknowledgement that all data 
have been captured and confirmed as accurate.
13.3.
Archiving of Case Report Forms and Source Documents 
13.3.1.
Sponsor Responsibilities
The sponsor will have final responsibility for the processing and quality control of the data. Data 
management oversight will be carried out as described in the sponsor’s SOPs for clinical studies.
Day to day data management tasks for this study are delegated to a contract organization, and
these functions may be carried out as described in the SOPs for clinical studies at that 
organization. These SOPs will be reviewed by the sponsor before the start of data management 
activities. The original CRFs will be archived by the sponsor. Center-specific CRFs will be 
provided to the respective investigational centers for archiving.
13.3.2.
Investigator Responsibilities
The investigator must maintain all written and electronic records, accounts, notes, reports and 
data related to the study and any additional records required to be maintained under country, 
state/province, or other local laws, including, but not limited to, the following: 

full case histories

signed informed consent forms

patient identification lists

case report forms for each patient on a per-visit basis 

data results from other sources (eg, central laboratory, bioanalytical laboratory, 
central image center, electronic diary data)

safety reports

financial disclosure reports/forms

reports of receipt, use, and disposition of the study drug

copies of all correspondence with sponsor, the IRB/IEC, and any regulatory authority
The investigator will retain all records related to the study until the CRO or sponsor sends 
written notification that records may be destroyed. If, after 10 years from study completion, or 
earlier in the case of the investigative center closing or going out of business, the investigator 
reasonably determines that study record retention has become unduly burdensome, and sponsor 
has not provided written notification of destruction, then the investigator may submit a written 
request to sponsor at least sixty 60 days before any planned disposition of study records. Upon 
receipt of such request, the sponsor may make arrangements for appropriate archival or 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
93
disposition, including requiring that the investigator deliver such records to the sponsor. The 
investigator shall notify the sponsor of any accidental loss or destruction of study records. 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
94
14.
FINANCING AND INSURANCE
 
 
 
 
 
 
 


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
95
15.
REPORTING AND PUBLICATION OF RESULTS
The sponsor is responsible for ensuring that the public has access to the appropriate information 
about the study by conforming to local and regional requirements and regulations for registration 
and posting of results. 
The sponsor is responsible for the preparation of a clinical study report, in cooperation with the 
principal investigators. The final report is signed by the sponsor and, if applicable, by the 
principal investigators.
When the sponsor generates reports from the data collected in this study for presentation to 
regulatory authorities, drafts may be circulated to the principal investigators for comments and 
suggestions. An endorsement of the final report will be sought from the principal investigators.
All unpublished information given to the investigator by the sponsor shall not be published or 
disclosed to a third party without the prior written consent of the sponsor. The primary 
publication from this study will report the results of the study in accordance with the current 
“Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in 
Medical Journals” (www.ICMJE.org). Publication of the results will occur in a timely manner 
according to applicable regulations. Authorship will be based on meeting all the following 
4 criteria:

substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work

drafting the work or revising it critically for important intellectual content

final approval of the version to be published

agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved
The publications committee established by the sponsor will oversee this process. Additional 
publications may follow. Policies regarding the publication of the study results are defined in the 
financial agreement. 
No patent applications based on the results of the study may be made by the investigators nor 
may assistance be given to any third party to make such an application without the written 
authorization of the sponsor.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
96
16.
REFERENCES
Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits 
linking basal ganglia and cortex. Annu Rev Neurosci. 1986;9:357-81.
Brown M, Sinacore DR, Binder EF, Kohrt WM. Physical and performance measures for the 
identification of mild to moderate frailty. J Gerontol A Biol Sci Med Sci. 2000;55A(6):M350-5.
Carlsson A, Lindqvist M. Effect of chlorpromazine or haloperidol on formation of 3 
methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol (Copenh). 
1963;20:140-4.
Cepeda C, Cummings DM, André VM, Holley SM, Levine MS. Genetic mouse models of 
Huntington's disease: focus on electrophysiological mechanisms. ASN Neuro. 2010;2(2):e00033.
Craufurd D, Thompson JC, Snowden JS. Behavioral changes in Huntington Disease. 
Neuropsychiatry Neuropsychol Behav Neurol. 2001;14(4):219-26.
Dunlop BW, Nemeroff CB. The role of dopamine in the pathophysiology of depression. Arch 
Gen Psychiatry. 2007;64(3):327-37.
Dyhring T, Nielsen EØ, Sonesson C, Pettersson F, Karlsson J, Svensson P, et al. The 
dopaminergic stabilizers pridopidine (ACR16) and (-)-OSU6162 display dopamine D(2) receptor 
antagonism and fast receptor dissociation properties. Eur J Pharmacol. 2010;628(1-3):19-26.
Huntington Study Group. Unified Huntington's Disease Rating Scale: reliability and consistency. 
Huntington Study Group. Mov Disord. 1996;11(2):136-42.
Huntington Study Group. Dosage effects of riluzole in Huntington's disease: a multicenter 
placebo-controlled study. Neurology. 2003;61(11):1551-6.
Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease: a 
randomized controlled trial. Neurology. 2006;66(3):366-72.
Huntington Study Group TREND-HD Investigators. Randomized controlled trial of ethyl-
eicosapentaenoic acid in Huntington disease: the TREND-HD study. Arch Neurol. 
2008;65(12):1582-9.
Huot P, Lévesque M, Parent A. The fate of striatal dopaminergic neurons in Parkinson's disease 
and Huntington's chorea. Brain. 2007;130(Pt 1):222-32.
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.
Kung VW, Hassam R, Morton AJ, Jones S. Dopamine-dependent long term potentiation in the 
dorsal striatum is reduced in the R6/2 mouse model of Huntington's disease. Neuroscience. 
2007;146(4):1571-80.
Mahant N, McCusker EA, Byth K, Graham S. Huntington Study Group. Huntington's disease: 
clinical correlates of disability and progression. Neurology. 2003;61(8):1085-92.
Mestre T, Ferreira J, Coelho MM, Rosa M, Sampaio C. Therapeutic interventions for disease 
progression in Huntington's disease. Cochrane Database Syst Rev. 2009;(3):CD006455.


Uncontrolled Open-Label Study–Huntington's Disease
Clinical Study Protocol with Amendment 02
Study TV7820-CNS-20016
97
Mestre T, Ferreira J, Coelho MM, Rosa M, Sampaio C. Therapeutic interventions for 
symptomatic treatment in Huntington's disease. Cochrane Database Syst Rev. 
2009;(3):CD006456.
Natesan S, Svensson KA, Reckless GE, Nobrega JN, Barlow KB, Johansson AM, et al. The 
dopamine stabilizers (S)-(-)-(3-methanesulfonyl-phenyl)-1-propyl-piperidine [(-)-OSU6162] and 
4-(3-methanesulfonylphenyl)-1-propyl-piperidine (ACR16) show high in vivo D2 receptor 
occupancy, antipsychotic-like efficacy, and low potential for motor side effects in the rat. J 
Pharmacol Exp Ther. 2006;318(2):810-8.
Nieoullon A , Coquerel A. Dopamine: a key regulator to adapt action, emotion, motivation and 
cognition. Curr Opin Neurol. 2003;16 Suppl 2:S3-9.
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(1-3):88-
95.
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The Columbia-
Suicide Severity Rating Scale: initial validity and internal consistency findings from three 
multisite studies with adolescents and adults. Am J Psychiatry. 2011;168(12):1266-77.
Reilmann R, Bohlen S, Kirsten F, Ringelstein EB, Lange HW. Assessment of involuntary 
choreatic movements in Huntington's disease--toward objective and quantitative measures. Mov 
Disord 2011; 26(12):2267-73. 
Reilmann R, Kirsten F, Quinn L, Henningsen H, Marder K, Gordon AM. Objective assessment 
of progression in Huntington's disease: a 3-year follow-up study. Neurology 2001; 57(5):920-4.
Ware JE, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: Construction of scales 
and preliminary tests of reliability and validity. Medical Care, 1996;34(3):220-33. 
Ware, JE, Kosinski, M, Dewey JE (2000). How to Score Version Two of the SF-36 Health 
Survey. Lincoln, RI: QualityMetric, Incorporated.
Waters S, Pettersson F, Dyhring T, Sonesson C, Tedroff J, Waters N, et al. Pharmacology of the 
dopaminergic stabilizer pridopidine (ACR16). Clin Genet 2009;76(S1):74 (Abstract D10).
Wellbutrin® (bupropion hydrochloride tablets, for oral use). Highlights of prescribing 
information. GlaxoSmithKline, Research Triangle Park, NC 27709 [Updated: July 2014, cited: 
September 2014]. Available from: 
https://www.gsksource.com/gskprm/htdocs/documents/WELLBUTRIN-TABLETS-PI-MG.PDF.
Zhan L, Kerr JR, Lafuente MJ, Maclean A, Chibalina MV, Liu B, et al. Altered expression and 
coregulation of dopamine signalling genes in schizophrenia and bipolar disorder. Neuropathol 
Appl Neurobiol. 2011;37(2):206-19.
Zielonka D, Mielcarek M, Landwehrmeyer GB. Update on Huntington's disease: Advances in 
care and emerging therapeutic options. Parkinsonism Relat Disord. 2015;21(3):169-78.

SAP_001.pdf: 
Official Title: A Multi-Center, Open-Label Study Evaluating the Safety, Tolerability, 
and Efficacy of Pridopidine in Patients with Huntington’s Disease (Open PRIDE-HD) 
NCT Number: NCT02494778 
Document Date: 11 Jan 2018 


 
Uncontrolled Open-Label Study-Huntington’s Disease 
Statistical Analysis Plan 
Study TV7820-CNS-20016 
1 
TITL 
TITLE PAGE 
Statistical Analysis Plan 
Study Number TV7820-CNS-20016 
A Multi-Center, Open-Label Study Evaluating the Safety, Tolerability, and Efficacy of 
Pridopidine in Patients with Huntington’s Disease (Open PRIDE-HD)  
(Open PRIdopidine Dose Evaluation in Huntington's Disease) 
Phase 2 
 
 
 
IND number: 77,419  EudraCT number: 2015-000904-24 
 
 
Approval Date: 11 January 2018 
 
 
Sponsor 
Teva Branded Pharmaceutical  
Products R&D, Inc. 
 
 
 
 
 
 
 
 
Prepared by:
 
Global Statistics 
 
 
 


 
U nc o ntr olle d O pe n- La bel St u d y- H u nti n gt o n’s Disease 
Statistical A nal ysis Pla n  
St u d y T V 7 8 2 0- C N S - 2 0 0 1 6 
2 
S T A TI S TI C A L A N A L Y SI S  P L A N A P P R O V A L  
 
 
 
  
 


 
Uncontrolled Open-Label Study-Huntington’s Disease 
Statistical Analysis Plan 
Study TV7820-CNS-20016 
3 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
STATISTICAL ANALYSIS PLAN APPROVAL ..........................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................6 
INTRODUCTION ...........................................................................................................................7 
1. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................8 
1.1. 
Primary and Secondary Study Objectives ....................................................................8 
1.2. 
Study Endpoints ............................................................................................................8 
1.2.1. 
Safety Endpoints ...........................................................................................................8 
1.2.2. 
Tolerability Endpoints ..................................................................................................8 
1.2.3. 
Efficacy Endpoints ........................................................................................................8 
2. 
STUDY DESIGN .......................................................................................................10 
2.1. 
General Design ...........................................................................................................10 
2.2. 
Randomization and Blinding ......................................................................................12 
2.3. 
Data Monitoring Committee .......................................................................................12 
2.4. 
Sample Size and Power Considerations .....................................................................12 
2.5. 
Sequence of Planned Analyses ...................................................................................12 
2.5.1. 
Planned Interim Analyses ...........................................................................................12 
2.5.2. 
Final Analyses and Reporting .....................................................................................12 
3. 
ANALYSIS SETS ......................................................................................................13 
3.1.1. 
Intent-to-Treat Analysis Set ........................................................................................13 
3.1.2. 
Safety Analysis Set .....................................................................................................13 
3.1.3. 
Full Analysis Set .........................................................................................................13 
4. 
GENERAL ISSUES FOR DATA ANALYSIS ..........................................................14 
4.1. 
General ........................................................................................................................14 
4.2. 
Specification of Baseline Values ................................................................................14 
4.3. 
Scoring for Rating Scales ...........................................................................................14 
4.4. 
Handling Withdrawals and Missing Data ...................................................................15 
4.5. 
Study Days and Visits .................................................................................................16 
5. 
STUDY POPULATION .............................................................................................17 
5.1. 
General ........................................................................................................................17 
5.2. 
Patient Disposition ......................................................................................................17 


 
Uncontrolled Open-Label Study-Huntington’s Disease 
Statistical Analysis Plan 
Study TV7820-CNS-20016 
4 
5.3. 
Demographics and Baseline Characteristics ...............................................................17 
5.4. 
Medical History ..........................................................................................................17 
5.5. 
Prior Therapy and Medication ....................................................................................17 
5.6. 
Electrocardiography ....................................................................................................17 
5.7. 
Study Protocol Violations ...........................................................................................18 
6. 
EFFICACY ANALYSIS ............................................................................................19 
6.1. 
General ........................................................................................................................19 
6.2. 
Efficacy Endpoint and Analysis .................................................................................19 
7. 
SAFETY ANALYSIS ................................................................................................20 
7.1. 
General ........................................................................................................................20 
7.2. 
Duration of Exposure to Study Drug ..........................................................................20 
7.3. 
Adverse Events ...........................................................................................................20 
7.4. 
Clinical Laboratory Tests ...........................................................................................20 
7.5. 
Vital Signs ..................................................................................................................21 
7.6. 
Electrocardiography ....................................................................................................22 
7.7. 
Concomitant Medications or Therapies ......................................................................22 
7.8. 
Other Safety Assessments ...........................................................................................23 
8. 
TOLERABILITY VARIABLES AND ANALYSIS..................................................24 
9. 
STATISTICAL SOFTWARE ....................................................................................25 
10. 
CHANGES TO ANALYSES SPECIFIED IN THE STUDY PROTOCOL ..............26 
APPENDIX A. MODIFIED PHYSICAL PERFORMANCE TEST (MPPT)  
SCORING METHOD .................................................................................................27 
 


 
Uncontrolled Open-Label Study-Huntington’s Disease 
Statistical Analysis Plan 
Study TV7820-CNS-20016 
5 
LIST OF TABLES 
Table 1: 
Criteria for Potentially Clinically Significant Laboratory Values ..............................21 
Table 2: 
Criteria for Potentially Clinically Significant Vital Signs ..........................................22 
 


 
Uncontrolled Open-Label Study-Huntington’s Disease 
Statistical Analysis Plan 
Study TV7820-CNS-20016 
6 
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 
EoS 
End of Study 
HD 
Huntington’s disease 
ITT 
intent-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
mPPT 
Modified Physical Performance Test 
PBA-s 
Problem-Behaviors Assessment-Short Form 
PT 
preferred term 
Q-motor 
Quantitative motor 
R&D 
Research and Development 
SAP 
statistical analysis plan 
SD 
Standard Deviation 
SE 
Standard Error 
SF-12 
Short Form 12 
SMQ 
Standard MedDRA Queries 
SOC 
system organ class 
SOP 
standard operating procedure 
TC 
telephone contact 
TFC 
Total Functional Capacity 
TMS 
Total Motor Score 
UHDRS 
Unified Huntington’s Disease Rating Scale 
ULN 
upper limit of normal 
WHO 
World Health Organization 


 
Uncontrolled Open-Label Study-Huntington’s Disease 
Statistical Analysis Plan 
Study TV7820-CNS-20016 
7 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for Teva 
Branded Pharmaceutical Products R&D, Inc. study TV7820-CNS-20016 (A Multi-Center, Open-
Label Study Evaluating the Safety, Tolerability, and Efficacy of Pridopidine in Patients with 
Huntington’s Disease (Open PRIDE-HD)), 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 (eg 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. 


 
Uncontrolled Open-Label Study-Huntington’s Disease 
Statistical Analysis Plan 
Study TV7820-CNS-20016 
8 
1. 
STUDY OBJECTIVES AND ENDPOINTS 
1.1. 
Primary and Secondary Study Objectives 
The primary objective of this study is to evaluate safety and tolerability of pridopidine in patients 
with Huntington’s disease (HD). 
The secondary objectives of the study are to assess the effects of long-term, open-label dosing 
with pridopidine on motor symptom severity, overall patient function, physical performance, and 
health-related quality of life in patients with HD. 
1.2. 
Study Endpoints 
1.2.1. 
Safety Endpoints 
The safety endpoints for this study are as follows: 
• adverse events (AEs) throughout the study 
• vital signs assessments 
• concomitant medication usage throughout the study 
• physical examination findings  
• clinical laboratory evaluations (hematology, clinical chemistry, and urinalysis) 
• electrocardiogram (ECG) findings  
• Suicidality [using the Columbia-Suicide Severity Rating Scale (C-SSRS)] and 
Problem Behaviors Assessment-Short form (PBA-s) 
1.2.2. 
Tolerability Endpoints 
The tolerability endpoints for this study are as follows: 
• Proportion of subjects (%) who prematurely discontinued from the study 
• Proportion of subjects (%) who prematurely discontinued from the study due to AEs 
1.2.3. 
Efficacy Endpoints 
Efficacy endpoints for this study include the following: 
• Unified Huntington’s Disease Rating Scale – Total Motor Score (UHDRS-TMS) 
• Modified Physical Performance Test (mPPT) 
• Unified Huntington’s Disease Rating Scale - Total Functional Capacity         
(UHDRS-TFC) 
• Short Form 12 (SF-12) questionnaire (acute version) 
• Problem Behaviors Assessment-Short form (PBA-s) (also part of safety assessments) 


 
Uncontrolled Open-Label Study-Huntington’s Disease 
Statistical Analysis Plan 
Study TV7820-CNS-20016 
9 
• Quantitative motor (Q-motor) assessments (up to 104 weeks; not applicable for newly 
enrolled patients after Global Amendment 02) 


 
Uncontrolled Open-Label Study-Huntington’s Disease 
Statistical Analysis Plan 
Study TV7820-CNS-20016 
10 
2. 
STUDY DESIGN 
2.1. 
General Design 
This is a multicenter, open-label study to evaluate the safety, tolerability, and efficacy of 
pridopidine treatment at a dosage of 45 mg bid in adults with HD. The study will consist of a 
screening period up to 2 weeks, followed by an open-label treatment period.  
The assessments and procedures performed during each study visit are detailed in Section 3.12 of 
the protocol. 
Up to 650 patients from the PRIDE-HD, Open PRIDE-HD, Open-HART, or future safety and 
efficacy clinical trials of pridopidine studies are planned to be enrolled to receive a total daily 
dose of 90 mg pridopidine (45 mg bid) for the duration of the study. 
If medically necessary (eg following discussion with the medical monitor), the patient may be 
allowed to de-escalate to a dose of 22.5 mg bid. The start date and reason for de-escalation will 
be entered into the electronic case report form (eCRF).  
 
 
 
In addition, patients who have already completed their defined study period under 
Open PRIDE-HD global or local amendments and have discontinued treatment with pridopidine 
can be re-enrolled and re-enter the Open PRIDE-HD study. A repeat, 2nd screening and baseline 
visit will be scheduled after completion of the End of Study (EoS) visit. These patients will 
complete the repeated (2nd) screening and baseline visit assessments (including meeting all 
eligibility criteria, see procedures for V1 and V2), and undergo a 1-week titration period and 
resume attendance of the study visits from the point at which they exited. 
All patients will be treated with study drug during the course of the study. After the 1 week 
titration period, patients will be seen at weeks 4, 12, 26, 52, 78, and every 26 weeks thereafter. 
An EoS follow-up visit will take place 2 weeks after end of treatment visit. Safety evaluation 
telephone calls will be performed at weeks 18, 38, and every 26 weeks thereafter. The alternating 
safety visits and telephone contacts (TCs) result in a safety assessment frequency of 
approximately every 3 months throughout the entire study duration. The safety TCs must be 
conducted by the study investigator. During these phone calls, inquiries about adverse events, 
concomitant medication (including changes in use of benzodiazepines and antidepressants), 
changes in use of alcohol and illicit drugs, C-SSRS, and an abbreviated PBA-s (a subset of PBA-
s questions on depressed mood, suicidal ideation, anxiety, irritability, loss of motivation, and 
obsessive-compulsive behaviors) will be conducted. 
During the TCs, if the patient receives a score of 0 on the C-SSRS and PBA-s suicidal ideation 
assessments, the subsequent safety TCs will remain as scheduled as long as the scores of 0 are 
unchanged. If the patient receives a score of 1 or 2 on the C-SSRS or PBA-s suicidal ideation 
assessments, the safety TCs will be conducted every 4 weeks to monitor the patient's status until 
the scores change to 0 (after which the frequency of safety TCs will revert back as scheduled, as 
described above). Patients with a C-SSRS ideation score of 3 and above or a PBA-s suicidality 


 
Uncontrolled Open-Label Study-Huntington’s Disease 
Statistical Analysis Plan 
Study TV7820-CNS-20016 
11 
score of 3 and above, and all patients with C-SSRS suicidal attempts or acts (behavior), will be 
discontinued from treatment with study medication and will be referred to a psychiatrist for 
further evaluation and assessment, and handled as described in Section 6.1.5. of the protocol. 
For patients with a C-SSRS or PBA-s score of 1 or 2, if in the judgment of the investigator, the 
patient is not in good mental health during an in-clinic visit or safety TC, the frequency and the 
methods for monitoring may be changed (ie, more frequent visits or TCs may be added as 
deemed necessary, or the patient can be referred to a psychiatrist for additional evaluation and 
treatment and will be monitored until recovery or their condition stabilizes, in accordance with 
the instructions provided in Section 6.1.5 and Section 7.8.1 of the protocol. 
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. 
Patients who withdraw from the study will have the early termination procedures and 
assessments performed at their final visit.  
An independent internal safety committee will oversee the study (see Section 3.6.1 of the 
protocol). 
Digital Health Sub-study (optional participation):  
Motor symptoms can be objectively assessed in HD patients using different quantitative motor 
assessments.  
Objective motor assessments aim at improving the limited sensitivity observed with categorical 
clinical rating scales, and reducing the intra- and inter-rater variability, as well as potential 
placebo effect observed in scales such as the UHDRS. Improved sensitivity for early-stage 
clinical studies of efficacy of a new drug on motor dysfunction is expected with objective 
assessments and may support early go/no go decisions in smaller cohorts of patients.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study procedures and assessments are outlined in Table 1 of the sub-study protocol. 


 
Uncontrolled Open-Label Study-Huntington’s Disease 
Statistical Analysis Plan 
Study TV7820-CNS-20016 
12 
 
2.2. 
Randomization and Blinding  
This is a non-randomized, open-label study and there is no blinding. 
2.3. 
Data Monitoring Committee  
During the conduct of this study, an internal safety committee will review accumulating safety 
data on a regular basis (or adhoc if required, as detailed in the internal safety committee charter) 
to ensure the continuing safety of the study patients and study conduct issues. Additional details 
are outlined in Section 3.6.1 of the protocol. 
2.4. 
Sample Size and Power Considerations 
This is an open-label study. The sample size for this study is not based on statistical 
considerations; hence, only descriptive statistics will be presented. Up to 650 patients who 
completed the PRIDE-HD, exited from Open PRIDE-HD global or local amendments, 
completed any future safety and efficacy clinical trials of pridopidine, or transitioned from the 
ongoing Open-HART study and met patient exclusion/inclusion criteria will be enrolled. 
2.5. 
Sequence of Planned Analyses 
2.5.1. 
Planned Interim Analyses 
There will be no formal interim analysis for this study. 
2.5.2. 
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). 
The data collected in the digital health sub-study will be analyzed and reported separately from 
this SAP by
 
 
 


 
Uncontrolled Open-Label Study-Huntington’s Disease 
Statistical Analysis Plan 
Study TV7820-CNS-20016 
13 
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. A patient is considered enrolled according to the status 
reported in the database. 
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. 
 


 
Uncontrolled Open-Label Study-Huntington’s Disease 
Statistical Analysis Plan 
Study TV7820-CNS-20016 
14 
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 
For patients from the PRIDE-HD study, the baseline value is the last observed data prior to the 
first dose of study drug in this study. For patients from the ACR16C015 (OpenHART) study, the 
baseline value is the last observed data prior to the first dose of study drug in the Open-HART 
study.            
ECGs at screening are performed in triplicate. If the screening value has to be used for the 
baseline value for patients from the PRIDE-HD study, then for the ECG variables use the mean 
of 3 measurements as the baseline value. For the ECG finding, use “abnormal” as the baseline 
value if any of the responses are abnormal, and “normal” as the baseline value if all responses 
are normal.                              
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 mPPT quantifies the patient’s performance in physical tasks. It is a standardized 9-item test 
that measures the patient’s performance on functional tasks. Both the speed and accuracy at 
which the patients complete the items are taken into account during scoring. The maximum score 
of the test is 36, with higher scores indicating better performance. The mPPT total score 
calculated as the sum of the 9 items. SeeAppendix A for details of the scoring method for the 
mPPT total score. 
 The TFC scale of the UHDRS assesses 5 functional domains associated with disability 
(occupation, finances, domestic chores, activities of daily living, and care level). Scores on each 
item range from 0 to either 2 or 3 (eg, Occupation: 0 = unable, 1 = marginal work only, 2 = 
reduced capacity for usual job, 3 = normal). The 5 items are summed to yield a TFC total score, 
which ranges from 0 to 13, with greater scores indicating higher functioning. 
The SF-12® is a multipurpose short-form generic measure of health status. The 12 items in the 
SF-12® are a subset of those in the SF-36®; SF-12® includes 1 or 2 items from each of the 
8 health concepts. The SF-12® total score is calculated as the sum of the 12 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 


 
Uncontrolled Open-Label Study-Huntington’s Disease 
Statistical Analysis Plan 
Study TV7820-CNS-20016 
15 
covers several broad symptom domains relevant to HD, comprising 11 items. Each symptom is 
rated for both severity and for frequency on a 5-point scale. 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. 
Q-Motor assessments will be performed only in those sites that have access to the devices 
needed to perform the assessments and, where this is the case, only in those patients who are 
capable of performing the assessments. All Q-Motor assessments are based on the application of 
pre-calibrated and temperature-controlled force transducers and 3-dimensional position sensors 
with very high sensitivity and test-retest reliability across sessions and sites in a multicenter 
clinical study. If a certain test has a left and right value, an average value will be calculated from 
the test. 
4.4. 
Handling Withdrawals and Missing Data 
For all variables, only the observed data from the patients will be used in the statistical analyses, 
i.e., 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. 
For mPPT, item 1 (balance tasks), item 4 (put on and remove a jacket), and item 6 (turn 360 
degrees) have to be calculated before calculating the total score. For all 3 items, if any questions 
are missing then the missing responses will not be replaced and the item will be sets to missing. 
After calculating items 1, 4, and 6, 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.  
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 SF-12, 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. 
For 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. 
For Q-motor assessments, if either the left or right value is missing for a certain test, then the 
average value will be equal to the nonmissing value. 


 
Uncontrolled Open-Label Study-Huntington’s Disease 
Statistical Analysis Plan 
Study TV7820-CNS-20016 
16 
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.        
             
 
                                                                                   


 
Uncontrolled Open-Label Study-Huntington’s Disease 
Statistical Analysis Plan 
Study TV7820-CNS-20016 
17 
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.                                             
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 within 2 weeks prior to screening will be 
recorded on the 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, 
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. 


 
Uncontrolled Open-Label Study-Huntington’s Disease 
Statistical Analysis Plan 
Study TV7820-CNS-20016 
18 
5.7. 
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. 
 


 
Uncontrolled Open-Label Study-Huntington’s Disease 
Statistical Analysis Plan 
Study TV7820-CNS-20016 
19 
6. 
EFFICACY ANALYSIS 
6.1. 
General 
The ITT 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. 
• mPPT total score change from baseline to each visit that this is measured.  
• UHDRS-TFC change from baseline to each visit that this is measured. 
• SF-12 total score change from baseline to each visit that this is measured.   
• PBA-s total score change from baseline to each visit that this is measured. 
• Q-motor assessments (digitomotography, dysdiadochomotography, manumotography 
and choreomotography, and pedomotography) 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.  
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. 
 
 


 
Uncontrolled Open-Label Study-Huntington’s Disease 
Statistical Analysis Plan 
Study TV7820-CNS-20016 
20 
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. Weeks on treatment using the categories 
≤4 weeks, >4 to ≤12 weeks, >12 to ≤26 weeks, >26 to ≤52 weeks, >52 to ≤78 weeks,              
>78 to ≤104 weeks, and >104 weeks 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. 
7.4. 
Clinical Laboratory Tests 
Laboratory test results will be presented in standard international (SI) units. 
Summary statistics for serum chemistry, hematology, and urinalysis laboratory tests will be 
presented at baseline and each visit. Laboratory tests values and changes from baseline to each 
visit will be summarized using descriptive statistics. 
Shifts (below, within, and above the normal range) from baseline to each visit will be 
summarized using patient counts. 
The incidence of potentially clinically significant abnormal values will be summarized for 
laboratory tests using descriptive statistics with the criteria specified in Table 1. These 
summaries willl include all postbaseline values (including scheduled, unscheduled, and early 
termination visits).  
 


 
Uncontrolled Open-Label Study-Huntington’s Disease 
Statistical Analysis Plan 
Study TV7820-CNS-20016 
21 
Table 1: 
Criteria for Potentially Clinically Significant Laboratory Values 
Test 
Criterion value 
Serum chemistry 
 
  Alanine aminotransferase (ALT) 
≥3x ULN 
  Aspartate aminotransferase (AST) 
≥3x ULN 
  Alkaline phosphatase 
≥3x ULN 
  Gamma-glutamyl transpeptidase (GGT) 
≥3x ULN 
  Lactate dehydrogenase (LDH) 
≥3x ULN 
  Blood urea nitrogen (BUN) 
≥10.71 mmol/L 
  Creatinine 
≥177 µmol/L 
  Uric acid 
Men 
≥625 µmol/L 
 
Women 
≥506 µmol/L 
  Bilirubin (total) 
≥34.2 µmol/L 
Hematology 
 
  Hematocrit 
Men 
<0.37 L/L 
 
Women 
<0.32 L/L 
  Hemoglobin 
Men 
≤115 g/L 
 
Women 
≤95 g/L 
  White blood cell (WBC) counts 
≤3 x 109/L  
≥20 x 109/L 
  Eosinophils 
≥10% 
  Absolute neutrophil counts (ANC) 
≤1 x 109/L 
  Platelet counts 
≤75 x 109/L  
≥700 x 109/L 
Urinalysis 
 
  Blood (HGB) 
≥2 unit increase from baseline 
  Glucose 
≥2 unit increase from baseline 
  Total protein 
≥2 unit increase from baseline 
 ULN=upper limit of normal  
7.5. 
Vital Signs 
Summary statistics for pulse, blood pressure (supine/sitting and standing), body temperature, 
weight, and orthostatic blood pressure (supine/sitting – standing value) will be presented at 
baseline and each visit. Vital signs values and changes from baseline to each visit will by 
summarized using descriptive statistics. 


 
Uncontrolled Open-Label Study-Huntington’s Disease 
Statistical Analysis Plan 
Study TV7820-CNS-20016 
22 
The incidence of potentially clinically significant abnormal values will be summarized for vital 
signs using descriptive statistics with the criteria specified in Table 2. 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. 
Table 2: 
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 
Orthostatic SBP (mmHg) 
>= 20 mmHg 
 
Orthostatic DBP (mmHg) 
>= 10 mmHg 
 
7.6. 
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 criteria specified below. 
• QTcF values >450 msec or >480 msec or >500 msec. 
• 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. 
 
7.7. 
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. 


 
Uncontrolled Open-Label Study-Huntington’s Disease 
Statistical Analysis Plan 
Study TV7820-CNS-20016 
23 
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 
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. 
 


 
Uncontrolled Open-Label Study-Huntington’s Disease 
Statistical Analysis Plan 
Study TV7820-CNS-20016 
24 
8. 
TOLERABILITY VARIABLES AND ANALYSIS 
Tolearbility is summarized with the safety analysis. 


 
Uncontrolled Open-Label Study-Huntington’s Disease 
Statistical Analysis Plan 
Study TV7820-CNS-20016 
25 
9. 
STATISTICAL SOFTWARE 
All data listings, summaries, and statistical analyses will be generated using SAS® version 9.4 or 
later. 


 
Uncontrolled Open-Label Study-Huntington’s Disease 
Statistical Analysis Plan 
Study TV7820-CNS-20016 
26 
10. 
CHANGES TO ANALYSES SPECIFIED IN THE STUDY 
PROTOCOL 
There are no changes to analyses specified in the study protocol. 


 
Uncontrolled Open-Label Study-Huntington’s Disease 
Statistical Analysis Plan 
Study TV7820-CNS-20016 
27 
APPENDIX A. MODIFIED PHYSICAL PERFORMANCE TEST (MPPT)  
SCORING METHOD 
No. 
Task 
Items Score Values 
1. 
Balance Tasks 
Standing Balance Feet Together 
• ≥ 10 sec                       = 1 
• 0 - <10 sec or Unable  = 0 
Standing Balance Semi Tandem 
• ≥ 10 sec                      = 1 
• 0 - <10 sec or Unable = 0 
Standing Balance Tandem 
• ≥ 10 sec                     = 2 
• 3 – <10 sec                = 1 
• 0 - <3 sec or Unable  = 0 
2. 
 
Chair rise 
• >0  - 11 sec      = 4 
• >11 - 14 sec     = 3 
• >14 - 17 sec     = 2 
• >17 sec             = 1 
• 0, Unable          = 0 
3. 
Lift a book and put it on a shelf 
     
 
• >0 - 2 sec      = 4 
• >2 - 4 sec      = 3 
• >4 - 6 sec      = 2 
• >6 sec            = 1 
• 0, Unable       = 0 
4. 
Put on and remove a jacket (sum of time to put 
and to remove the jacket) 
 
• >0 - 10 sec     = 4 
• >10 - 15 sec   = 3 
• >15 – 20 sec   = 2 
• >20 sec           = 1 
• 0, Unable        = 0 
5. 
Pick up a penny from floor 
• >0 - 2 sec        = 4 
• >2 - 4 sec        = 3 
• >4 - 6 sec        = 2 
• > 6 sec             = 1 
• 0, Unable         = 0 
6. 
Turn 360 degrees 
Steps 
• Continuous      = 2 
• Discontinuous = 0 
Steadiness 
• Steady                                 = 2 
• Unsteady (grabs, staggers) = 0 
7. 
50-foot walk test 
• >0  - 15 sec     = 4 
• >15 - 20 sec    = 3 
• >20 - 25 sec    = 2 
• >25 sec            = 1 
• 0, Unable         = 0 


 
Uncontrolled Open-Label Study-Huntington’s Disease 
Statistical Analysis Plan 
Study TV7820-CNS-20016 
28 
8. 
Climb one flight of stairs 
• >0 - 5 sec        = 4 
• >5 - 10 sec      = 3 
• >10 – 15 sec    = 2 
• >15 sec            = 1 
• 0, Unable         = 0 
9. 
Climb 4 flights of stairs (Number of flights 
climbed up and down) 
• 4 flights           = 4  
• 3 flights           = 3 
• 2 flights           = 2 
• 1 flights           = 1 
• Unable             = 0 
 
Total mPPT Score 
Sum of all Item score values [0-36]